Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression.

OBJECTIVE The association between stressful life events and the onset of major depression decreases as the number of previous depressive episodes increases. How do genetic risk factors for major depression impact on this "kindling" phenomenon? In particular, do those at high genetic risk exhibit an increase in the speed of kindling, or are they "prekindled"? METHOD Using discrete-time survival analysis, the authors examined the interaction between genetic risk, number of previous depressive episodes, and life event exposure in the prediction of episodes of major depression in female-female twin pairs from a population-based registry. The twins were interviewed four times over a 9-year period, producing 92,521 person-months of exposure. RESULTS The decline in the association between stressful life events and risk for major depression as the number of previous depressive episodes increased was strongest in those at low genetic risk and was weak to absent in those at high genetic risk. In the absence of previous depressive episodes, those at high genetic risk frequently experienced depressive episodes without major environmental stressors. CONCLUSIONS Genetic risk factors for depression produce a "prekindling" effect rather than increase the speed of kindling. The "kindled" state, wherein depressive episodes occur with little provocation, may be reached by two pathways: many previous depressive episodes, perhaps driven by multiple adversities, and high genetic risk.