mood disorders rachel nosheny november 25, 2002. lecture outline i.overview of disorders a. types b....
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Mood Disorders
Rachel NoshenyNovember 25, 2002
Lecture Outline
I. Overview of disordersA. TypesB. SymptomsC. EpidemiologyD. Pharmacotherapy
II. Theories of the Pathophysiology of Mood Disorders
III. An example of current research: The effect of antidepressants on growth factor levels
Types of Mood Disorders
Major Depressive Disorder (MDD)
Bipolar Disorder
Types of Mood Disorders
Major Depressive Disorder (MDD)• around 16% of those affected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke
Bipolar Disorder• around 29% of those affected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized
Types of Mood Disorders
Major Depressive Disorder (MDD)• around 16% of those affected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke
Bipolar Disorder• around 29% of those affected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized
economic burden of tens of billions of dollars in the USA due to disability and premature death
Types of Mood Disorders
Major Depressive Disorder (MDD)• around 16% of those affected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke
Bipolar Disorder• around 29% of those affected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized
economic burden of tens of billions of dollars in the USA due to disability and premature death
Epidemiology of MDD
• Lifetime prevalence: 10%-25% in women
5%-12% in men
• most common age of onset: 25 to 44 years
• 1.5-3 times greater risk of developing the disorder if a first degree relative is affected
Diagnostic Criteria
•Depressed mood and/or loss of interest or pleasure (anhedonia)
• 4 other symptoms that impair functioning for at least a 2-week period, such as:
changes in sleep changes in interest level
changes in energy level changes in appetite
difficulty concentrating crying spells
suicidal ideation and/or plan feelings of worthlessness
feelings of hopelessness guilt or worry
psychomotor agitation or retardation
• symptoms are not a result of an underlying medical problem
Diagnostic Criteria
•Depressed mood and/or loss of interest or pleasure (anhedonia)
• 4 other symptoms that impair functioning for at least a 2-week period, such as:
changes in sleep changes in interest level
changes in energy level changes in appetite
difficulty concentrating crying spells
suicidal ideation and/or plan feelings of worthlessness
feelings of hopelessness guilt or worry
psychomotor agitation or retardation
• symptoms are not a result of an underlying medical problem
Dysfunction of the brain’s reward system?
Pharmacotherapy
SSRIs, Tricyclics(inhibit re-uptake)
MAOIs(inhibit breakdown)
Side effects:
Dry mouth
Constipation
Bladder problems
Sexual problems
Blurred vision
Dizziness
Drowsiness
Increased heart rate
Atypical Antidepressants
•Buproprion (wellbutrin or zyban)selective inhibitor of dopamine re-uptake
•Mianserin (tolmin)5-HT2 antagonistadrenergic autoreceptor antagonist
Types of Mood Disorders
Major Depressive Disorder (MDD)• around 16% of those effected will attempt suicide•A major risk factor for cardiovascular disease and death following stroke
Bipolar Disorder• around 29% of those effected will attempt suicide• full “functional recovery”occurs in only around 24% of those hospitalized
Epidemiology of Bipolar Disorder
•Lifetime prevalence of 1.6%
•Onset typically in late adolescence to early adulthood
•Effects men and women equally
Symptoms of Mania
•A distinct period of persistently elevated, expansive, or irritable mood lasting at least 1 week
• 3 or more of the following symptoms during the mood disturbance:
inflated self-esteem decreased need for sleep
pressure to keep talking flight of ideas/racing thoughts
distractibility increase in goal-directed activity
excessive involvement in pleasurable and risky activities
• the mood disturbance disrupts normal functioning and/or has psychotic features
Subtypes of Bipolar Disorder
•Bipolar I: at least 1 lifetime manic episode
•Rapid cycling: occurrence of 4 or more mood episodes over the course of 1 year
• Mixed episode: co-occurrence of a depressive and manic episode
•Bipolar II: 1 or more episodes of depression and at least 1 mild manic (hypomanic) episode
Types of Mood Disorders
Do mania and depression
represent opposite ends of the
mood spectrum?
