WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.
WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.
Lancet Psychiatry. 2022 Aug;9(8):614-624. doi: 10.1016/S2215-0366(22)00158-4. Epub 2022 Jun 23.
Although antipsychotic maintenance treatment is widely recommended to prevent relapse in chronic psychoses, evidence-based guidelines do not provide clear indications on different maintenance treatment strategies, including continuing the antipsychotic at standard doses, reducing the dose, switching to another antipsychotic, or even stopping the antipsychotic. We aimed to compare the effectiveness of these maintenance treatment strategies, hypothesising the superiority of all strategies over stopping, and of continuing at standard doses over both switching and reducing the dose.
We did a systematic review and network meta-analysis of randomized controlled trials (RCTs) that investigated antipsychotics for relapse prevention in adults with schizophrenia-spectrum disorders who were clinically stable, and which compared four treatment strategies: continuing the current antipsychotic at standard doses recommended for acute treatment; reducing the current antipsychotic dose; switching to a different antipsychotic; and stopping the antipsychotic and replacing it with placebo. We excluded RCTs with fewer than 25 individuals, a prerandomisation washout period greater than 4 weeks, a follow-up shorter than 6 weeks, and those recruiting treatment-resistant individuals. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, and online trial registers for published and unpublished RCTs from inception to Sept 1, 2021, combining terms describing all available antipsychotics, and terms describing continuation, maintenance, or long-term treatment for schizophrenia-spectrum disorders. Relative risks (RRs) and standardised mean differences were pooled using random-effects pairwise and network meta-analyses. We assessed risk of bias of each RCT with the Cochrane Risk-of-Bias 2 tool, and confidence of pooled estimates with CINeMA. The primary outcome was relapse prevention. The study protocol was registered in advance in the Open Science Forum registry.
Of 3936 records identified, 119 records, reporting on 101 RCTs, were eligible, 98 of which (including 13 988 individuals) provided data that could be meta-analysed for at least one outcome. The mean proportion of female participants per study was 38% (range 0-100; median 39%, IQR 29-50), whereas for male participants it was 62% (range 0-100; median 61%, IQR 50-71), and the overall mean age was 38·8 years (range 23·2-63·9; median 39·3, IQR 35·0-43·9). Of the 98 RCTs meta-analysed, 89·8% were done in high-income and upper-middle-income countries. The ethnic group White or so-called Caucasian was the most represented (mean 56% participants per study), although this information was relatively scarce. All continuation strategies were significantly more effective in preventing relapse than stopping antipsychotic treatment, with a large risk reduction for continuing at standard doses (RR 0·37, 95% CI 0·32-0·43; number-needed-to-treat [NNT] 3·17, 95% CI 2·94-3·51) and antipsychotic switching (RR 0·44, 0·37-0·53; NNT 3·57, 3·17-4·25), and moderate risk reduction for dose reduction (RR 0·68, 0·51-0·90; NNT 6·25, 4·08-20·00). Continuing and switching antipsychotics did not differ significantly (RR 0·84, 0·69-1·02; with lower values favouring continuing), whereas reducing antipsychotic dose was outperformed by both continuing (RR 0·55, 0·42-0·71; NNT 4·44, 3·45-6·90) and switching (RR 0·65, 0·47-0·89; NNT 5·17, 3·77-18·18). Results were supported by moderate confidence of evidence and confirmed by secondary analyses and by several sensitivity and subgroup analyses, including removing studies with abrupt antipsychotic discontinuation or fast tapering (≤4 weeks). No tolerability differences emerged between treatment strategies. According to the Cochrane Risk-of-Bias tool, version 2, 16·8% of included RCTs had an overall high risk of bias for the primary outcome. We found moderate heterogeneity (τ=0·13; I=61%) and no overall incoherence for the primary analysis. Results were supported by moderate confidence of evidence and confirmed by secondary analyses.
Contrary to our original hypothesis, we found that continuing antipsychotic treatment at standard doses or switching to a different antipsychotic are similarly effective treatment strategies, whereas reducing antipsychotic doses below standard doses is associated with higher risk of relapse than the other two maintenance treatment strategies and should therefore be limited to selected cases. Despite limitations, including moderate heterogeneity and moderate certainty of evidence, these results are of pragmatic relevance for clinicians, and should support the update of evidence-based guidelines.
