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BACKGROUND: Preliminary evidence suggests evening chronotype relates to poorer efficacy of selective-serotonin reuptake inhibitors (SSRIs). It is unknown whether this is specific to particular medications, self-rated chronotype, or efficacy. METHODS: In the Australian Genetics of Depression Study (N=15,108; 75% female; 18-90 years; 68% with ≥1 other lifetime diagnosis), a survey assessed experiences with 10 antidepressants and the reduced Morningness-Evening Questionnaire; a chronotype polygenic score (PGS) was calculated. Age- and sex-adjusted regression models (Bonferroni-corrected) estimated associations among antidepressants variables ("how well the antidepressant worked" [efficacy], duration of symptom improvement, side effects, discontinuation due to side effects) and self-rated and genetic chronotypes. RESULTS: The chronotype-PGS explained 4% of the variance in self-rated chronotype (r=0.21). Higher self-rated eveningness was associated with poorer efficacy of escitalopram (OR=1.04; 95% CI 1.02-1.06; p=0.000035), fluoxetine (OR=1.03; 95% CI 1.01-1.05; p=0.001), sertraline (OR=1.02; 95% CI 1.01-1.04; p=0.0008), and desvenlafaxine (OR=1.03; 95% CI 1.01-1.05; p=0.004), and a profile of increased side effects (80% of those recorded; ORs=0.93-0.98), with 'difficulty getting to sleep' most likely. Self-rated chronotype was not related to duration of improvement or discontinuation due to side effects. The chronotype-PGS was only associated with suicidal thoughts and attempted suicide (self-reported). While our measures are imperfect, and not of circadian phase under controlled conditions, the model coefficients suggest that dysregulation of phenotypic chronotype relative to its genetic proxy was driving relationships with antidepressant outcomes. CONCLUSIONS: The idea that variation in circadian factors influences antidepressant responses was supported and encourages exploration of circadian mechanisms of depressive disorders and antidepressant treatments.

Original publication




Journal article


Biol Psychiatry

Publication Date



antidepressants, circadian, depressive disorders, diurnal, pharmacotherapy, treatment