2026 ECNP Congress

PS03-3253

The efficacy of mirtazapine on sleep is independent of dose: a systematic review and meta-analysis

Anastasios Stefanou — E. Pinioti, A. Nousios, D. Georgiou, A. Lappas, V.P. Bozikas, M. Samara · Aristotle University of Thessaloniki, 2nd Department of Psychiatry - School of Medicine, Thessaloniki, Greece

2026 ECNP Congress

Background

Mirtazapine is frequently prescribed off label to treat sleep disturbances, based on its pharmacodynamic properties, particularly its potent H1 receptor antagonism (Hassanein et al., 2024; Liaskopoulos et al., 2025). Its sedative effect is commonly thought to be pronounced at lower doses (Zemach et al., 2026), although this practice lacks meta-analytic evidence support. The aim of this systematic review and meta-analysis was to evaluate the effects of mirtazapine on sleep, with particular focus on dose-response.

Methods

We systematically searched MEDLINE, Embase, PsycINFO, Cochrane CENTRAL, WHO ICTRP, ClinicalTrials.gov until April 2026 for randomized controlled trials (RCT) comparing mirtazapine with placebo. We included studies irrespective of diagnoses. The outcomes included subjective total sleep time and sleep quality, as measures of efficacy. Study selection and data extraction were conducted independently by at least two reviewers. Risk of bias was assessed with Cochrane’s risk of bias tool. Analyses employed random-effects models, calculating weighted mean differences (MD) for continuous outcomes, and standardised mean differences (SMD) when scales varied, along with the respective 95% confidence intervals (95% CI). Heterogeneity was assessed with inspection of forest plots and quantified with the use of the I2-statistic. Subgroup analyses per diagnosis examined heterogeneity, while meta-regression or a subgroup analysis (depending on the number of studies per outcome) assessed dose-related effects of mirtazapine.

Results

We included 12 RCTs, with a total of 1,083 participants randomized to receive either mirtazapine or placebo. Mean age of participants ranged from 24.4 to 72.4 (mean of means was 40.5 years) and 57.8% were female. Mirtazapine showed robust efficacy on sleep quantity (subjective total sleep time: MD=49.12 minutes, 95% CI: 30.42; 67.82) and quality (SMD=0.46, 95% CI: 0.16; 0.76) compared to placebo. The effects of mirtazapine were consistent across dosing regimens for both sleep outcomes. Heterogeneity was considerable only in the outcome of sleep quality, largely driven by outlier studies with diagnoses such as Alzheimer’s Disease, Substance Use Disorder and PTSD.

Conclusions

Mirtazapine shows consistent efficacy in improving sleep across diverse diagnoses with clinically significant effect sizes, as evidenced by an increase in subjective total sleep time by approximately 50 minutes. Contrary to existing assumptions that lower doses produce greater hypnotic effects, our meta-analysis showed consistent efficacy across dosing regimens, a finding which supports flexible approaches depending on overall treatment goals. When sedation is the primary objective, lower doses are preferable to minimize adverse effects. However, in the presence of comorbid depressive symptoms requiring higher doses, such an escalation may be considered without compromising sleep benefits. Limitations of our research include the use of subjective measurements, as well as the small number of studies, although the total sample exceeded 1,000, a standard threshold considered to stabilize effect estimates in meta-analyses of RCTs (Trikalinos et al., 2004). Overall, these findings support mirtazapine as a promising option for sleep disturbances, although further research is required, especially including trials that compare mirtazapine head-to-head with other hypnotics.

References

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