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Bipolar Disorder Dr. Mohamed Nasreldin A. Prof. of Psychiatry Cairo University 2012

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Page 1: Bipolar  dis   copy

Bipolar DisorderDr Mohamed Nasreldin

A Prof of Psychiatry

Cairo University

2012

Introduction

Bipolar disorder (BD) is a mental illness associated with negative social and occupational consequences with a potentially devastating impact on patientsrsquo well-being morbidity and mortality and significant health care cost

Introduction cont

Individuals with bipolar disorder are twice as likely as the general population to have metabolic syndrome but are often not diagnosed

Metabolic syndrome (Met S) is a constellation of metabolic abnormalities that has been identified as a risk factor for the development of CVD and diabetes type 2

Risk Factors for Bipolar Disorder

Bipolar DisorderPrevalence

The rates of bipolar spectrum disorder (bipolar I bipolar II cyclothymia and others) may be considerably higher than bipolar I alone

The prevalence rates reported in 11 studies of bipolar II disorder were between 03 and 3

The lifetime prevalence rates for bipolar spectrum disorder were reported between 3 and 65

Gender and Age

In contrast to MD epidemiologic data show no significant sex differences in rates of bipolar disorder

Mean age of onset for bipolar depression was generally younger than for MD ranging from 18 to 27 years of age in different countries

Risk Factors for Bipolar Disorder

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 2: Bipolar  dis   copy

Introduction

Bipolar disorder (BD) is a mental illness associated with negative social and occupational consequences with a potentially devastating impact on patientsrsquo well-being morbidity and mortality and significant health care cost

Introduction cont

Individuals with bipolar disorder are twice as likely as the general population to have metabolic syndrome but are often not diagnosed

Metabolic syndrome (Met S) is a constellation of metabolic abnormalities that has been identified as a risk factor for the development of CVD and diabetes type 2

Risk Factors for Bipolar Disorder

Bipolar DisorderPrevalence

The rates of bipolar spectrum disorder (bipolar I bipolar II cyclothymia and others) may be considerably higher than bipolar I alone

The prevalence rates reported in 11 studies of bipolar II disorder were between 03 and 3

The lifetime prevalence rates for bipolar spectrum disorder were reported between 3 and 65

Gender and Age

In contrast to MD epidemiologic data show no significant sex differences in rates of bipolar disorder

Mean age of onset for bipolar depression was generally younger than for MD ranging from 18 to 27 years of age in different countries

Risk Factors for Bipolar Disorder

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 3: Bipolar  dis   copy

Introduction cont

Individuals with bipolar disorder are twice as likely as the general population to have metabolic syndrome but are often not diagnosed

Metabolic syndrome (Met S) is a constellation of metabolic abnormalities that has been identified as a risk factor for the development of CVD and diabetes type 2

Risk Factors for Bipolar Disorder

Bipolar DisorderPrevalence

The rates of bipolar spectrum disorder (bipolar I bipolar II cyclothymia and others) may be considerably higher than bipolar I alone

The prevalence rates reported in 11 studies of bipolar II disorder were between 03 and 3

The lifetime prevalence rates for bipolar spectrum disorder were reported between 3 and 65

Gender and Age

In contrast to MD epidemiologic data show no significant sex differences in rates of bipolar disorder

Mean age of onset for bipolar depression was generally younger than for MD ranging from 18 to 27 years of age in different countries

Risk Factors for Bipolar Disorder

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 4: Bipolar  dis   copy

Risk Factors for Bipolar Disorder

Bipolar DisorderPrevalence

The rates of bipolar spectrum disorder (bipolar I bipolar II cyclothymia and others) may be considerably higher than bipolar I alone

The prevalence rates reported in 11 studies of bipolar II disorder were between 03 and 3

The lifetime prevalence rates for bipolar spectrum disorder were reported between 3 and 65

Gender and Age

In contrast to MD epidemiologic data show no significant sex differences in rates of bipolar disorder

Mean age of onset for bipolar depression was generally younger than for MD ranging from 18 to 27 years of age in different countries

Risk Factors for Bipolar Disorder

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 5: Bipolar  dis   copy

Bipolar DisorderPrevalence

The rates of bipolar spectrum disorder (bipolar I bipolar II cyclothymia and others) may be considerably higher than bipolar I alone

The prevalence rates reported in 11 studies of bipolar II disorder were between 03 and 3

The lifetime prevalence rates for bipolar spectrum disorder were reported between 3 and 65

Gender and Age

In contrast to MD epidemiologic data show no significant sex differences in rates of bipolar disorder

