Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review

Ketamine, including its enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine), has demonstrated rapid antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD), yet clinical responses vary widely, highlighting the need to identify mechanisms underlying treatment efficacy and related potential predictors. Growing evidence suggests that alterations in sleep and circadian rhythms may contribute to the antidepressant effects of ketamine and predict clinical outcomes. Therefore, this systematic review aimed to synthesize studies evaluating the association of ketamine treatment with measures of sleep and circadian rhythmicity in patients with MDD and BD, specifically assessing whether these parameters mediate or predict treatment outcomes. A systematic search in PubMed, Embase, PsychInfo, and Web of Science identified 830 records, from which 26 studies (N = 1694) met the inclusion criteria. Findings indicate that ketamine is associated with favourable effects on subjective sleep quality and provide preliminary evidence that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Studies also suggest beneficial effects on objective sleep and circadian rhythmicity, but this finding should be interpreted with caution given the limited number of published articles. Future research should clarify the impact of ketamine on objective circadian measures and explore its potential synergy with chronotherapeutic interventions for mood disorders.