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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)
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
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
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
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