Mean age of onset for bipolar depression was generally younger than for MD ranging from 18 to 27 years of age in different countries

Risk Factors for Bipolar Disorder

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 6: Bipolar  dis   copy

Gender and Age

In contrast to MD epidemiologic data show no significant sex differences in rates of bipolar disorder

Mean age of onset for bipolar depression was generally younger than for MD ranging from 18 to 27 years of age in different countries

Risk Factors for Bipolar Disorder

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 7: Bipolar  dis   copy

Other Sociodemograghic Variables

Historically bipolar disorder was thought to be more frequent among higher socioeconomic classes (probably due to misdiagnosis of bipolar patients as schizophrenics in lower income groups)

However population- based studies over the last two decades have not replicated this finding In the ECA occupation income and education were not found to influence prevalence

In the ECA bipolar disorder was much less frequent among married people as contrasted with divorced or never-married people

Risk Factors for Bipolar Disorder

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 8: Bipolar  dis   copy

Familial Factors

Bipolar I disorder was seven times more likely among relatives of bipolar I probands than of controls

These studies also demonstrate an increased risk of MD in relatives of bipolar probands although the relative risk is lower than for bipolar I

Early age of onset and number of ill relatives increases the risk of illness in relatives

Risk Factors for Bipolar Disorder

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 9: Bipolar  dis   copy

Familial Factors

Family history (1st degree relative with bipolar I)

1048708 10-20 risk of bipolar I

1048708 1-5 risk of bipolar II

1048708 10-15 risk of MDD

Risk Factors for Bipolar Disorder

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 10: Bipolar  dis   copy

Familial Factors

There have been a number of investigations aimed at determining the actual genes involved in bipolar illness

Attempts to demonstrate linkage to the X-chromosome to color blindness to chromosomes 4 11 18 and others have not been conclusive

Risk Factors for Bipolar Disorder

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 11: Bipolar  dis   copy

Environmental Factors

Although genetic factors have long been known to play a major role in the etiology of bipolar disorder psychosocial factors are gaining attention

In particular many studies have identified the association between stressful life

events and social rhythm disruptions and onset of recurrence

It is unlikely that psychosocial factors play a major role in the risk of first onset of bipolar disorder but they may have an important role in increasing the risk of recurrence

Risk Factors for Bipolar Disorder

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 12: Bipolar  dis   copy

Environmental Factors

Severe social rhythm disruptions (eg returning from international trips moving losing a job) were associated with onsets of mania but not depression in bipolar patients

Risk Factors for Bipolar Disorder

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 13: Bipolar  dis   copy

Bipolar Disorder Risk among Adolescents

Adolescence and the late teens are also the years in which bipolar disorder will begin to manifest itself in women

40 of adolescents with major depressive disorder will develop bipolar disorder later (in 5 years of onset of MDD)

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 14: Bipolar  dis   copy

Risk of Bipolar Disorder among Adolescents with Major Depressive Disorders

Predictors of Bipolar I Disorder Onset Early onset MDD Psychomotor retardation Psychosis Family history of psychotic depression Heavy familial loading for mood disorders Pharmacologically induced hypomania

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 15: Bipolar  dis   copy

The Recent Change In The Conceptualization Of Bipolar Disorder

Past Present

Lifetime prevalencein the community

Diagnosis Easy and reliable Sometimesdifficulty

Outcome Good Often poor

Straightforward Complex and and effective inconstantly

effective

Psychotherapies No role Several types are useful

Low Relatively high (1-16) (3-65)

Pharmacologicaltreatment

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 16: Bipolar  dis   copy

Epidemiology Bipolar I range from 05 to 75

Bipolar II gt bipolar I

Frequently misdiagnosed as recurrent major depression

The estimated life time prevalence of bipolar spectrum is as high

as 4

Men = female Bipolar II female gt male

The majority of cases have an onset before the age of 30

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 17: Bipolar  dis   copy

Problems of bipolar disorder Recurrent long-term illness

Misdiagnosis

Suicide risk At least 25 attempt suicide1

Suicide rate 11-191

25-50 suicidal ideation in mixed mania23

Co morbidity complications

Psychosocial consequences

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 18: Bipolar  dis   copy

Clinical Features that predict Bipolarity

Early age of onset Psychotic depression before age 25 Postpartum seasonal onset Rapid onset More than 5 episodes of depression Cyclothymic hyperthymic personality traits Switching or lack of efficacy with antidepressants Mixed depressive states Family history of bipolar disorder or several generations with

depression Reverse vegetative symptoms (overeating oversleeping)