Symptoms of Mania
inflated self-esteem decreased need for sleep
pressure to keep talking flight of ideas/racing thoughts
distractibility increase in goal-directed activity
excessive involvement in pleasurable and risky activities
Irritable mood
changes in sleep changes in interest level
changes in energy level change in appetite
difficulty concentrating crying spells
suicidal ideation and/or plan feelings of worthlessness
feelings of hopelessness guilt or worry
psychomotor agitation or retardation
Symptoms of MDD
Lithium Chloride
Side Effects
drowsiness
weakness
nausea
fatigue
hand tremor
increased thirst and urination
weight gain
• limits excitability by modulating glutamate signaling
• inhibits cell death
•Of limited therapeutic value for treating those with:
mixed mania or rapid cycling
no relatives with bipolar disorder
many depressive episodes
co-morbid substance abuse
Glutamate Receptors
Leighton et al 2001
Mechanism of Excitotoxicity
Glutamate
Increased intracellular Calcium
•Protein Kinase C•Calcium calmodulin-dependent protein kinase II•Phospholipase•Proteases•Phosphatases•Nitric Oxide Synthase•Endonucleases
Mechanism of Excitotoxicity
•DNA damage•Decreased mitochondrial function•Increased free radicals
Lithium Chloride
Side Effects
drowsiness
weakness
nausea
fatigue
hand tremor
increased thirst and urination
weight gain
• limits excitability by modulating glutamate signaling
• inhibits cell death
•Of limited therapeutic value for treating those with:
mixed mania or rapid cycling
no relatives with bipolar disorder
many depressive episodes
co-morbid substance abuse
Anticonvulsants
CarbamazepineValproateLamotrigineGabapentinTopiramate
• epilepsy and bipolar disorder may both involve hyperexcitability
• Side effects include gastrointenstinal problems dizzinessheadache anxietydouble vision confusion
Anticonvulsants increase GABAergic activity
• inhibit enzymatic metabolism of GABA
• enhance Cl- influx through GABA receptor
• increase concentration of GABA
• increase rate of GABA synthesis
• upregulate GABA receptors
Anticonvulsants decrease hyperexcitability
• antagonize AMPA glutamate receptors
• inhibit sodium channel activity
• inhibit voltage-gated calcium channels
Other BD Pharmacotherapeutics
1. Antipsychotics
2. Calcium channel blockers
3. Cholinergic drugs*co-administration of lithium and choline*acetylcholinesterase inhibitors
What causes mood disorders?
• Monoaminergic dysfunction?
• Glutamate-mediated hyperexcitability?
• Excessive apoptosis?
• Insufficient neurotrophic support?
• Dysfunctional synaptic plasticity?
The Monoamine Hypothesis:
Depression is caused by insufficient activity at monoaminergic (serotonergic
and adrenergic) synapses
Evidence supporting the Monoamine Hypothesis:
• drugs that elevate mood increase levels of serotonin and/or norepinephrine in the synaptic cleft
• the monoaminergic systems are distributed throughout the limbic, striatal, and prefrontal circuits
• electroconvulsive shock elevates mood and changes expression of serotonergic receptors
• some depressed patients have abnormal monoaminergic tone
• drugs that deplete monoamines (like reserpine) can trigger depression
Limitations of the monoamine hypothesis
1. Cannot explain therapeutic lag time
2. Conflicting evidence regarding the overall effect of antidepressants on serotonergic and adrenergic tone
3. The number of neurotransmitters, neuromodulators, and hormones affected implicates intracellular signaling cascades
Manji et al 2001
What causes mood disorders?
•Monoaminergic dysfunction?
• Glutamate-mediated hyperexcitability?
• Excessive apoptosis?
• Insufficient neurotrophic support?
• Dysfunctional synaptic plasticity?
