salzman neurobiology of bipolar disorder

8/12/2019 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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GLUTAMATE

Stimulatory neurotransmitter

Decreasing glutamate may have

therapeutic consequences:

Lamotrigine: decreased presynaptic release


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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

salzman neurobiology of bipolar disorder

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