salzman neurobiology of bipolar disorder
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ESSENTIAL
PSYCHOPHARMACOLOGY,2011:
NEUROBIOLOGY OF
BIPOLAR DISORDER
Carl Salzman MDMontreal
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BIPOLAR DISORDER AS
ABNORMALITIES IN CELLULAR
PLASTICITY CASCADES Cellular signalling cascades regulate
multiple neurotransmitter and
neuropeptide systems Originate and project to limbic-related regions
such as hippocampus, hypothalamus, brain
stem (associated with neurovegetative
symptoms)
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BIPOLAR DISORDER: RECENT TRENDS
Lower age of onset (from 30 years ago to 19
presently)
Broader definition of bipolar disorder (now includes
schizoaffective disorder under DSM-IV)
More comorbid, Axis-II disorders
More substance abuse comorbidity (increased from
20% to over 50%)
Antidepressants are used more now which may be
changing the illness and making it more treatment
resistant
General impression is that lithium is less effective
than in previous years; best lithium responders have
clear, symptom-free intervals between episodes
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MECHANISM OF GLYCOGEN
SYNTHASE KINASE-3
Cellular serine/threonine kinase
Regulated by protein kinases A and C
Activates CREB and other transcription factors
May be phosphorylated (activated) by 5HT
Regulates mood
Inhibited by lithium, anticonvulsants
May have neuroprotective and adjunctiveantidepressant properties
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GSK-3 NEUROTROPHIC
CASCADES
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GLYCOGEN SYNTHASE KINASE:
ROLE OF POLYMORPHISMS
GSK 3 is anti-apoptotic
Leads to activation of cell survival-transcription factors
such as CREB Polymorphism (C vs. T) of the promoter region
Bipolar patients with CC and CT genotypes respond better
to lithium prophylaxis
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LITHIUM AUGMENTATION AND GSKB
TT genotype
CC/CT genotype
Adli 2007; Biol Psychiat 62:1295
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BDNF IN BIPOLAR DISORDER
Serum BDNF levels are decreased in BD
Negative correlation with severity of
symptoms
May be associated with treatment response
Val66met polymorphism is associated with
susceptibility to rapid cycling
Affects synthesis and releases of BDNF
Tramontina; 2007;Mol Psychiat 12:230; Machado-Vieira, 2006
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INVERSE CORRELATION WITH DEGREE OF MANIA AND PLASMA BDNF
Machado-Viera, 2007
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NEUROCHEMISTRY OF
MANIA Catecholamines
Thyroid dysfunction
Second messengers
Arachidonic acid pathways Glutamate dysfunction
HPA dysfunction
GABA dysfunction GSK-3 Neurotransmission
Decreased BDNF
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NEUROCHEMISTRY OF
MANIA: CATECHOLAMINES Mania and impulsivity related to
catecholamine function
Amphetamine challenge predicts
antidepressant response in bipolar
depression
Elevated MHPG in bipolar depression
Lithium increases cortical levels of 5-HT
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HIGH COMORBIDITY BETWEEN PANIC DISORDER
AND BIPOLAR DISORDER
Bipolar disorder patients have a higher frequency of
short allele of the serotonin transporter (5-HTTLPRpolymorphism)
Highest in BP patients without panic disorder
Frequency of COMT variant is higher for bipolar disorder
patients
Highest effect in BP patients without panic disorder
Conclusion: BP patients without panic disorder may
represent a homogeneous form of the illness
genetically distinct from BP patients with panic
disorder This form is strongly related to the function of the COMT and
5-HTTLPR genotypes
Genetic linkage suggested between comorbid panic
disorder and bipolar illness
A distinct genetic type of bipolar disorder
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NEUROCHEMISTRY OF MANIA:
THYROID DYSFUNCTION
Patients with bipolar disorders are sensitive tovariations in thyroid function within the normal range
Lower values of thyroxin index and higher values of
TSH associated with longer times to response to
treatment
Combination of lower pretreatment TSH and higher
pretreatment FTI associated with markedly more
rapid remission of depression
Consistent with hypothesis that lower levels of thyroid
hormones may represent inadequate compensatory
homeostatic response of CNS to depression
increased circulating thyroid may increase beta receptor
sensitivity
NEUR HEMI TRY F
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NEUR HEMI TRY FMANIA: Phosphoinositide
second messenger system Serotonin receptor stimulation activates
phospholipase C enzyme. This triggers breakdown
of PIP2 to IP3 and DAG. IP3 stimulation releases intracellular calcium. In turn,
this increase in intracellular calcium feeds back onto
the IP3 recognition site preventing the further release
of intracellular calcium. IP3, DAG, and Ca
+2 are second messengers which
increase gene transcription
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Effects of Lithium on
Phosphoinositide System Lithium inhibits the breakdown of IP3
which dampens the PI system by
preventing the formation of PIP2 andsubsequent IP3.
Depletes second messenger inositol
levels Decreases pKc, GSK-3 resulting in
decreased neurogenesis, CREB and
BDNF
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NEUROBIOLOGY OF MANIA:
PKc INHIBITION PKc: enzyme activated by second
messenger system in serotonin pathway
Inhibition decreases mania
Tamoxifan is a PKc inhibitor that can
decrease mania
Yildiz, ArchGenPsych 2008; 65:255
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NEUROCHEMISTRY OF
MANIA: Arachidonic Acid
Cascade
AA is n-6 polyunsaturated fatty acid (PUFA). Its first
double bond is at the carbon 6 position (in contrast tothe carbon 3 position of omega 3, -3, fatty acids)..
Intraneuronal AA is released from the endoplasmic
reticulum and mitochondria into the cell by stimulation
of phospholipase A2
and, to a lesser extent, DAG.
Once released into the cell, it is metabolized to active
second messengers by several enzymes: cyclo-
oxygenase 1 or 2, or CP450. Most of the AA is
recycled back into phospholipids by acetyl CoA
enzymes.
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NEUROCHEMISTRY OF MANIA:
GLUTAMATE
Stimulatory neurotransmitter
Decreasing glutamate may have
therapeutic consequences:
Lamotrigine: decreased presynaptic release
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NEUROCHEMISTRY OF MANIA:
THYROID DYSFUNCTION
Patients with bipolar disorders are sensitive tovariations in thyroid function within the normal range
Rapid cycling patients often have hypothyroid
function
Increasing T4 helps regulate rapid cycling
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NEUROCHEMISTRY OF
BIPOLAR DISORDER:
Arachidonic Acid Cascade
AA is n-6 polyunsaturated fatty acid (PUFA).
Plays an important role in neuronal membrane stabilization and
neurotransmission
May be dysregulated in bipolar disorder
Long-chain fatty acids containing -3 (omega 3) fatty acid may correct
this dysfunction