A 30-Year Study of 3 Generations at High Risk and Low Risk for Depression
Authors: Myrna M. Weissman, Obianuju O. Berry, Virginia Warner, Marc J. Gameroff, Jamie Skipper, Ardesheer Talati, Daniel J. Pilowsky, Priya Wickramaratne
Journal: JAMA Psychiatry (2016)

<h3>Importance</h3> The increased risk of major depression in the offspring of depressed parents is well known. Whether the risk is transmitted beyond 2 generations is less well known. To our knowledge, no published study with direct interviews of family members and the generations in the age of risk for depression has evaluated beyond 2 generations. This information is important for detecting individuals at highest risk who may benefit from early intervention. <h3>Objective</h3> To examine the familial aggregation of psychiatric disorder and functioning in grandchildren by their biological parents' and grandparents' depression status. <h3>Design, Setting, and Participants</h3> Longitudinal retrospective cohort family study of 251 grandchildren (generation 3 [mean age, 18 years]) interviewed a mean of 2.0 times and their biological parents (generation 2) interviewed a mean of 4.6 times and grandparents (generation 1) interviewed up to 30 years. The study dates were January 1982 (wave 1) to June 2015 (wave 6). <h3>Main Outcomes and Measures</h3> Cumulative rates of psychiatric disorders and functioning collected for all generations by clinically trained interviewers and best-estimate diagnosis made blind to diagnoses in members of previous generations. <h3>Results</h3> There were 91 families (G1) in the original sample, of whom 77 were eligible for inclusion (had a grandchild older than 5 years), and 80.5% (62 of 77) participated in the study. When first examining only 2 generations, the biological children (generation 3) of depressed compared with nondepressed parents (generation 2) had 2-fold increased risk for major depressive disorder (MDD) (hazard ratio [HR], 2.02; 95% CI, 1.08-3.79;<i>P</i> = .03), any disruptive disorder (HR, 1.70; 95% CI, 1.05-2.75;<i>P</i> = .03), substance dependence (HR, 2.96; 95% CI, 1.24-7.08;<i>P</i> = .01), any suicidal ideation or gesture (HR, 2.44; 95% CI, 1.28-4.66;<i>P</i> = .007), and poor functioning (<i>F</i> = 38.25,<i>P</i> &lt; .001). When 3 generations were examined stratified by parental and grandparental depression status, association of a parent's MDD on the grandchild's MDD but not other disorders varied with the grandparent's depression status: grandchildren with both a depressed parent and grandparent (n = 38) were at highest risk for MDD. Among grandchildren without a depressed grandparent, those with (n = 14) vs without (n = 74) a depressed parent had overall poorer functioning (<i>F</i> = 6.31,<i>P</i> = .01) but not higher rates of any of the disorders. Potential confounding variables did not have a meaningful effect on the association between grandchild outcomes and parental or grandparental depression. <h3>Conclusions and Relevance</h3> In this study, biological offspring with 2 previous generations affected with major depression were at highest risk for major depression, suggesting the potential value of determining family history of depression in children and adolescents beyond 2 generations. Early intervention in offspring of 2 generations affected with moderate to severely impairing MDD seems warranted. The specificity of the transmission of depression across 3 generations may make this group a homogeneous sample for biological marker studies.