ESSENTIAL

PSYCHOPHARMACOLOGY,

2011:

NEUROBIOLOGY OF

BIPOLAR DISORDER

Carl Salzman MD

Montreal

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)

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

(Goodwin, 2001)

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 adjunctive

antidepressant properties

GSK-3 NEUROTROPHIC

CASCADES

GLYCOGEN SYNTHASE KINASE:

ROLE OF POLYMORPHISMS

• GSK 3ß 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

LITHIUM AUGMENTATION AND GSKB

TT genotype

CC/CT genotype

Adli 2007; Biol Psychiat 62:1295

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

INVERSE CORRELATION WITH DEGREE OF MANIA AND PLASMA BDNF

Machado-Viera, 2007

NEUROCHEMISTRY OF

MANIA• Catecholamines

• Thyroid dysfunction

• Second messengers

• Arachidonic acid pathways

• Glutamate dysfunction

• HPA dysfunction

• GABA dysfunction

• GSK-3 Neurotransmission

• Decreased BDNF

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

HIGH COMORBIDITY BETWEEN PANIC DISORDER

AND BIPOLAR DISORDER

• Bipolar disorder patients have a higher frequency of

short allele of the serotonin transporter (5-HTTLPR

polymorphism)

– 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

– Comorbidity rates between between BP disorder and PD are

NEUROCHEMISTRY OF MANIA:

SEROTONIN

• Tryptophan hydroxylase regulates

serotonin levels

• TPH2 gene regulates serotonin production

– Polymorphisms may be associated with

depression

– Some may be protective against bipolar

disorder

Van Den Bogaert, 2006

NEUROCHEMISTRY OF MANIA:

THYROID DYSFUNCTION• Patients with bipolar disorders are sensitive to

variations 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

NEUROCHEMISTRY OF

MANIA: 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

Effects of Lithium on

Phosphoinositide System

• Lithium inhibits the breakdown of IP3

which dampens the PI system by

preventing the formation of PIP2 and

subsequent IP3.

• Depletes second messenger inositol

levels

• Decreases pKc, GSK-3 resulting in

decreased neurogenesis, CREB and

BDNF

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

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 to

the carbon 3 position of omega 3, ω-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.

NEUROCHEMISTRY OF MANIA:

GLUTAMATE

• Stimulatory neurotransmitter

• Decreasing glutamate may have

therapeutic consequences:

– Lamotrigine: decreased presynaptic release

NEUROCHEMISTRY OF MANIA:

THYROID DYSFUNCTION• Patients with bipolar disorders are sensitive to

variations in thyroid function within the normal range

• Rapid cycling patients often have hypothyroid

function

– Increasing T4 helps regulate rapid cycling

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