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 19: Bipolar  dis   copy

Differential Diagnosis Medical Disorders

Medical Disorders Mononucleosis pneumonia in the elderly Adrenal and thyroid Dysfunction Cancer stomach pancreas breast Medications

Interferon for Hepatitis C Cardiac and antihypertensive Sedative hypnotics Phenothiazines Anticholinesterases Steroids Antibacterial and antifungal Cancer chemotherapy Stimulants and appetite suppressants

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 20: Bipolar  dis   copy

Differential Diagnosis Neuropsychiatric Conditions

Mainly in the elderly

- Dementia

- Parkinsonism

- Cerebrovascular disease

- Tumours

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 21: Bipolar  dis   copy

Differential Diagnosis Mental Disorders

Cyclothymia

Alcohol and Drug induced mood swings

Borderline and histrionic personality disorder

Schizoaffective disorder

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 22: Bipolar  dis   copy

A common disease Prevalence estimated between 1-3Prevalence estimated between 1-3

(depends on diagnostic criteria)(depends on diagnostic criteria)

Males=femalesMales=females Found across cultures and ethnicitiesFound across cultures and ethnicities Strongly heritableStrongly heritable

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 23: Bipolar  dis   copy

Bipolar disorder (BPD) is a common chronic recurrent mental illness that affects the lives and functioning of millions of individuals

worldwide A growing number of recent studies indicate that for a majority of

these individuals outcome is quite poor -High rates of relapse -Chronicity -Residual symptoms -Sub-syndromes -Cognitive impairment and -Functional impairment -Psychosocial disability and -Diminished well-being are unfortunately common occurrences in BPD

(Belmaker 2004)

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 24: Bipolar  dis   copy

Furthermore BPD is a systemic disease that is frequently associated with a wide range of

physiological disorders and medical problems including cardiovascular disease diabetes

mellitus obesity and thyroid disease (Kupfer 2005)

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 25: Bipolar  dis   copy

Neurobiological studies of mood disorders over the past 40 years have primarily focused on abnormalities of the monoaminergic neurotransmitter systems on characterizing alterations of individual neurotransmitters in disease states and on assessing response to mood stabilizer and antidepressant medications

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 26: Bipolar  dis   copy

The monoaminergic systems are extensively distributed throughout the network of limbic

striatal and prefrontal cortical neuronal circuits thought to support the behavioral and

visceral manifestations of mood disorders (Drevets 2000)

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 27: Bipolar  dis   copy

Studies of-cerebrospinal fluid chemistry

-neuroendocrine responses to pharmacological challenge and

-neuroreceptor and transporter binding have demonstrated a number of abnormalities in

monoaminergic neurotransmitter and neuropeptide systems in mood disorders

(Goodwin and Jamison 2007)

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 28: Bipolar  dis   copy

Unfortunately these observations have not yet greatly advanced our understanding of the

underlying biology of recurrent mood disorders which must include an explanation for the

predilection to episodic and often profound mood disturbance that can become

progressive over time

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 29: Bipolar  dis   copy

BPD likely arises from the complex interaction of multiple susceptibility (and protective) genes and environmental factors and the phenotypic expression of the disease includes not only mood disturbance but also a constellation of cognitive motor autonomic endocrine and sleepwake abnormalities

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 30: Bipolar  dis   copy

Furthermore while most antidepressants exert their initial effects by increasing intrasynaptic levels of serotonin andor norepinephrine their clinical antidepressant effects are observed only after chronic administration (over days to weeks) suggesting that a cascade of downstream events is ultimately responsible for their therapeutic effects

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 31: Bipolar  dis   copy

These observations have led to the idea that while dysfunction within the monoaminergic neurotransmitter systems is likely to play an important role in mediating some facets of the pathophysiology of BPD it likely represents the downstream effects of other more primary abnormalities in signaling pathways

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 32: Bipolar  dis   copy

Consider Plasticity Cascades as Playing a Central Role in the Pathophysiology and

Treatment of BPD

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 33: Bipolar  dis   copy

Plasticity the ability to undergo and sustain change is essential for the proper functioning of our nervous system

This capacity for change allows organisms to adapt to complex alterations in both their internal and external environments a feature fundamentally important for survival and reproduction

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 34: Bipolar  dis   copy

The biological basis of this capacity to adapt encompasses a diverse set of cellular and molecular mechanisms that fall under the broad term lsquoneuroplasticityrsquo

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 35: Bipolar  dis   copy

Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neurotransmission

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 36: Bipolar  dis   copy

More specifically the term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse

