Remission of maternal depression has a positive effect on both mothers and their children, whereas mothers who remain depressed may increase the rates of their children's disorders. These findings support the importance of vigorous treatment for depressed mothers in primary care or psychiatric clinics and suggest the utility of evaluating the children, especially children whose mothers continue to be depressed.

The association between parental MDD and child diagnosis is moderated by grandparental MDD status. The rates of psychopathology are highest in grandchildren of parents and grandparents with a moderately to severely impairing depression. Anxiety disorders are the early sign of psychopathology in the young grandchildren. Early interventions in the offspring of 2 generations affected with moderately to severely impairing MDD seem warranted. This familial group may be the target for neuroimaging, genetic, and other biological studies.

The offspring of depressed parents remain at high risk for depression, morbidity, and mortality that persists into their middle years. While adolescence is the major period of onset for major depression in both risk groups, it is the offspring with family history who go on to have recurrences and a poor outcome as they mature. In the era of personalized medicine, until a more biologically based understanding of individual risk is found, a simple family history assessment of major depression as part of clinical care can be a predictor of individuals at long-term risk.

Adolescents involved with foster care have a higher prevalence of psychiatric symptoms and drug use disorders than those never placed in foster care. Additionally, the results of this study suggest that they may be at elevated risk for suicide attempts.

IMPORTANCE 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. OBJECTIVE To examine the familial aggregation of psychiatric disorder and functioning in grandchildren by their biological parents’ and grandparents’ depression status. DESIGN, SETTING, AND PARTICIPANTS 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). MAIN OUTCOMES AND MEASURES 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. RESULTS 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; P = .03), any disruptive disorder (HR, 1.70; 95% CI, 1.05–2.75; P = .03), substance dependence (HR, 2.96; 95% CI, 1.24–7.08; P = .01), any suicidal ideation or gesture (HR, 2.44; 95% CI, 1.28–4.66; P = .007), and poor functioning (F = 38.25, P < .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 (F = 6.31, P = .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. CONCLUSIONS AND RELEVANCE 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 depress...