Molecular Psychiatry (2014) 19, 209–213 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Specificity of psychosis, mania and major depression in a contemporary family study CL Vandeleur1, KR Merikangas2, M-PF Strippoli1, E Castelao1 and M Preisig1 There has been increasing attention to the subgroups of mood disorders and their boundaries with other mental disorders, particularly psychoses. The goals of the present paper were (1) to assess the familial aggregation and co-aggregation patterns of the full spectrum of mood disorders (that is, bipolar, schizoaffective (SAF), major depression) based on contemporary diagnostic criteria; and (2) to evaluate the familial specificity of the major subgroups of mood disorders, including psychotic, manic and major depressive episodes (MDEs). The sample included 293 patients with a lifetime diagnosis of SAF disorder, bipolar disorder and major depressive disorder (MDD), 110 orthopedic controls, and 1734 adult first-degree relatives. The diagnostic assignment was based on all available information, including direct diagnostic interviews, family history reports and medical records. Our findings revealed specificity of the familial aggregation of psychosis (odds ratio (OR) ¼ 2.9, confidence interval (CI): 1.1–7.7), mania (OR ¼ 6.4, CI: 2.2–18.7) and MDEs (OR ¼ 2.0, CI: 1.5–2.7) but not hypomania (OR ¼ 1.3, CI: 0.5–3.6). There was no evidence for cross-transmission of mania and MDEs (OR ¼ .7, CI:.5–1.1), psychosis and mania (OR ¼ 1.0, CI:.4–2.7) or psychosis and MDEs (OR ¼ 1.0, CI:.7–1.4). The strong familial specificity of psychotic, manic and MDEs in this largest controlled contemporary family study challenges the growing assertion that the major types of mood disorders are manifestations of a common underlying diathesis. Molecular Psychiatry (2014) 19, 209–213; doi:10.1038/mp.2013.132; published online 15 October 2013 Keywords: family aggregation patterns; mood disorders; psychosis; mania; hypomania; major depression INTRODUCTION relationships of the full range of disorders across the mood Recent diagnostic systems in psychiatry include numerous disorder spectrum, including SAF disorder, psychotic and non- disorders and subtypes of schizophrenia (SZA), bipolar disorder psychotic BPD and major depression. Moreover, no previous study (BPD) and major depressive disorder (MDD) and their overlap to has examined the familial aggregation patterns of the core represent the spectrum of expression of mood and psychotic components of these conditions without applying the arbitrary disorders. However, the discrete boundaries between the broad distinctions specified in the diagnostic nomenclature. Therefore, categories of these disorders have been increasingly disputed the goals of this report are: (1) to assess the familial aggregation with the emergence of results from molecular genetic studies,1 and co-aggregation patterns of the full spectrum of mood particularly recent large genome-wide association studies that disorders based on contemporary diagnostic criteria; and (2) to demonstrate common polymorphisms underlying the broad evaluate the familial specificity of their major subgroups, including range of psychotic and mood disorders.2 Previous family studies psychotic, manic and major depressive episodes (MDEs). of the specificity of these conditions have been contradictory, with studies suggesting some specificity of these disorders (for 3–6 3,4 7 example, SZA, BPD and schizoaffective (SAF) disorder ), METHODS whereas others have demonstrated significant familial overlap Participants across these conditions.8–15 Likewise, overlap has been found There were a total of 403 probands, including 293 patients with mood between SZA and SAF.4,16 Therefore, SZA, BPD and MDD have 17 disorders and 110 controls selected from the local psychiatric and been postulated to belong to the same continuum. Most of this orthopedic departments. Probands with mood disorders were consecu- research was based on earlier diagnostic systems, including the tively recruited from the inpatient (61%) and outpatient (39%) facilities of Research Diagnostic Criteria (18), and the Diagnostic and Statistical the psychiatric departments of Lausanne and Geneva, Switzerland. These Manual of Mental Disorders (DSM)-III and III-R criteria, that psychiatric university departments cover the majority of inpatient specified different conventions for the diagnosis of psychotic treatments of the population of these respective regions. More severe symptoms that occurred in the context of mood disorders. Such patients and more patients who have been hospitalized are treated in the conventions as well as the exclusion of anxiety disorders that outpatient units of Lausanne and Geneva than by the private psychiatrists occur solely during mood disorders19 led to important differences in