ESSENTIAL PSYCHOPHARMACOLOGY, NEUROBIOLOGY OF BIPOLAR DISORDER - 2011: Carl Salzman MD Montreal

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

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
       Adli 2007; Biol Psychiat 62:1295

                 TT genotype

                      CC/CT genotype

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

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