First Episode of Depression in Children at Low and High Familial Risk for Depression DOUGLAS E. WILLIAMSON, PH.D., BORIS BIRMAHER, M.D., DAVID A. AXELSON, M.D., NEAL D. RYAN, M.D., AND RONALD E. DAHL, M.D. ABSTRACT Objective: To examine the development of first-onset major depressive disorder (MDD) in children at high and low familial risk for depression in a prospective study. Method: High-risk children (n = 76) who were free of any lifetime affective disorder and had at least one first-degree and one second-degree relative with a lifetime history of childhood- onset, recurrent, bipolar, or psychotic depression were included. Low-risk children (n = 63) were included if they were free of any lifetime psychiatric disorder and had no first-degree relatives and fewer than 20% of their second-degree relatives with a lifetime affective disorder. Children and their parents were assessed in a prospective design using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version (K-SADS-E). The average interval between follow-up interviews was 18 months, and the average follow-up period was 6 years. Results: High-risk children had approximately a threefold increased risk of developing first-onset MDD compared with low-risk children (odds ratio = 3.21). The average age of new-onset MDD was 14.0 ± 2.9 years (range 9.5–19.5 years). Above and beyond the familial loading for MDD, mother’s lifetime anxiety disorder (odds ratio = 2.84) and lifetime behavioral disorder (odds ratio = 3.25) in the child significantly added to the risk of developing a first-onset MDD. Conclusions: Having high familial loading for affective disorders, a mother with and anxiety disorder, and a behavioral disorder in the child all significantly contributed to the risk of developing depression. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(3):291–297. Key Words: high risk, depression, childhood, family genetics. Family studies of depressed adults (Gershon et al., 1976, 1982; Tsuang et al., 1985a,b Weissman et al., 1984b), adolescents (Kutcher and Marton, 1991; Strober, 1983, 1984; Williamson et al., 1995), and children (Kovacs et al., 1997; Puig-Antich et al., 1989; Todd et al., 1993) have all shown that depression ag- gregates in families. Interestingly, an inverse relation- ship between age at onset of initial depression and the degree of familial loading has been observed (Brodaty et al., 1991; Maier et al., 1991; Weissman et al., 1984b; Williamson et al., 1995), which has led some investigators to wonder whether child-onset major de- pressive disorder (MDD) represents the most genetic form of the disorder (Kovacs et al., 1997; Todd et al., 1993). Supporting evidence for the familial transmission of depression in children and adolescents has been re- ported from studies examining the offspring of de- pressed parents, primarily mothers (Beardslee et al., 1988; Grigoroiu-Serbanescu et al., 1991; Hammen et al., 1991; Klein et al., 1988; Orvaschel et al., 1988; Radke-Yarrow et al., 1992; Sylvester et al., 1987; Weissman et al., 1984a, 1987; Welner and Rice, 1988). Together, these studies have shown an increased risk for depression in the children of depressed parents compared to the children of parents with nonmood psychiatric disorders and normal controls. In one 10- year longitudinal study, Weissman et al. (1997) re- ported that among the children of depressed parents, the risk for depression peaked between 15 and 20 years of age, paralleling the age-at-onset estimates reported from the Epidemiological Catchment Area (ECA) Accepted September 23, 2003. From the Department of Child and Adolescent Psychiatry, University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pitts- burgh. This research was supported by NIMH grants P01-MH41712 (Dr. Ryan) and K01-MH001957 (Dr. Williamson). Correspondence to Dr. Williamson, Department of Psychiatry, University of Pittsburgh School of Medicine, Room E-723, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: WilliamsonDE@ upmc.edu. 0890-8567/04/4303–0291©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000103179.91435.b6 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004 291