Intracellular signaling pathways important in mood disorders
Apoptotic proteins Neurotrophic factors2nd messenger cascades
*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription
Cell survival
Manji et al 2001
Brain imaging findings in MDD
Glucose metabolism/Blood flow Indicates change in activity
increases:• amygdala•Orbital cortex•Medial thalamus
decreases:• dorsolateral prefrontal cortex• cingulate cortex
Brain Structure Indicates cell atrophy/death
•enlarged 3rd ventricle
•reduced grey matter volume in prefrontal cortex, hippocampus, and striatum
• decreased volume of hippocampus
DepressedControl
Blue=less glucose metabolizedGreen=more glucose metabolized
Hypoactivity in frontal and prefrontal cortex and basal ganglia in depression
Brain imaging findings in MDD
Glucose metabolism/Blood flow Indicates change in activity
increases:• amygdala•Orbital cortex•Medial thalamus
decreases:• dorsolateral prefrontal cortex• cingulate cortex
Brain Structure Indicates cell atrophy/death
•enlarged 3rd ventricle
•reduced grey matter volume in prefrontal cortex, hippocampus, and striatum
• decreased volume of hippocampus
Chronic stress causes cell atrophy in the hippocampus
The hippocampus•sensitive to the neurotoxic effects of stress• important in LTP, learning, and memory
Intracellular signaling pathways important in mood disorders
Apoptotic proteins Neurotrophic factors2nd messenger cascades
*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription
Cell survival
Apoptosis
• a special kind of “controlled” cell death that minimizes damage to surrounding tissue
• essential for normal development of the nervous system
• occurs through tightly regulated signal transduction cascades inside the cell
• glutamate-mediated excitotoxicity is associated with excessive apoptosis
Lithium normalizes grey matter volume in BD patients
Lithium and Apoptosis
Bcl-2 inhibits apoptosis
• binds to proteins which destabilize the mitochondria •prevents release of ions/proteins from mitochondria
• inhibits activation of proteins which cause apoptosis
Lithium and valproate inhibit apoptosis
Du
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Increase in neurogenesis in hippocampus after chronic antidepressant treatment
Antidepressants may limit cell loss by increasing adult neurogenesis
Neurotrophic Factors
• essential for normal nervous system development
• important in the adult brain for maintenance of neurons and glia
• different neurotrophins are important for promoting survival of different cell types in different areas
Neurotrophic Factors
• essential for normal nervous system development
• important in the adult brain for maintenance of neurons and glia
• different neurotrophins are important for promoting survival of different cell types in different areas
Serotonergic neurons
Intracellular signaling cascades activated by neurotrophins
Effect of antidepressants on BDNF
• BDNF is a growth factor that is involved in serotonergic cell survival
• BDNF expression is increased in hippocampus by chronic antidepressant administration in rats
•Animals subjected to forced swim test show decreased BDNF levels in the hippocampus; antidepressants normalize these levels
•BDNF is protective against hippocampal atrophy associated with chronic stress
How do antidepressants upregulate BDNF?
•cAMP levels are up-regulated by chronic antidepressant treatment
•Levels of CREB mRNA in the hippocampus are increased by antidepressant treatment
• Drugs which inhibit cAMP breakdown may be antidepressant
Intracellular signaling pathways important in mood disorders
Apoptotic proteins Neurotrophic factors2nd messenger cascades
*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription
Cell survival
Intracellular signaling pathways important in mood disorders
Apoptotic proteins Neurotrophic factors2nd messenger cascades
*activated by neurotransmitter binding to metabotropic receptor*indirectly opens ion channels*alters gene transcription
Cell survivalPlasticity
Synaptic Plasticity
• change in the structure or biochemistry of a synapse that alters its effects on a post-synaptic neuron
• important for learning and memory
• can occur by
1. insertion of new AMPA receptors at synapse2. synaptogenesis3. neurogenesis4. axon and dendrite outgrowth5. Inhibition of cell death
Synaptic Plasticity
• change in the structure or biochemistry of a synapse that alters its effects on a post-synaptic neuron
• important for learning and memory
• can occur by
1. insertion of new AMPA receptors at synapse2. synaptogenesis3. neurogenesis4. axon and dendrite outgrowth5. Inhibition of cell death
antidepressants & mood stabilizers
Summary: Neuroplasticity and Mood Disorders
Via activation of serotonin and norepinephrine-mediated 2nd messenger cascades
Current Research: Effect of antidepressants on fibroblast growth factor
1. Explore the role of other growth factors in the mechanism of action of antidepressants
2. investigate whether growth factors are up-regulated in specific brain areas important in mood
Neurotrophic Factors
• essential for normal nervous system development
• important in the adult brain for maintenance of neurons and glia
• different neurotrophins are important for promoting survival of different cell types in different areas
Serotonergic neurons
•Supports survival of monaminergic and dopaminergic neurons• supports growth of glutamatergic synapses
Chronic desipramine causes up-regulation of FGF mRNA in frontal cortex
Mallei et al 2002
Chronic desipramine causes up-regulation of FGF in an anatomically-specific manner
control Desipramine-treatedM
alle
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Chronic desipramine treatment alters composition of cortical glutamate receptors
Leighton et al 2001
Summary
1. How can we reconcile cell death and dysfunction in mood disorders with the lack of severe cognitive abnormalities?
2. Is there a distinct mood circuitry in the brain?
3. Can alteration of single molecules in a signal transduction cascade cause complex disorders such as mood disorders?
4. Can we design drugs based on our knowledge of dysfunctional intracellular signaling?
5. Is MDD (and is BD) one disease, or a group of different disorders?