The regulation of transmission at the synapse may be mediated by changes in

-neurotransmitter levels

-receptor subunit phosphorylation

-surfacecellular levels or receptors and

-conductance changes among others

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 37: Bipolar  dis   copy

Neuroplastic mechanisms can be of short duration or long lasting and this is determined by the qualitative quantitative and temporal characteristics of the precipitating stimuli

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 38: Bipolar  dis   copy

Research on the biological underpinnings of mood disorders has therefore moved away from focusing on absolute changes in neurochemicals such as monoamines and neuropeptides and

instead has begun highlighting the role of neural circuits and synapses and the plastic processes controlling their function

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 39: Bipolar  dis   copy

Neuroplasticity is a broader term that encapsulates -changes in intracellular signaling cascades and -gene regulation (see McClung and Nestler 2008 in this issue) -modifications of synaptic number and strength variations in

neurotransmitter release-modeling of axonal and dendritic architecture and in some

areas of the CNS -the generation of new neurons

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 40: Bipolar  dis   copy

Thus these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 41: Bipolar  dis   copy

The role of cellular signaling cascades has the potential to explain much of the complex neurobiology of BPD (Goodwin and Jamison 2007)

Cellular signaling cascades regulate the multiple neurotransmitter and neuropeptide systems implicated in the disorder and are targets for the most effective treatments Signaling pathways are also targets for hormones that have been implicated in the pathophysiology of BPD

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 42: Bipolar  dis   copy

The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily to limbic-related regions such as the hippocampus hypothalamus and brain stem which are likely associated with neurovegetative symptoms

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 43: Bipolar  dis   copy

Abnormalities in cellular signaling cascades that regulate diverse physiologic functions also likely explain the tremendous medical co-morbidity associated with BPD Furthermore many of these pathways play critical roles not only in synaptic (and therefore behavioral) plasticity but also in long-term atrophic processes

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 44: Bipolar  dis   copy

Targeting these cascades in the treatment of mood disorders may stabilize the underlying disease process by reducing the frequency and severity of the profound mood cycling that contributes to morbidity and mortality

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 45: Bipolar  dis   copy

Putative Roles for Signaling Pathways in Mood Disorders Amplify attenuate and integrate multiple signals that form the basis for

intracellular circuits and cellular modules Regulate multiple neurotransmitter and peptide systems Play critical role in cellular memory and long-term neuroplasticity Regulate complex signaling networks that form the basis for higher order

brain function mood and cognition Act as major targets for many hormones implicated in mood disorders

including gonadal steroids thyroid hormones and glucocorticoids Act as targets for medications that are most effective in the treatment of

mood disorders

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 46: Bipolar  dis   copy

CLINICAL EVIDENCE SUPPORTING THE CONTENTION THAT ABNORMALITIES IN SYNAPTIC AND CELLULAR PLASTICITY

PLAY AN IMPORTANT ROLE IN BPD

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 47: Bipolar  dis   copy

It is clear that BPD is not a classical mitochondrial disorder However emerging data suggest that many upstream abnormalities (likely nuclear genome coded) converge to regulate mitochondrial function and that mitochondrial function is implicated in acute abnormalities of both synaptic and neural plasticity (Goodwin and Jamison 2007) Thus in addition to the well-known function of energy production via oxidative phosphorylation neuronal mitochondria also play an important role in apoptosis and in the regulation of intracellular calcium increasing evidence suggests that the latter action may be critically important in regulating the release of and response to neurotransmitters Furthermore mounting evidence suggests that activation of mitochondrial-apoptotic cascades may lead to a process of lsquosynaptic apoptosisrsquo in which apoptotic processes are activated in a highly localized manner (Mattson 2007)

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 48: Bipolar  dis   copy

A growing body of evidence suggests that mitochondria may be integrally involved in the general processes of synaptic plasticity (Mattson 2007 Yang et al 2003) In addition increased synaptic activity has been shown to induce the expression of mitochondrial-encoded genes suggesting that a long-lasting up-

regulation of energy production may be triggered by synaptic activity playing role in the long-term regulation of synaptic strength Williams et al 1998) Thus

mitochondrial dysfunction exerts major effects on lsquohere and nowrsquo neurotransmitter function in addition to its better appreciated long-term

cytoprotective effects

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 49: Bipolar  dis   copy

Post-mortem Morphometric Brain Studies in Mood Disorders Demonstrating Cellular Atrophy andor Loss

