1. Incidence of psychopathology in offspring of parents with bipolar and unipolar mood disorders: 10-year follow-up M. Preisig, C. Vandeleur, M.-P. Strippoli, E. Castelao, M. Gholam- Mezaee, K.R. Merikangas, J.M. Aubry

2. Psychotic symptoms Manic symptoms Depressive symptoms Bipolar disorder Heterogeneous disorders  Clinical manifestations  Course  Treatment response Bipolar disorders: clinical heterogeneity

3. Bipolar disorders: Unclear boundaries Psychotic symptoms Manic symptoms Depressive symptoms Bipolar disorder Borderline personality Depressive disorders Anxiety disorders ADHD Schizophrenia Unipolar schizo-affective disorder Bipolar schizo-affective disorder Mood spectrum

4. Bipolar disorders: Unclear boundaries Psychotic symptoms Manic symptoms Depressive symptoms Bipolar disorder Borderline personality Depressive disorders Anxiety disorders ADHD Schizophrenia Unipolar schizo-affective disorder Bipolar schizo-affective disorder Mood spectrum Clinical heterogeneity and unclear boundaries of bipolar disorders as defined by DSM-IV/DSM-5 are likely to be a major impediment for the progress of research.

5. Intermediate phenotpyes

6. Familial aggregation of psychotic and mood episode types in adults Relatives Probands OR = 2.9** ** p < 0.01; ** p < 0.05 Major depressive episodes Hypomanic episodes Manic episodes Psychotic features Major depressive episodes Hypomanic episodes Manic episodes Psychotic features OR = 6.4** OR = 2.0*** Vandeleur CL et al (2014) Mol Psychiatry 19:209-13

7. Early onset subtype (<21 years) Later onset subtype Age of onset of mood disorders Severity (course, comorbidity, suicidality) Family studies (uncontrolled or pooled relatives with BPD and MDD) Higher risk of mood disorders among relatives of probands with early onset, as compared to those of probands with later onset. (Schürhoff et al., 2000; Grigoroiu- Serbanescu et al., 2001; Lin et al., 2006; Oquendo et al., 2013). Clinical studies

8. Objectives Using a prospective cohort of offspring of patients with unipolar and bipolar mood disorders, the goals of the present study were to: 1.test the specificity of the aggregation patterns of mood disorders and episodes among parents and offspring; 2.establish the cumulative risk of non-mood psychopathology in offspring; 3.establish the cumulative risk of mood and non-mood psychopathology in offspring as a function of age at onset of mood disorders in parents.

9. Lausanne/Geneva High Risk Study: Recruitment BPD N=81 Probands N=207 MDD N=64 Clinical controls N=62 N=144 Offspring N=365 N=112 N=109 Spouses N=201 N=80 N=60N=61

10. Lausanne/Geneva High Risk Study: Assessments in offspring (n=365) Age Diagnostic instruments N Interviewed 135 75 % 222 85 % 252 87 % % 269 85 % % DIGS Self-reports DIGS Self-reports DIGS Self-reports 221 74 % 154 73 % 94 72 % DIGS Self-reports DIGS Self-reports DIGS Self-reports 47 72 % 13 69 % 6 33 % 1013197162522312834 K-SADS Dominique K-SADS Self-reports K-SADS Self-reports K-SADS Self-reports Mean age at intake: 10.0 yrs (s.d. 4.3 yrs) Mean follow-up length: 10.6 yrs (s.d. 1.3 yrs)

11. Lausanne/Geneva High Risk Study: Offspring (n=365) Bipolar (n=144) MDD (n= 112) Control (n= 109) p Girls (%)515244n.s. Age at first assessment (mean) 10.410.39.5n.s. # Assessments (mean)4.23.64.4<.001 # Interviews (mean)3.22.83.2n.s. SES of the family (1-5)3.32.83.5<.001

12. Cumulative lifetime prevalence of psychiatric disorders in offspring Offspring disorder Proband disorders Bipolar (n=136) MDD (n=111) Control (n=106) %HR § % % BP-I or BP-II12.42.84.40.73.6 MDD36.60.946.11.337.5 Separation anxiety40.71.753.92.4*26.8 Other anxiety disorders43.51.241.71.038.4 ADHD16.61.422.61.913.4 Alcohol disorders15.92.715.73.910.7 Drug disorders18.61.320.01.213.4 § Hazard ratios adjusted for age, sex and SES in offspring, proband comorbidity, the co-parent’s disorders and within-family correlations. * p <.05.

13. Risk of BPD in offspring as a function of proband mood disorder onset p<0.001 p = n.s.

14. Risk of MDD in offspring as a function of proband mood disorder onset p = n.s. p<0.01 p = n.s.

15. Risk (HR § ) of disorders in offspring as a function of proband mood disorder onset Offspring disorders Proband disorder BPD<21yrsBPD>21 yrsMDD<21yrsMDD>21 yrs BP-I or BP-II7.9**1.41.30.8 MDD0.61.01.61.1 Separation anxiety1.71.62.22.4* Other anxiety disorders1.01.32.20.7 ADHD1.51.11.91.7 Alcohol disorders7.9*1.85.14.4 Drug disorders3.01.01.71.3 § Hazard ratios adjusted for age, sex and SES in offspring, proband comorbidity, the co-parent’s disorders and within-family correlations. ** p <.05 ; * p <.05. Not explained by severity: remains highly significant after adjustment for lifetime GAF score.

