Samara Myrto, Lappas Andreas S, Pinioti Elisavet, Glarou Eleni, Fober Iwo, Christogiannis Christos, Siafis Spyridon, Christodoulou Nikos, Helfer Bartosz, Mavridis Dimitris, Leucht Stefan
Department of Psychiatry, Faculty of Medicine, University of Thessaly, Larisa, Greece.
Department of Geriatric Psychiatry, Aneurin Bevan University Health Board, United Kingdom.
EClinicalMedicine. 2025 Jun 7;84:103291. doi: 10.1016/j.eclinm.2025.103291. eCollection 2025 Jun.
Treatment-resistant schizophrenia (TRS) poses significant challenges for both clinicians and patients. This systematic review and network meta-analysis (NMA) aimed to compare the efficacy and tolerability of all available pharmacotherapy options.
We systematically searched MEDLINE, Cochrane Central, Embase, PsycINFO, ClinicalTrials.gov, WHO trials registry, and FDA website through March 2025 for randomised controlled trials (RCTs) comparing pharmacological treatments for TRS. NMA estimated pooled effects, with the primary outcome being overall symptom change. Secondary outcomes included treatment response, individual symptom domains, discontinuation, adverse events, quality of life, and functioning. Effect sizes were reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, with 95% confidence intervals (CIs). Meta-regression and sensitivity analyses explored variability in findings.
150 RCTs with 11,375 patients examined 78 drug options or placebo. Clozapine showed superior efficacy for overall symptoms compared to haloperidol, chlorpromazine, quetiapine, and sulpiride (SMDs 0.35 to 1.00). It slightly outperformed olanzapine for positive symptoms (SMD 0.19; 95% CI 0.00 to 0.37) and risperidone for response rates (OR 0.64; 95% CI 0.41 to 1.01). Clozapine combinations with amisulpride, duloxetine, memantine, mirtazapine, topiramate, and ziprasidone improved overall symptoms more than clozapine monotherapy (SMDs -1.53 to -0.51). In a similar vein, clozapine combinations with amisulpride, lamotrigine, and topiramate reduced positive symptoms more than monotherapy (SMDs -1.13 to -0.54), while with duloxetine, memantine, and ziprasidone negative symptoms (SMDs -1.98 to -0.99). Some antipsychotic combinations may outperform monotherapy, but data on non-clozapine combinations were limited. Higher baseline severity was associated with higher clozapine efficacy. Confidence in most estimates was low or very low.
Clozapine remains the gold standard, outperforming several antipsychotics, while specific combinations may offer added benefits but require careful risk-benefit evaluation. Networks sparsity increases the likelihood of chance findings for estimates based on single studies. These results emphasise the need for personalised treatment, further research comparing non-clozapine antipsychotic combinations to high-dose clozapine monotherapy, and studies on long-term outcomes.
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难治性精神分裂症（TRS）给临床医生和患者都带来了重大挑战。本系统评价和网状Meta分析（NMA）旨在比较所有可用药物治疗方案的疗效和耐受性。
我们系统检索了截至2025年3月的MEDLINE、Cochrane中心、Embase、PsycINFO、ClinicalTrials.gov、世界卫生组织试验注册库和美国食品药品监督管理局网站，以查找比较TRS药物治疗的随机对照试验（RCT）。NMA估计汇总效应，主要结局为总体症状变化。次要结局包括治疗反应、个体症状领域、停药、不良事件、生活质量和功能。效应量以连续结局的标准化均数差（SMD）和二分结局的比值比（OR）表示，并给出95%置信区间（CI）。Meta回归和敏感性分析探讨了研究结果的变异性。
150项RCT（涉及11375名患者）研究了78种药物或安慰剂。与氟哌啶醇、氯丙嗪、喹硫平和舒必利相比，氯氮平在总体症状方面显示出更高的疗效（SMD为0.35至1.00）。在阳性症状方面，它略优于奥氮平（SMD为0.19；95%CI为0.00至0.37），在反应率方面优于利培酮（OR为0.64；95%CI为0.41至1.01）。氯氮平与氨磺必利、度洛西汀、美金刚、米氮平、托吡酯和齐拉西酮联合使用比氯氮平单药治疗更能改善总体症状（SMD为-1.53至-0.51）。同样，氯氮平与氨磺必利、拉莫三嗪和托吡酯联合使用比单药治疗更能减轻阳性症状（SMD为-1.13至-0.54），而与度洛西汀、美金刚和齐拉西酮联合使用能减轻阴性症状（SMD为-1.98至-0.99）。一些抗精神病药物联合使用可能优于单药治疗，但非氯氮平联合使用的数据有限。基线严重程度越高，氯氮平的疗效越高。大多数估计的可信度较低或非常低。
氯氮平仍然是金标准，优于几种抗精神病药物，而特定联合使用可能会带来额外益处，但需要仔细评估风险效益。网络稀疏性增加了基于单一研究估计出现偶然结果的可能性。这些结果强调了个性化治疗的必要性、进一步比较非氯氮平抗精神病药物联合使用与高剂量氯氮平单药治疗的研究以及长期结局研究的必要性。
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