Reduced volume Cortical thickness of rostral orbitofrontal cortex in MDD Laminar cortical thickness in layers III V and VI in subgenual anterior

cingulate cortex in BPD Volume of subgenual prefrontal cortex in MDD and BPD Volumes of nucleus accumbens and basal ganglia in MDD and BPD Parahippocampal cortex size in suicideReduced neuronal size andor density Neuronal size in layer V and VI in prefrontal cortex in MDD and BPD Pyramidal neuronal density layers III and V in dorsolateral prefrontal cortex

in BPD and MDD

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 50: Bipolar  dis   copy

Post-mortem Morphometric Brain Studies in Mood Neuronal density and size in layers IIndashVI in orbitofrontal cortex in MDD Neuronal density in layers III V and VI in subgenual anterior cingulate cortex in BPD Neuronal size in layer VI in anterior cingulate cortex in MDD Layer-specific interneurons in anterior cingulate cortex in BPD and MDD Nonpyramidal neuronal density in layer II in anterior cingulate cortex in BPD Nonpyramidal neuronal density in the CA2 region in BPDReduced glia Densitysize of glia in dorsolateral prefrontal cortex and caudal orbitofrontal cortex in MDD and BPD Glial cell density in layer V in prefrontal cortex in MDD Glial number in subgenual prefrontal cortex in familial MDD and BPD Glial cell density in layer VI in anterior cingulate cortex in MDD Glial cell counts glial density and glia neuron ratio in amygdala in MDD

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 51: Bipolar  dis   copy

EVIDENCE THAT CELLULAR PLASTICITY

CASCADES ARE THE TARGETS OF

MOOD-STABILIZING AGENTS

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 52: Bipolar  dis   copy

Inositol Monophosphatase

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 53: Bipolar  dis   copy

Phosphatidylinositol signaling pathway Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l45- trisphosphate (IP3) Inositol-monophosphatase (IMPase) is the final common step for conversion of monophosphorylated inositols into myo-inositol and therefore inhibition of IMPase can reduce the level of myo-inositol The inositol depletion hypothesis proposes that inhibition of this step may interfere with the synthesis of phosphatidylinositol (PI) The PI signaling cascade starts with surface receptor-mediated activation of phospholipase C (PLC) Activated PLC catalyzes the hydrolysis of PIP2 to diacylglycerol (DAG) and IP3 DAG activates protein kinase C (PKC) that among many other functions activates myristoylated aknine-rich C kinase substrate (MARCKS) Lithium and valproate both decrease levels of phosphorylated and total MARCKS

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 54: Bipolar  dis   copy

Glycogen Synthase Kinase-3

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 55: Bipolar  dis   copy

Glycogen synthase kinase 3 (GSK-3) autoregulatory loop In addition to directly inhibiting GSK-3 lithium (as well as other inhibitors) induces N-terminal phosphorylation of GSK-3 This inhibitory

phosphorylation may enhance the effect of direct inhibitors and appears to be achieved both through activation of Akt and through inhibition of protein phosphatase 1 (PP1) These observations

reveal an autoregulatory loop in which GSK-3 maintains itself in an active state which is then interrupted by direct inhibition of GSK-3 (lsquoPrsquo indicates phosphorylation IRS-1 insulin receptor

substrate-1 PI3K phosphatidylinositol-3 kinase PP1 protein phosphatase 1 I-2 PP1-specific inhibitor-2 - -| indicates inhibitory step and - -4 indicates activating step)

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 56: Bipolar  dis   copy

Erk pathway and bcl-2 Lithium and valproate (VPA) at therapeutically relevant concentrations robustly activate the extracellular receptor coupled kinase (ERK) MAPK cascade One of the major

downstream targets of the ERK MAPK cascades is arguably one of the most important neuroprotective proteins bcl-2 Bcl-2 is expressed in the nervous system and is localized to the

outer mitochondrial membrane endoplasmic reticulum and nuclear membrane It is now clear that bcl-2 is a protein that inhibits both apoptotic and necrotic cell death induced by diverse stimuli Bcl-2 attenuates apoptosis by sequestering proforms of caspases preventing the release of mitochondrial

apoptogenic factors such as calcium and cytochrome c and by enhancing mitochondrial calcium uptake

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 57: Bipolar  dis   copy

Neurotrophic and Neuroprotective Effects of Lithium Protects brain cells fromGlutamate and NMDA toxicityCalcium toxicityThapsigargin (which mobilizes MPP+ and Ca2+) toxicityb-Amyloid toxicityAging-induced cell deathGrowth factor and serum deprivationGlucose deprivationLow K+C2-ceramide

Page 58: Bipolar  dis   copy