1. SPECIFICITY OF PSYCHOSIS, MANIA AND MAJOR DEPRESSION IN A CONTEMPORARY FAMILY STUDY CL. Vandeleur, KR. Merikangas, M-PF. Strippoli, E. Castelao, M. Preisig National Institute of Mental Health, USA

2. PSYCHIATRIC DISORDERS IN THE DIAGNOSTIC NOMENCLATURE Psychosis Substance use disorders Major depression Anxiety disorders Bipolar disorders Other disorders Separate entities?

3. UP BPD CTRL 3-10% 1% BPD UP 30% UP 30% UP 15% EVIDENCE FROM PREVIOUS FAMILY STUDIES  Increased rates of depression among relatives of bipolar probands, but not the converse.

4. EVIDENCE FROM PREVIOUS FAMILY STUDIES  Meta-analytic evidence for the familial co-aggregation of schizophrenia and bipolar disorder: - Relatives of probands with schizophrenia show increased rates of bipolar disorder; -Relatives of probands with bipolar disorder also show increased rates of schizophrenia; -> However, lack of a control group in many studies. (Van Snellenberg & de Candia, 2009)  Controversial evidence for the familial cross-aggregation patterns of psychosis and depression.  Well-established familial aggregation of schizophrenia, bipolar disorder and major depression, but mixed evidence regarding specificity.  Lack of specificity for the familial aggregation of bipolar I vs. II subtypes. (Gershon et al, 1982)

5. THE BEGINNING OF THE END FOR THE KRAEPELINIAN DICHOTOMY (1899) Dementia praecox Manic- depressive psychosis Schizophrenia (Bleuler, 1911) Bipolar disorders continuum Depression ? Schizo- affective disorder ? Craddock & Owen, 2005; 2010

6. MAJOR LIMITATIONS OF PREVIOUS FAMILY STUDIES OF MOOD DISORDERS  Methodological limitations including lack of a normal control group and small sample sizes;  Lack of controlling for the effects of non-mood comorbid disorders in probands and family members;  Few controlled studies including probands with both unipolar and bipolar mood disorders, which allows to test the specificity of the familial transmission of the subtypes of mood disorders.

7. STUDY GOALS 1.to assess the familial aggregation and co- aggregation patterns of the full spectrum of mood disorders based on the DSM-IV criteria; 2.to evaluate the familial specificity of their major components including psychotic, manic and major depressive episodes.

8. LAUSANNE-GENEVA FAMILY STUDY Bipolar disorder MDD Alcohol or Heroin dependence Medical controls Parents Offspring Siblings

9. INTERVIEW Diagnostic Interview for Genetic Studies (DIGS) Nurnberger et al. 1994; French translation: Leboyer et al. 1995; Preisig et al. 1999. MEDICAL RECORDS FAMILY HISTORY Family history – Research Diagnostic Criteria (FH-RDC) Andreasen et al., 1977; Yale version: Merikangas et al. 1998; French translation: Department of Psychiatry, Lausanne. BEST ESTIMATE DIAGNOSIS BEST ESTIMATE PROCEDURE

10. PROBAND SAMPLE CHARACTERISTICS (N=403) SABP n=62 BP-I n=100 BP-II n=23 MDD n=108 Control n=110 p Females (%)3960394946 n.s. Age (mean)3742 4139 n.s. SES (mean)3.03.53.02.93.3 <.01 Anxiety disorders (%) 452948569 <.0001 Alcohol abuse / dependence (%) 443552456 <.0001 Drug abuse / dependence (%) 402144297 <.0001

11. RELATIVE SAMPLE CHARACTERISTICS (N=1’734) Proband diagnosis SABP n=251 BP-I n=432 BP-II n=98 MDD n=460 Control n=493 p Females (%)5250565351 n.s. Age (mean)4951 50 n.s. Age range (yrs)18-9118-9519-8718-9718-90 - Interviewed (%)5250463936 <.001

12. MOOD AND PSYCHOTIC DISORDERS IN RELATIVES (%, OR) Dx in Rels. Proband episode type SABP (n=251) BP-I (N=432) BP-II (N=98) MDD (N=460) CTRL (N=493) %OR% % % % SABP 2.86.4*1.42.70-0.71.70.8 BP-I 2.84.6*6.912.2***2.02.41.11.40.4 BP-II 4.43.0*2.32.04.12.62.41.61.4 MDD 27.11.422.91.235.72.1*38.92.4***19.5 * p <.05; *** p <.001. adjusted for sex and age in relatives, anxiety and substance use disorders in probands and relatives

