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
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…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 1,945 participants or records.
Read the paper
Related studies
- A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials Evaluating the Evidence Base of Melatonin, Light Exposure, Exercise, and Complementary and Alternative Medicine for Patients with Insomnia Disorder
- Use of Melatonin and/on Ramelteon for the Treatment of Insomnia in Older Adults: A Systematic Review and Meta-Analysis
- Influence of evening light exposure on polysomnographically assessed night-time sleep: A systematic review with meta-analysis
- Use of melatonin in children and adolescents with idiopathic chronic insomnia: a systematic review, meta-analysis, and clinical recommendation
- Significant potential of melatonin therapy in Parkinson’s disease – a meta-analysis of randomized controlled trials
- Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.