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尽管抗精神病药维持治疗被广泛推荐用于预防慢性精神病的复发，但循证指南并未提供不同维持治疗策略的明确指示，包括继续使用标准剂量的抗精神病药、减少剂量、换用另一种抗精神病药，甚至停用抗精神病药。我们旨在比较这些维持治疗策略的有效性，假设所有策略均优于停药，且继续使用标准剂量优于换用或减少剂量。
我们对随机对照试验（RCT）进行了系统评价和网络荟萃分析，这些试验调查了抗精神病药在临床稳定的精神分裂症谱系障碍成人中的复发预防作用，比较了四种治疗策略：继续使用目前推荐用于急性治疗的标准剂量的抗精神病药；减少目前的抗精神病药剂量；换用另一种抗精神病药；停用抗精神病药并用安慰剂替代。我们排除了每组少于 25 人的 RCT、洗脱期超过 4 周、随访时间短于 6 周以及招募难治性患者的 RCT。我们检索了 MEDLINE、EMBASE、PsycINFO、CINAHL、CENTRAL 和在线试验注册中心，从成立到 2021 年 9 月 1 日，搜索了关于所有可用抗精神病药以及继续、维持或长期治疗精神分裂症谱系障碍的描述性术语的已发表和未发表的 RCT。使用随机效应成对和网络荟萃分析汇总相对风险（RR）和标准化均数差。我们使用 Cochrane 风险偏倚工具 2 评估每个 RCT 的偏倚风险，并使用 CINeMA 评估汇总估计的可信度。主要结局是预防复发。该研究方案已提前在开放科学论坛登记处登记。
从 3936 条记录中，有 119 条记录，涉及 101 项 RCT，符合纳入标准，其中 98 项（包括 13988 名参与者）提供了至少一项结局的可进行荟萃分析的数据。每项研究中女性参与者的平均比例为 38%（范围 0-100；中位数 39%，IQR 29-50），而男性参与者的平均比例为 62%（范围 0-100；中位数 61%，IQR 50-71），总体平均年龄为 38.8 岁（范围 23.2-63.9；中位数 39.3，IQR 35.0-43.9）。在进行荟萃分析的 98 项 RCT 中，89.8% 是在高收入和中高收入国家进行的。白人或所谓的白种人是最常见的种族（每项研究中平均有 56%的参与者是白人），尽管这方面的信息相对较少。所有继续治疗策略在预防复发方面均明显优于停药，继续使用标准剂量的风险降低幅度较大（RR 0.37，95%CI 0.32-0.43；NNT 3.17，95%CI 2.94-3.51）和换用另一种抗精神病药的风险降低幅度较大（RR 0.44，0.37-0.53；NNT 3.57，3.17-4.25），而减少抗精神病药剂量的风险降低幅度中等（RR 0.68，0.51-0.90；NNT 6.25，4.08-20.00）。继续治疗和换用抗精神病药的效果无显著差异（RR 0.84，0.69-1.02；较低值有利于继续治疗），而减少抗精神病药剂量的效果不如继续治疗和换用抗精神病药（RR 0.55，0.42-0.71；NNT 4.44，3.45-6.90；RR 0.65，0.47-0.89；NNT 5.17，3.77-18.18）。这些结果得到了中度证据可信度的支持，并通过二次分析和多项敏感性及亚组分析得到证实，包括排除了突然停药或快速减药（≤4 周）的研究。治疗策略之间没有出现耐受性差异。根据 Cochrane 风险偏倚工具 2，纳入的 16.8% RCT 在主要结局方面存在整体高偏倚风险。我们发现存在中度异质性（τ=0.13；I=61%），且没有整体不协调性。主要分析结果得到了中度证据可信度的支持，并通过二次分析得到了证实。
与我们最初的假设相反，我们发现继续使用标准剂量的抗精神病药或换用另一种抗精神病药是同样有效的治疗策略，而将抗精神病药剂量减少到低于标准剂量与其他两种维持治疗策略相比，复发风险更高，因此应将其限制在特定病例中。尽管存在中度异质性和中度证据确定性等局限性，但这些结果对于临床医生具有实际意义，应支持更新循证指南。
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