16. Transmission and Cross-transmission of Mania/Hypomania and Major Depressive Episodes (MDE) Shared gamma frailty models adjusted for sex and age in offspring, socio-economic status of the family, the proband’s comorbidity, the co-parent’s disorders and within-family correlations. *** p < 0.001 HR = 1.6 EARLY ONSET MDE Offspring Probands EARLY ONSET (HYPO)MANIA HR = 12.0*** MANIA / HYPOMANIA MDE LATER ONSET (HYPO)MANIA HR = 0.9 HR = 1.4 LATER ONSET MDE

17. Conclusions and new questions: Mood spectrum? 1.Confirmation of the strong and specific familial aggregation of BPD and its main component mania;  Additional evidence suggesting that mania and depression may represent distinct underlying pathways rather than increasingly severe manifestations of a common underlying diathesis. 2.Evidence of a strong effect of the age of onset for the transmission of BPD: elevated risk of BPD in adolescence only in offspring of parents with early-onset BPD; - Are early and late-onset BPD distinct disorders? - Is only early-onset BPD transmittable?

18. Conclusions and new questions: Mood and other disorders 1.Increased incidence of separation anxiety in offspring of probands with MDD. - Anxiety as an early precursor of unipolar depression? - Shared diathesis of depression and anxiety disorders? 2.Increased incidence of alcohol use disorders in offspring of probands with early-onset BPD. - What is the mechanism of this association?

19. Limitations  Small sample size: only 27 children with mania/hypomania;  Relatively young cohort that did not allow us to accurately determine the incidence of disorders after age 20;  Ages at onset of proband mood disorders determined retrospectively;  High risk sample: problem of representativeness;  Large age range of first assessment: 7-17 years;  3-year intervals between assess.

20. Disclosure Unrestricted research grants related to this presentation from:  Swiss National Science Foundation;  GlaxoSmithKline Clinical Genetics Honoraria for scientific presentations in the last 3 years from: Servier, AstraZeneca, Lundbeck, Janssen Martin Preisig, DP CHUV, Site de Cery, CH-1008 Prilly martin.preisig@chuv ch

22. Lausanne/Geneva High Risk Study: Probands (n=207) Bipolar (n=81) MDD (n=64) Control (n=62) p Females (%)585645n.s. Age at intake (mean) 4041 n.s. Married (%)625877<.05 Offspring per proband 1.8 n.s.

23. Lausanne/Geneva High Risk Study: Spouses (n=201) Spouses of Bipolar (n=80) Spouses of MDD (n=60) Spouses of Controls (n=61) p Females (%)444257n.s. Age at first interview (mean) 42 n.s. Bipolar spectrum (%)10123n.s. Unipolar disorders (%)28 33n.s. Substance misuse (%)25338<.01

24. Lifetime prevalence (%) of psychiatric disorders in offspring (baseline) Offspring diagnoses Proband diagnosis p Bipolar (n=139) MDD (n=110) Control (n=127) Any mood disorder34.525.512.6<.001 Any BPD3.62.70.0n.s. Any depression30.922.712.6.002 MDD recurrent7.93.61.6.04 MDD single11.56.45.5n.s. Any anxiety disorder42.544.622.8<.001 Separation anxiety28.836.415.8.001 Vandeleur et al. 2012 Bipolar Disord 14: 641–653

25. Risk (%) of BPD in offspring (n=340) as a function of mood disorders in both parents Disorder in co-parent Disorder in proband BPDMDDControl BPD30.8%(4/13)0%(0/9)0%(0/2) MDD10.6%(5/47)4.2%(1/24)2.8%(1/36) None15.2%(12/79)11.1%(7/63)3.0%(2/67)

26. Risk (%) of MDD in offspring (n=340) as a function of mood disorders in both parents Disorder in co-parent Disorder in proband BPDMDDControl BPD 30.8%(4/13)66.7%(6/9)100%(2/2) MDD 51.1%(24/47)54.2%(13/24)36.1%(13/36) None 36.7%(29/79)39.7%(25/63)35.8%(24/67)

27. Risk (HR § ) of disorders in offspring as a function of the co-parent’s mood disorder Offspring diagnoses Co-parent’s diagnosis BPDMDD BPD spectrum0.71.1 BPD1.70.9 Subthr. BPD0.41.2 Depressive spectrum1.71.4 MDD1.21.4 Subthr. depression2.01.1 Any anxiety1.71.4 Separation anxiety1.71.7* § adjusted for age, sex and SES in offspring, proband comorbidity and the co-parent’s disorders.* p <.05.