this area. Inclusion criteria for psychiatric probands were: (1) a lifetime diagnosis of SAF (SAF disorder, manic subtype (with at least one manic in the classification and familial aggregation of these disorders 20 episode); SAF disorder, depressive episode (with at least one MDE of over time. substantial duration of the total duration of psychosis)), BPD-I, BPD-II or There are few controlled direct interview family studies that MDD, (2) age between 18 and 65 years, (3) ability to speak sufficient used the most recent DSM-IV nomenclature to evaluate the French or English to complete the diagnostic interview, and (4) having a 1Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland and 2Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA. Correspondence: Dr CL Vandeleur, Department of Psychiatry, University Hospital of Lausanne, Site de Cery, Prilly 1008, Switzerland. E-mail: [email protected] Received 9 April 2013; revised 28 July 2013; accepted 22 August 2013; published online 15 October 2013 Specificity of psychosis, mania and major depression CL Vandeleur et al 210 Table 1. Demographic characteristics and comorbidity in probands and relatives by proband disorder subgroup Proband disorder Schizoaffective Bipolar I Bipolar II MDD Controla Statistic P-value Probands (N ¼ 403) 62 100 23 108 110 — — 2 Sex (% female) 38.7 60.0 39.1 49.1 45.5 X4 ¼ 8.9 NS Mean age (s.d.) 36.8 (10.8) 41.5 (11.8) 42.4 (10.7) 41.1 (11.5) 38.8 (12.9) F4 ¼ 2.3 NS Age range (years) 19.2–61.6 20.4–66.7 24.0–60.7 19.4–68.0 17.2–68.0 — — b Mean SES (s.d.) 3.0 (1.1) 3.5 (1.0) 3.0 (0.9) 2.9 (1.1) 3.3 (1.1) F4 ¼ 4.6 o0.01 c 2 Anxiety Dx (%) 45.2 29.0 47.8 55.6 9.1 X4 ¼ 59.1 o0.001 d 2 Alcohol Dx (%) 43.6 35.0 52.2 45.4 6.4 X4 ¼ 50.4 o0.001 e 2 Drug Dx (%) 40.3 21.0 43.5 28.7 7.3 X4 ¼ 32.9 o0.001 Relatives (N ¼ 1734) 251 432 98 460 493 — — 2 Sex (% female) 52.2 50.2 56.1 53.0 50.7 X4 ¼ 1.7 NS Mean age (s.d) 48.5 (17.4) 50.7 (18.4) 50.5 (19.2) 50.4 (18.1) 50.2 (18.3) F4 ¼ 0.7 NS Age range (years) 18.0–91.0 18.0–95.0 19.0–86.7 18.0–97.0 18.0–90.0 — — 2 Interviewed (%) 51.7 50.1 46.4 38.9 35.9 X4 ¼ 25.5 o0.001 Abbreviations: MDD, major depressive disorder; NS, not significant; SES, socio-economic status. aIncludes probands with subthreshold bipolar disorder, cyclothymia, hyperthymic personality, subthreshold depression, dysthymia without MDD, depressive personality without MDD, anxiety disorders and alcohol or drug abuse/dependence when recruited in the orthopedic departments. bSocio-economic status of the family: a value of 3 represents an SES of III (middle class) on the Hollingshead scale. cAnxiety disorders, including generalized anxiety disorder, agoraphobia, panic disorder and/or social phobia. dAlcohol abuse/ dependence. eDrug abuse/dependence, including the following substances: marijuana, cocaine, narcotics, solvents, hallucinogens, stimulants and sedatives. first-degree adult relative who agrees to participate in the study. Diagnoses information on non-interviewed relatives. The validity of the French of SAF, BPD-I, BPD-II and MDD were assigned according to the DSM-IV, with version of the FH-RDC has previously been established through the the exception of criterion A for SAF regarding the concomitant manifesta- assessment of agreement between diagnoses relying on direct interviews tion of a major mood disorder during an uninterrupted period of SZA. and family history reports for a series of diagnoses in adults26,27 and A sample of inpatients (10%) and outpatients (90%) were recruited from children.28 These analyses as well as similar analyses for mood diagnosis the orthopedic departments of hospitals in Lausanne and Geneva during have also allowed us to lower the diagnostic thresholds for disorders in the same time period to serve as a comparison or control group (n ¼ 110). order to minimize information bias due to the low sensitivity of the family Inclusion and exclusion criteria were the same as for the mood disorder history method. DSM-IV diagnoses were assigned according to a best- probands with the exception of the lack of a history of a mood or psychotic estimate procedure,29 which was based on review of information from disorder. Non-psychiatric medical controls were included in order to direct interviews, family history reports and medical records for subjects control for the inpatient setting of proband recruitment. Orthopedic who had been treated for a psychiatric disorder. The diagnoses of non- settings were selected for recruitment of controls because of their similar interviewed family members were based on all available family history age composition, and orthopedic conditions have not been shown to be reports based on the FH-RDC. differentially associated with mood disorders whereas disorders from most other specialties have high rates of comorbidity with mood disorders.