13. MOOD AND PSYCHOTIC EPISODE TYPES IN RELATIVES (%, OR) Dx in Rels. Proband episode type Psychosis (n=505) Mania (N=628) Hypomania (N=113) MDE (N=1182) CTRL (N=493) %OR% % % % Psych 5.92.9*5.10.9 0.43.61.01.6 Mania 5.91.06.26.4***1.81.63.91.70.4 Hypo 5.71.25.62.14.41.34.20.82.4 MDE 35.31.033.40.739.81.038.12.0***22.1 * p <.05; *** p <.001 adjusted for sex and age in relatives, comorbid disorders in probands and relatives, as well as for alternate mood episode types in relatives. X

14. SIMILAR FINDINGS INCLUDING 43 SUBJECTS WITH SCHIZOPHRENIA (N=1’777) Dx in rels. Proband episode type Psychosis (n=547) Mania (N=628) Hypomania (N=113) MDE (N=1206) CTRL (N=493) %OR% % % % Psych 5.52.3*5.11.20.90.53.61.11.6 Mania 5.51.06.26.8***1.81.63.81.70.4 Hypo 5.91.35.61.94.41.34.30.82.4 MDE 35.31.033.40.739.81.038.12.0***22.1 p <.05; *** p <.001. adjusted for sex and age in relatives, comorbid disorders in probands and relatives, as well as for alternate mood episode types in relatives. X

15. INDEPENDENCE OF FAMILIAL TRANSMISSION OF MANIA AND DEPRESSION: RESULTS OF THE NIMH FAMILY STUDY OF AFFECTIVE SPECTRUM DISORDERS Merikangas et al. National Institute of Mental Health, USA

16. Merikangas et al., 2014

17. INDEPENDENCE OF MANIA AND DEPRESSION: EVIDENCE FOR SEPARATE INHERITANCE OF MANIA AND DEPRESSION CHALLENGES CURRENT CONCEPTS OF BIPOLAR MOOD DISORDER Hickie University of Sydney, Australia

18. Hickie, 2014

19. CONCLUSIONS AND PERSPECTIVES Implications for research  “Future genetic and environmental risk studies, as well as clinical trials of relevant pharmacotherapeutic agents, may benefit from the use of such a multi-axial system. That is, it may be more relevant to use continuous unidirectional measures of depression severity and psychotic symptoms, as well as bidirectional measures of motor or psychic activation, as the basis for selecting subjects for inclusion in studies or determining specific outcomes [….].” Hickie, 2014

20. ACKNOWLEDGEMENTS The Swiss study presented here was supported by:  five grants from the Swiss National Science Foundation (#3200-049746, #3200-061974 to M. Preisig; and #32-40677.94, #32003B-105969, #32003B-118326 to F. Ferrero);  a grant from GlaxoSmithKline Clinical Genetics (to M. Preisig).

21. SUMMARY  Patterns according to the disorder analysis  Strong familial aggregation of BPD and a more than two-fold increase of MDD among relatives of probands with MDD. Strong familial aggregation of SABP, but no evidence for aggregation of BP-II disorder.  Cross-aggregation patterns among SABP and BP-I + BP-II disorder, as well as between MDD and BP-II disorder.  Patterns according to the episodic analysis  Strong evidence for the familial specificity of psychotic features, manic and major depressive episodes, without evidence for shared familial risk across these manifestations of mood disorders;  No evidence for the familial aggregation of hypomania.

22. STRENGTHS AND LIMITATIONS Strengths  Simultaneous comparison of the risk of specific mood disorders in the relatives of probands with both major subtypes of mood disorders and of SABP;  Novel approach assessing the risk of mood episode types, independently of the disorders during which they occurred: importance of suspension of arbitrary diagnostic distinctions.  Large sample sizes for most disorders/episode types. Limitations  Small sample size to accurately estimate the risk of BPD-II disorder/hypomania;  Diagnoses of more than half of the relatives were based on family history reports rather than direct interviews;  Sample of treated probands with substantial comorbidity, limiting the generalizability of our findings to community samples.