Importance The doses of antipsychotic drugs needed for relapse prevention in schizophrenia is a debated issue. Objective To examine dose-response findings in a meta-analysis of randomized clinical trials. Data Sources Studies were identified through the Cochrane Schizophrenia Group's Study-Based Register of Trials (March 9, 2020), PubMed (January 1, 2021), and previous reviews. First authors and/or pharmaceutical companies were contacted for additional information. Study Selection Two reviewers independently selected randomized clinical trials that compared fixed doses of a second-generation antipsychotic, haloperidol, or fluphenazine for relapse prevention in patients with stable schizophrenia. Data Extraction and Synthesis Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters in duplicate were extracted and frequentist dose-response random-effects meta-analyses were conducted. Main Outcomes and Measures Study-defined relapse (primary outcome), rehospitalization, Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale total score reduction from baseline, all-cause discontinuation, and dropouts due to adverse events. Results Evidence from 72 dose arms from 26 studies with 4776 participants was analyzed. The efficacy-related dose-response curves had a hyperbolic shape meaning that the probability to relapse decreased rapidly with doses of up to 5-mg/d risperidone equivalent (relative relapse risk, 0.43; 95% CI, 0.31-0.57; standardized mean difference for Positive and Negative Syndrome Scale total score reduction, -0.55; 95% CI, -0.68 to -0.41), but flattened thereafter. In contrast, dropouts due to adverse events continued to increase beyond this dose (relative risk at 5 mg/d, 1.38; 95% CI, 0.87-2.55; relative risk at 15 mg/d, 2.68; 95% CI, 1.49-4.62). In a subgroup analysis of patients in remission, a plateau was reached earlier, at approximately 2.5-mg/d risperidone equivalent. Conclusions and Relevance The findings of this meta-analysis suggest that doses higher than approximately 5-mg/d risperidone equivalent may provide limited additional benefit for relapse prevention but more adverse events. For patients in remission or who are receiving high-potency first-generation antipsychotics, doses as low as 2.5-mg/d risperidone equivalent may be sufficient. However, caution is needed at this low dose end when further decreases of dose may be accompanied by a disproportionally higher relapse risk. Moreover, the observations are averages, and factors such as slow or rapid metabolism, age, illness stage, comorbidities, and drug-drug interactions suggest that individual patients will often need higher or lower doses.

中文翻译：

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稳定型精神分裂症患者预防复发的抗精神病药物剂量检查：一项荟萃分析。


重要性 预防精神分裂症复发所需的抗精神病药物剂量是一个有争议的问题。目的 通过随机临床试验的荟萃分析来检验剂量反应结果。数据来源 研究是通过 Cochrane 精神分裂症小组基于研究的试验登记册（2020 年 3 月 9 日）、PubMed（2021 年 1 月 1 日）和之前的评论确定的。我们联系了第一作者和/或制药公司以获取更多信息。研究选择 两名评价者独立选择了随机临床试验，比较固定剂量的第二代抗精神病药、氟哌啶醇或氟奋乃静对稳定型精神分裂症患者复发的预防作用。数据提取和合成使用系统评价和荟萃分析指南的首选报告项目，提取重复的所有参数，并进行频率剂量反应随机效应荟萃分析。主要结果和措施 研究定义的复发（主要结果）、再住院、阳性和阴性综合征量表或简要精神病评定量表总分较基线降低、全因停药以及因不良事件而退出。结果 对来自 26 项研究、4776 名参与者的 72 个剂量组的证据进行了分析。疗效相关的剂量反应曲线呈双曲线形状，这意味着当利培酮当量剂量达到 5 mg/d 时，复发概率迅速下降（相对复发风险，0.43；95% CI，0.31-0.57；标准化平均差）阳性和阴性症状量表总分降低，-0.55；95% CI，-0.68 至 -0.41），但此后趋于平缓。相比之下，超过该剂量后，因不良事件而退出的人数继续增加（5 mg/d 的相对风险，1.38；95% CI，0.87-2）。55; 15 mg/d 时的相对风险为 2.68； 95% CI，1.49-4.62）。在对缓解期患者的亚组分析中，较早地达到了平台期，约为 2.5 mg/d 利培酮当量。结论和相关性 这项荟萃分析的结果表明，高于约 5 mg/d 利培酮当量的剂量可能对预防复发提供有限的额外益处，但会产生更多的不良事件。对于缓解期患者或正在接受高效第一代抗精神病药物的患者，低至 2.5 毫克/天利培酮当量的剂量可能就足够了。然而，在这种低剂量结束时需要谨慎，因为进一步减少剂量可能会伴随着不成比例的更高的复发风险。此外，观察结果是平均值，新陈代谢缓慢或快速、年龄、疾病阶段、合并症和药物间相互作用等因素表明，个体患者通常需要更高或更低的剂量。