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 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
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 PIP
2
to IP
3
and DAG.
IP
3
stimulation releases intracellular calcium. In turn,
this increase in intracellular calcium feeds back onto
the IP
3
recognition site preventing the further release
of intracellular calcium.
IP
3
, DAG, and Ca
+2
are second messengers which
increase gene transcription
Effects of Lithium on
Phosphoinositide System
Lithium inhibits the breakdown of IP
3
which dampens the PI system by
preventing the formation of PIP
2
and
subsequent IP
3.
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, -3, fatty acids)..
Intraneuronal AA is released from the endoplasmic
reticulum and mitochondria into the cell by stimulation
of phospholipase A
2
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 T
4
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