Efficacy and tolerability of Z-drug adjunction to antidepressant treatment for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials

  • Taro KishiEmail author
  • Shinji Matsunaga
  • Nakao Iwata
Original Paper


No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of Z-drug adjunctive therapy in antidepressant-treated major depressive disorder (MDD) patients. Randomized, placebo-, or antidepressant-alone-controlled trials of Z-drugs in MDD patients were included. The primary outcome measures for efficacy and safety were remission rate and all-cause discontinuation, respectively. The secondary outcome measures were response rate, Hamilton Depression Rating Scale (HAMD) total score improvement, discontinuation due to inefficacy and adverse events, and individual adverse effects. Risk ratio (RR), number needed to treat/harm (NNT/NNH), 95 % confidence intervals, and standardized mean difference (SMD) were calculated. We identified six studies [antidepressants were selective serotonin reuptake inhibitors and venlafaxine, mean duration of study was 10.5 weeks, mean age of patients (mean ± standard deviation) was 44.4 ± 11.8 years old, total n = 2089, eszopiclone + antidepressants = 642, placebo + antidepressants = 930, antidepressants alone = 112, and zolpidem + antidepressants = 405]. Pooled Z-drug + antidepressants was superior to placebo + antidepressants regarding the remission rate (RR = 0.85, NNT = 10). Although pooled Z-drug + antidepressants was also superior to placebo + antidepressants/antidepressants alone regarding HAMD score improvement (SMD = −0.23), there was not significant difference in response rate and discontinuation due to inefficacy between groups. There was no difference in all-cause discontinuation between groups. Although there was also no difference in discontinuation due to adverse events between groups, pooled Z-drug + antidepressants was associated with a higher incidence of at least one adverse event (RR = 1.09, NNH = 20) and dizziness (RR = 1.76, NNH = 25) compared with the placebo + antidepressants/antidepressants alone. In conclusion, Z-drugs + antidepressants improves the treatment efficacy for MDD compared with the placebo + antidepressants/antidepressants alone. However, the therapy requires close monitoring of adverse events, particularly dizziness.


Z-drugs Eszopiclone Zolpidem Major depressive disorder Meta-analysis Systematic review 


Author contribution

Drs. Kishi and Matsunaga had complete access to all the data used in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design, analysis and interpretation of data, data acquisition, and statistical analysis were performed by Dr. Kishi. The manuscript was written by Drs. Kishi, Matsunaga, and Iwata. Dr. Iwata supervised the review.

Compliance with ethical standards

Conflicts of interest

Drs. Kishi, Matsunaga, and Iwata declare that they have no direct conflicts of interest relevant to this study. No grant support or other sources of funding were used to conduct this study or prepare this manuscript. Dr. Kishi has received speaker’s honoraria from Abbvie, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Mochida, Shionogi, Tanabe-Mitsubishi, Tsumura, Novartis, and Pfizer and has a Fujita Health University School of Medicine research grant and Grant-in-Aid for Young Scientists (B). Dr. Matsunaga has received speaker’s honoraria from Eisai, Janssen, Novartis, Daiichi Sankyo, Ono, Eli Lilly, Takeda, and Otsuka and has a Fujita Health University School of Medicine research grant and Grant-in-Aid for Young Scientists (B). Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and Pfizer and had research grants from Dainippon Sumitomo, GlaxoSmithKline, Tanabe-Mitsubishi, and Otsuka.

Supplementary material

406_2016_706_MOESM1_ESM.docx (294 kb)
Supplementary material 1 (DOCX 293 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of PsychiatryFujita Health University School of MedicineToyoakeJapan

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