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...

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Mental health care is ripe for innovation. Less than a third of people with mental health disorders receive treatment, and even a smaller proportion receive adequate care. 1 The private sector has taken notice of this economic mismatch (high demand with inadequate supply) and is aggressively pursuing mental health and wellness as an investment opportunity. In 2019 alone, venture capital (VC) companies invested a recordbreaking $637 million in more than 60 different mental health-oriented companies, which is more than 22.8 times the investment in 2013. 2 Calm, a smartphone application focused on audio-guided meditation, reached a milestone valuation of more than $1 billion, making it the first "unicorn" mental health-oriented start-up. This rapid rise in investment in the mental health and wellness space brings new challenges related to defining, quantifying, and assessing products and services that had previously resided within traditional health care. In this Viewpoint, we review the largest VC-backed mental health companies and propose potential concerns and benefits associated with the rise of for-profit start-ups.