1. Manic disorder as an element of the mood spectrum IRPB Lisbon, 26-28 March 2015 Jules Angst, M.D. Psychiatric Hospital University of Zurich, Switzerland jules.angst@uzh.ch

2. History of mania and the mood spectrum Folie circulaire: Falret 1851 Manic-Depressive Disorder: Kraepelin 1899 Mania as a state of hyperfunction of nerve transmission, an independent disorder: Wernicke 1906 Bipolar vs. depressive disorder: Angst 1966, Perris 1966, Winokur, Clayton and Reich 1969 Bipolar-II disorder: Dunner, Gershon and Goodwin 1976 Affective spectrum: Akiskal 1983: Dep – BP-II – BP-I Spectrum: D – BP-II – BP-I – Md – M: Angst 1978, 1980 DSM-5 2014: no Mania ICD-11: no Mania

3. Three-dimensional mood spectrum Angst, J et al. 2015 submitted for publication

4. Epidemiological studies on unipolar mania (UM) and hypomania (um) EDSP Munich*: UM=1.5%, um=1.8% (follow-up over 10 years) NCS-A USA** : M/Md=1.7% (no follow-up) * Beesdo et al. 2009: Bipolar Disord 11:637-649 ** Merikangas et al. 2012: Arch Gen Psychiat 69: 943-951

5. Zurich Study: cumulative incidence of DSM-III-R/DSM-IV mood disorders from age 20 to 50 (Eun, J et al. Poster APPA 2015)

6. Major mood disorders: four groups Modified DSM-5 concept without hierarchy of energy/activity over elated and irritable mood. M/Md Mania/Mania with minor depr. dis. N=18 BP-I Bipolar-I disorder N=19 MDE/m/msx: BP-II (N=8) or MDE with manic symptoms (N=86), together N=96 MDD without manic symptoms N=102 OTHERS without minor depr. dis. or manic sx.N=174 Statistics comparing the four groups of mood disorders

7. Major mood disorders by gender (N) Zurich Study: modified DSM-5 concept N

8. Major mood disorders: % family history for mania, depression and anxiety/panic p<.03 p<.006

9. Major mood disorders: temperament (%) p<.0005 * p<.0001 * significant p values between M/Md and BP-I

10. Major mood disorders: comorbidity with abuse/dependence (%) p<.003 p<.04

11. Major mood disorders: comorbidity with suicide attempts, anxiety/panic (%) Stars refer to significant p values between M/Md and BP-I p<.008

12. Clinical studies on unipolar mania (UM) BP-I N UM N UM % Western countries - 6 retrospective studies108625123.1 - 3 prospective studies4394311.0 Non-Western countries - 12 retrospective studies196469835.9 - 1 prospective study1045552.6 Angst, J. & Grobler, C., Eur Arch Psychiatry Clin Neurosci 2015 DOI 10.1007/s00406-015-0577-1

13. Diagnostic stability of unipolar mania (UM) DSM=Diagnostic and Statistical Manual of Mental Disorders RDC=Research Diagnostic Criteria BP-I= Bipolar-I Disorder CountryYearDiagnosis Min epis. Follow-up years Total sample UM% prospective Xu and ChenChina1992DSM-III mania1+10241875.0 retrospectiveAuthor MakanjuolaNigeria1982RDC mania2+1+ (median)361233.3 Solomon et alUSA2003 BP-I or schizo- mania 1+15-2027725.9 Yazici et al.Turkey2008DSM-IV mania4+7343088.2 Angst, J. & Grobler, C., Eur Arch Psychiatry Clin Neurosci 2015 DOI 10.1007/s00406-015-0577-1

14. Clinical characteristics of UM compared to BP-I (review of literature) Earlier onset Fewer episodes Lower comorbidity with anxiety disorders Better long-term adjustment More psychotic features Fewer suicide attempts Less rapid cycling Lower response to lithium Hyperthymic temperament Weaker family history for MDD Angst, J. & Grobler, C., Eur Arch Psychiatry Clin Neurosci 2015 DOI 10.1007/s00406-015-0577-1

15. Selection of consecutive admissions Prospective examinations 1959-1963 196519701975198019851991 M o r t a l i t y 1997 Outcome Affective disorder in-patient study: Zurich 1959-2009 (N=403) 2003 2009

16. Mortality rates DiagnosisNDeathsDeaths % MDD=(D)18316590.2 BP-II=(Dm)605388.3 BP-I=(MD)13011689.2 M/Md302376.7 Total40335788.6 J. Angst et al. 2013: Eur Arch Psychiat Clin Neurosci 263:425-434

18. Cardiovascular mortality (N=353 deaths) ** (*) J. Angst et al. 2013: Eur Arch Psychiat Clin Neurosci 263:425-434 *

19. Conclusions I Two large epidemiological studies identified M/Md in 1.5-1.7% of the population. In the Zurich Study most subjects with MDE were classified as having MDD and very few with BP-II, BP- I or M/Md. 45% of subjects with MDD reported manic symptoms and this group shows some signs of hidden bipolarity. Mania and BP-I were equally rare but differed in some respects: manic subjects tended to have a weaker family history of depression (50% vs 68%), were more often hyperthymic (44% vs 5%) but less often cyclothymic (22% vs 58%).

20. Conclusions II Associations with GAD and panic (58%) much stronger in BP-I disorder than in mania (17%), and a bit stronger with suicide attempts (BP-I:16%; mania:11%). Clinical studies suggest higher rates of psychotic symptoms, earlier age of onset, fewer episodes and better remission of mania compared to BP-I disorders. Deaths by suicide were highest in MDD and lowest in M/Md; the reverse was found for cardiovascular mortality. A diagnosis of M is best based on 3+ episodes. Much more research is needed on mania as an independent disorder. Our knowledge is still very limited.

21. Thank you for your attention