Factors Associated with Successful Antipsychotic Dose Reduction in Schizophrenia: A Systematic Review of Prospective Clinical Trials and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: The authors conducted a systematic review and meta-analysis to identify predictors associated with successful antipsychotic dose reduction in schizophrenia. Methods: We searched MEDLINE and Embase on Mar 31, 2019 for prospective clinical trials and randomized controlled trials (RCTs) examining antipsychotic dose reduction in schizophrenia. Findings: A total of 37 trials were identified. Only eight studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Among 24 studies that evaluated relapse or symptom changes, 20 studies (83·3%) met the criteria for successful dose reduction. Study duration of 40 years of age, duration of illness of >10 years, and post-reduction chlorpromazine equivalent (CPZE) dose of >200 mg/day were associated with successful dose reduction. Clinical deterioration was mostly re-stabilized by increasing the dose back to the baseline (N=7/8, 87·5%). A meta-analysis of 18 RCTs demonstrated that relapse rate was significantly higher in the reduction than the maintenance group (risk ratio [RR] 1·96 [95% CI 1·23-3·12]) whereas neurocognition significantly improved (standardized mean difference [SMD] 0·69 [0·25-1·12]). Subgroup analysis indicated that only post-reduction CPZE dose of ≤200 mg/day was associated with an increased risk of relapse (RR 2·79 [1·29-6·03]). Interpretation: Clinicians should consider the risk of relapse in the long run among younger patients with a relatively short illness duration when reducing the doses of antipsychotics, and the final doses may be kept higher than CPZE 200 mg/day. Further studies, especially with SGAs, are warranted to elucidate optimal strategies for successful antipsychotic dose reduction in schizophrenia. Funding Statement: The authors state: There was no funding source for this study. Declaration of Interests: HT has received a grant from Eli Lilly; manuscript or speaker’s fees from Dainippon Sumitomo Pharma, Otsuka Pharmaceutical, Wiley Japan and Yoshitomi Yakuhin. ST has no competing interests to disclose. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, and Meiji-Seika Pharmaceutical; speaker’s honoraria from Otsuka Pharmaceutical, Eli Lilly, Pfizer, Yoshitomi Yakuhin, DainipponSumitomo Pharma, Meiji-Seika Pharma, and MSD; and advisory panel payments from Dainippon-Sumitomo Pharma. TS has received manuscript or speaker’s fees from Astellas, Dainippon Sumitomo Pharma, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Novartis, Otsuka Pharmaceutical, Shionogi, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Mochida Pharmaceutical, and Meiji Seika Pharma. MM has received has received speaker’s honoraria from Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin; and grants from Daiichi Sankyo, Eisai, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi, and Tsumura. HTak has received fellowship grants from Astellas Foundation for Research on Metabolic Disorders, the Canadian Institutes of Health Research (CIHR), Centre for Addiction and Mental Health (CAMH) Foundation, and the Japanese Society of Clinical Neuropsychopharmacology, speaker’s honoraria from Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomiyakuhin, and manuscript fees from Sumitomo Dainippon Pharma. We declare no financial relationships to disclose related to this study. Ethics Approval Statement: This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.