Comparative efficacy and acceptability of treatment strategies for antipsychotic-induced akathisia: a systematic review and network meta-analysis

Background: Antipsychotics are the treatment of choice for schizophrenia, but they often induce akathisia. However, comparative efficacy of treatment strategies for akathisia remains unclear. Design: We performed a systematic review and network meta-analyses (PROSPERO CRD42023450720). We searched multiple databases on 24th July 2023. We included randomized clinical trials comparing one or more treatment strategies for antipsychotic-induced akathisia against each other or control conditions. We included adults with schizophrenia or other psychiatric disorders treated with antipsychotics. The primary outcome was akathisia severity at posttreatment. Secondary outcomes included akathisia response, all-cause dropout, psychotic symptoms, and long-term akathisia severity. We synthesized data in random effects frequentist network meta-analyses and assessed confidence in the evidence using CINeMA. Results: We identified 19 trials with 661 randomized participants (mean age 35.9 [standard deviation 12.0]; 36.7 % [195 of 532] women). No trials examined dose-reduction or switching of antipsychotics. Findings suggested 5-HT2A antagonists (k=6, n=108; standardized mean difference [SMD] -1.07 [95% confidence interval, -1.42; -0.71]) and beta-blockers (k=8, n=105; SMD -0.46 [-0.85; -0.07]) may improve akathisia severity, but confidence in the evidence was deemed low. We also found that benzodiazepines (k=2, n=13; SMD -1.62 [-2.64; -0.59]) and vitamin B6 (k=3, n=67; SMD -0.99 [-1.49; -0.50]) might also be beneficial, but confidence in the evidence was very low. Analyses of secondary outcomes did not provide additional insights. Conclusions: Our findings suggest that 5-HT2A antagonists, beta blockers, and with a lesser certainty, benzodiazepines and vitamin B6 might improve akathisia. These conclusions are extremely preliminary and further trials are needed. ### Competing Interest Statement YF has received consultancy fee from Panasonic and lecture fee from Otsuka outside the submitted work. YT has received research grant from Kobayashi Pharmaceutical outside the submitted work. SL has received honoraria as a consultant and/or advisor and/or for lectures from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharp and Dohme, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, Mitsubishi. The other authors declare no interests. ### Clinical Protocols ### Funding Statement No financial support was used. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used only openly available data. Data and code will be shared upon reasonable request to the corresponding author. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The study used only openly available data. Data and code will be shared upon reasonable request to the corresponding author.