Stressful life events and relapse of psychosis: analysis of causal association in a 2-year prospective observational cohort of individuals with first-episode psychosis in the UK

Background: Despite accumulating evidence of an association between stressful life events and psychosis relapse, the extent to which this is a causal relationship remains unclear. We aimed to examine the association between exposure to, and number of, stressful life events after initial psychosis onset and psychosis relapse. Methods: In this 2-year prospective observational study, we recruited individuals with first-episode psychosis, aged 18-65 years, who presented to psychiatric services in south London, UK. Participants were assessed via interview, with additional data obtained from electronic clinical records. Stressful life events were recorded at psychosis onset and during the 2-year follow-up using a brief questionnaire that assesses 12 major life events. Psychosis relapse was defined as inpatient admission because of symptom exacerbation within 2 years from psychosis onset. We examined the time to first psychosis relapse and the number and length of relapses using survival and binomial regression analyses. We used fixed-effects regression and cross-lagged path analysis to examine the directionality of effects and control for unmeasured confounders. Findings: Between April 12, 2002, and July 26, 2013, 256 individuals with first-episode psychosis (100 [39%] female and 156 [61%] male; 16 [6%] Asian, 140 [55%] Black African or Caribbean, 86 [34%] White, and 14 [6%] mixed ethnicity) were recruited, with a mean age of onset of psychosis of 28·06 years (SD 8·03; range 17·21-56·03). 93 (36%) participants experienced at least one relapse during the 2-year follow-up. 253 individuals had all relevant data and were included in analyses. For people exposed to stressful life events after the onset of psychosis, the adjusted hazard (hazard ratio [HR] 2·60, 95% CI 1·63-4·16, p<0·0001), incidence (incidence rate ratio [IRR] 1·87, 1·24-2·80, p=0·0026), and length (IRR 2·53, 1·40-4·67, p=0·0011) of relapse were greater than for those who were unexposed. These relationships were dose dependent (HR 1·36; 1·09-1·69, p=0·0054; incidence IRR 1·26, 1·02-1·53, p=0·023; length IRR 1·52, 1·12-2·12, p=0·0028). Adjusted fixed-effects models showed a higher (odds ratio [OR] 3·82, 1·82-8·00, p=0·0004) and dose-dependent (OR 1·62, 1·18-2·21, p=0·0028) risk of relapse when stressful life events preceded relapse compared with the period when they did not. Cross-lagged path analysis confirmed an effect of stressful life events on the number of subsequent relapses (β=0·66, p=0·0055) that was dose dependent (β=0·29, p=0·029), but it did not show an effect of relapses on subsequent risk or number of stressful life events. Interpretation: These results provide converging evidence of a causal effect of stressful life events on the risk of relapse in psychosis. They suggest that there is a need to develop interventions at the individual and health-service level that could mitigate the harmful effects of stressful life events. Funding: National Institute for Health Research, UK.