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

Transcription

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

2 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)

3 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

4 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

5 GSK-3 NEUROTROPHIC CASCADES

6 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

7 LITHIUM AUGMENTATION AND GSKB Adli 2007; Biol Psychiat 62:1295 TT genotype CC/CT genotype

8 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

9 INVERSE CORRELATION WITH DEGREE OF MANIA AND PLASMA BDNF Machado-Viera, 2007

10 NEUROCHEMISTRY OF MANIA Catecholamines Thyroid dysfunction Second messengers Arachidonic acid pathways Glutamate dysfunction HPA dysfunction GABA dysfunction GSK-3 Neurotransmission Decreased BDNF

11 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

12 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

13 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

14 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

15 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

16 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

17 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

18 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 A 2 and, to a lesser extent, DAG. Once released into the cell, it is metabolized to active second messengers by several enzymes: cyclooxygenase 1 or 2, or CP450. Most of the AA is recycled back into phospholipids by acetyl CoA enzymes.

19 NEUROCHEMISTRY OF MANIA: GLUTAMATE Stimulatory neurotransmitter Decreasing glutamate may have therapeutic consequences: Lamotrigine: decreased presynaptic release

20 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

21 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