The document provides an overview of bipolar disorder including: 1. The lifetime and 12-month prevalence of bipolar spectrum disorders based on a large US population study. 2. Bipolar disorder has a complex symptomatic presentation and patients experience a constant risk of relapse over decades. 3. Genetics plays a large role in bipolar disorder liability and genome-wide association studies have identified several susceptibility genes. 4. Structural and functional brain imaging research has found differences in bipolar patients in areas involved in emotion regulation, cognitive control, and reward processing.

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

2. Overview Clinical Presentation Aetiology Endophenotypes Cognition Brain structure Brain Function

3. 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)

4. The complexity of symptomatic presentation Post et al. 2003

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

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

7. Aetiology

8. 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

9. 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

10. 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

11. Beyond Symptoms Brain Structure Cognition Brain Function

12. 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

13. 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

14. 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”

15. Premorbid Phase Koenen et al. Am J Psychiatry 2009

16. 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

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

18. 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

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

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

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

22. Beyond Symptomatic Control? Moore et al Lancet 2000

23. 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

24. Genetic Predisposition

25. 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

26. Controls Healthy Relatives MDD Relatives Bipolar Patients