Effects of Agomelatine on Sleep Across Populations: A Systematic Review and Meta-Analysis

Agomelatine, a melatoninergic antidepressant, is often prescribed to improve sleep disturbance, though meta-analytic evidence is currently lacking. This systematic review and meta-analysis assessed its efficacy and tolerability in sleep outcomes compared to placebo. We systematically searched clinical trial registries (Cochrane Central, WHO ICTRP, ClinicalTrials.gov) and databases (MEDLINE, Embase, APA PsycINFO) up to February 16, 2025, for Randomised Controlled Trials (RCTs) comparing agomelatine with placebo that reported sleep-related outcomes. Analyses were conducted using a random-effects model on an intention-to-treat basis. Risk ratios (RR) were used for dichotomous outcomes, weighted mean differences (WMD) for continuous outcomes, and Hedge's adjusted g (SMD) when different scales were used. Primary outcomes included subjective and objective total sleep time, subjective sleep quality, and treatment-emergent somnolence and insomnia. Subgroup and sensitivity analyses explored heterogeneity and assessed robustness. Twenty-five RCTs with 6812 participants were included. No significant effect was found for objective total sleep time (MD = -15.73 min, 95% CI: -49.68; 18.22), while subjective sleep quality improved more with agomelatine than placebo (SMD = 0.31, 95% CI: 0.21; 0.40). Agomelatine was associated with fewer incidents of insomnia (RR = 0.59, 95% CI: 0.39; 0.90) but more incidents of somnolence (RR = 1.34, 95% CI: 1.02; 1.75). Agomelatine was found to cause marginally more adverse effects than placebo (RR = 1.05, 95% CI: 1.00; 1.11). Overall, agomelatine appears to slightly improve sleep quality and is well-tolerated and safe, although the limited data for many outcomes warrant cautious interpretation.