Updates on Bipolar Disorder

Sophia Frangou MD PhD FRCPsych Institute of Psychiatry, London Bipolar Disorder

Overview
Clinical Presentation
Aetiology
Endophenotypes
Cognition
Brain structure
Brain Function

Lifetime and 12-month prevalence of bipolar spectrum disorder National Comorbidity Survey Replication Merikangas et al 2007
Lifetime cases receiving no medication
Bipolar I disorder: 46.8%,
Bipolar II disorder: 59.9%
Bipolar disorder NOS: 75.3%
n=9282 (aged ≥18 years); US population Prevalence, mean (SD) Any bipolar disorder Bipolar I Bipolar II Bipolar NOS Lifetime 4.4 (24.3) 1.0 (13.2) 1.1 (10.6) 2.4 (23.3) 12-month 2.8 (18.9) 0.6 (9.2) 0.8 (9.9) 1.4 (15.1)

The complexity of symptomatic presentation Post et al. 2003

Number of DSM-IV Manic Symptoms During an Index Episode of Bipolar Depression in STEP-BD (N=1,380) Goldberg et al. 2009

Constant risk of relapse over 40yrs; 0.4episodes/year Angst et al. Eur Arch Psychiatry Clin Neurosci. 2003

Aetiology

Up to 80% of the liability for BD can be attributed to genetic factors
Up to 71% of the of the genetic liability to mania may be distinct from that to depression.
The spectrum of psychiatric abnormalities associated with predisposition to BD is wide:
The lifetime prevalence of BD spectrum disorders is very high for first-degree relatives of BD patients:
23.9% Anxiety Disorders
11.9% Substance Abuse Disorders
5.7-14% for Major Depressive Disorder (MD)
4.9% Bipolar Disorder type I (BDI)
4.4% Bipolar Disorder type II (BDII)
The Phenotypic Spectrum of Bipolar Disorder

Linkage studies
6q (for BD I) and 8q (for BD I and II)
Cytogenetic Studies
1q42: DISC1 and DISC2
Association Studies (?)
BDNF
Serotonin transporter gene
Dopamine transporter gene
G72
5,10 methylenetetrahydrofolate reductase (MTHFR)
tryptophan hydroxylase 2 (TPH2),
the NMDA glutamate receptor, subunit 2B (GRIN2B)
COMT
Susceptibility Genes

Susceptibility Genes
Genome Wide Association Studies
BD vs. healthy controls
DGKH, the gene encoding diacylglycerol kinase eta, involved Li response pathways
PALB2 : stability of key. nuclear structures, including chromatin
NDUFAB1: mitochondrial respiratory chain
DCTN5 : intracellular transport
CACNA1C: voltage gated calcium channel
ANK3: Spectrin binding protein
BD vs. other psychiatric disorders
12q21 KCNC2 gene (voltage-gated potassium channel), and SNPs at 1p31, 2q31, and 22q12

Beyond Symptoms
Brain Structure
Cognition
Brain Function

What do these circuits to? Amygdala Association of stimuli with reward and punishment Anterior Cingulate Processing conflicting info Effortful cognitive processing Dorsal PFC Maintenance/ Manipulation of task relevant info Cognitive set shifting Planning Ventral PFC Maintenance/ Manipulation of incentive info Response modification when contingencies change Planning

Copyright restrictions may apply. Kempton, M. J. et al. Arch Gen Psychiatry 2008;65:1017-1032. Continuous variables from the bipolar-control meta-analysis Meta-analysis of brain structural changes

RISK - Insula Involved emotional recall and self-regulation of affect Connected to the cingulate cortex and the brainstem RESILIENCE – Cerebellar Vermis Involved in the homeostatic control of autonomic function Contributes to the adaptive control of complex behaviour DISEASE – Substantia Nigra Has high concentration of D2 receptors Highest level of expression of the vesicular monoamine transporter gene, which is associated with BD Kempton et al. submitted Brain Structure and Bipolar “Spectrum”

Premorbid Phase Koenen et al. Am J Psychiatry 2009

Aetiology and Ethnicity in Schizophrenia and Other Psychosis (AESOP) : Premorbid and Post onset IQ Zanelli et al. Am J Psychiatry 2010 106 44 14 48 41 264

Stefanopoulou at al. 2009 Meta-analytic evidence: IQ decrement in chronic patients

Normal age related gray matter volume changes in BD Sarnicola et al. Bipol Disord. 2009 age from scanned 70.00 60.00 50.00 40.00 30.00 20.00 grey 1.000000 0.900000 0.800000 0.700000 0.600000 0.500000 control patient control patient pat_code1 R Sq Linear = 0.115 R Sq Linear = 0.184 Age (years) 70 60 50 40 30 20 1.00 0.90 0.80 0.70 0.60 0.50 control patient control patient R Sq Linear = 0.115 R Sq Linear = 0.184

Increased risk of dementia in BD Kessing et al. J Affect Disord 2000 100 97 94 0 10 20 diabetes artritis mania depression

Total white matter volume and IQ predict GAF score in BD patients Forcada et al. submitted

Lithium decreases the risk of dementia Kessing et al. Arch Gen Psychiatry 2008

Beyond Symptomatic Control? Moore et al Lancet 2000

Germana et al Acta Scan Psychiatrica 2010 Effect of Lithium on regional gray matter volume A B C
Right subgenual anterior cingulate extending to the hypothalamus (ma x 4, y -4 z 10)
B) Left hippocampus/amygdala (peak maxima x -16 y -28, z -12 )
C) Left postcentral gyrus (peak maxima x -30 y -24 z 64) and left insula (peak maxima x -32 y 4 z -2
Significant group differences in gray matter volume between BD patients treated with Lithium and all other treatment groups combined

Genetic Predisposition

WCST and HSCT Frangou et al. Biol Psychiatry. 2005 9 8 7 6 5 4 3 2 1 0 WCST categories achieved WCST perseverative errors HSCT A error scaled score HSCT B error scaled score BD Patients Offspring Controls

Controls Healthy Relatives MDD Relatives Bipolar Patients

Updates on Bipolar Disorder

by JP Rajendran on Aug 28, 2010

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Updates on Bipolar Disorder — Presentation Transcript