Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis

作者：Spyridon Siafis, Hui Wu, Dongfang Wang, Angelika Burschinski, Nobuyuki Nomura, Hiroyoshi Takeuchi, Johannes Schneider‐Thoma, John M. Davis, Stefan Leucht · 发表于：Molecular Psychiatry · 年份：2023 · DOI：10.1038/s41380-023-02203-y · 被引用次数：144 · 研究领域：Schizophrenia research and treatment、Electroconvulsive Therapy Studies、Pharmaceutical Practices and Patient Outcomes

Abstract Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D 2 receptor (D 2 R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3–26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses....