Efficacy and safety of each class of sleep medication for major depressive disorder with insomnia symptoms: A systematic review and meta-analysis of double-blind randomized controlled trials

source extracted confidence: high 2026-04-09
#humans #sleep-initiation-and-maintenance-disorders #major-depressive-disorder #randomized-controlled-trials-as-topic #antidepressive-agents

Efficacy and safety of each class of sleep medication for major depressive disorder with insomnia symptoms: A systematic review and meta-analysis of double-blind randomized controlled trials

Maruki et al., 2025 | Psychiatry Clin Neurosci | Meta Analysis

Citation

Maruki Taku, Takeshima Masahiro, ... Takaesu Yoshikazu. Efficacy and safety of each class of sleep medication for major depressive disorder with insomnia symptoms: A systematic review and meta-analysis of double-blind randomized controlled trials. Psychiatry Clin Neurosci. 2025-Jun;79(6):306-318. doi:10.1111/pcn.13811

Abstract

Combination therapy with antidepressants and sleep medications is a promising candidate treatment for major depressive disorder (MDD) with insomnia. This systematic review and meta-analysis examined the efficacy and safety of combination therapy with antidepressants and sleep medication for treating MDD with insomnia compared to antidepressant monotherapy by sleep medication class (benzodiazepine, Z-drug, melatonin receptor agonist, and orexin receptor antagonist). This study was preregistered with PROSPERO (CRD42025636571). PubMed, CENTRAL, and Embase were searched for double-blind randomized controlled trials published until June 2024, resulting in eight eligible studies (1945 participants; eszopiclone = 4, zolpidem = 2, triazolam = 1, ramelteon = 1). Meta-analyses were performed based on six trials of Z-drugs. Compared with antidepressant monotherapy, combination therapy with antidepressants and Z-drugs resulted in higher remission rates from depressive symptoms (risk ratio: 1.25, 95% confidence interval [CI]: 1.08-1.45, P = 0.003), greater improvement in depressive symptoms (standardized mean difference [SMD]: 0.17, 95% CI: 0.01-0.33, P = 0.04) and insomnia symptoms (SMD: 0.43, 95% CI: 0.28-0.59, P < 0.001) in the short-term (within 12 weeks), with no difference in safety outcomes except for dizziness. Combination therapy with antidepressants and Z-drugs may be more useful for MDD with insomnia symptoms than antidepressant monotherapy in the short term. However, this study did not evaluate the benefits and harms of long-term adjunctive Z-drug therapy. Further long-term studies are needed to draw definitive conclusions regarding the efficacy and safety of combination therapy with antidepressants and Z-drugs. Moreover, further research is warranted to assess whether the findings of this study are applicable to other sleep medication classes.

Key Findings

Moreover, further research is warranted to assess whether the findings of this study are applicable to other sleep medication classes.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size 1
Age Range See abstract
Condition insomnia

MeSH Terms

  • Humans
  • Sleep Initiation and Maintenance Disorders
  • Major Depressive Disorder
  • Randomized Controlled Trials as Topic
  • Antidepressive Agents
  • Drug Therapy, Combination
  • Double-Blind Method
  • Hypnotics and Sedatives
  • Sleep Aids, Pharmaceutical
  • Benzodiazepines
  • Orexin Receptor Antagonists

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Systematic Review, Meta-Analysis
  • Vertical: melatonin

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09