Andrade Chittaranjan
Department of Psychiatry, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India; Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India.
Corresponding Author: Chittaranjan Andrade, MD, Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India (
J Clin Psychiatry. 2025 Aug 25;86(3):25f16038. doi: 10.4088/JCP.25f16038.
Schizophrenia is a major mental illness with a median lifetime prevalence, across studies, of 0.5%. Across definitions of treatment resistance, about 37% of schizophrenia patients do not respond to treatment, and about 24% are treatment resistant from the first-episode, itself. Treatment resistance is addressed by trialing different antipsychotics and with antipsychotic augmentation strategies; what augmenting agent is used depends on what the target symptoms are. A landmark study in 1988 demonstrated the efficacy of clozapine in treatment resistant schizophrenia (TRS). Confirmatory studies and meta-analyses followed, establishing clozapine as the drug of choice for TRS in schizophrenia treatment guidelines across the world. Between 2016 and 2025, 2 network meta analyses (NMAs) and 1 individual participant data meta-analysis (IPD-MA) examined randomized controlled trials (RCTs) of clozapine vs other antipsychotics in TRS. The NMAs found that clozapine was superior to first-generation antipsychotics; however, clozapine did not head rankings for overall symptoms, positive symptoms, or negative symptoms, and, in pairwise analyses, there was little difference between clozapine and olanzapine and clozapine and risperidone for overall symptoms, positive symptoms, and negative symptoms. The IPD-MA found that clozapine was no better than comparator second-generation antipsychotics, considered singly or together, for overall symptoms, positive symptoms, and negative symptoms, in the short term, intermediate term, and long term. These findings fly in the face of clinical experience and treatment guideline recommendations. Among possible explanations, notable was that clozapine was significantly superior to comparator drugs when disregarding RCTs sponsored by the manufacturer of olanzapine. Clozapine is associated with many inconveniencing, distressing, and serious adverse effects that may be rare or common. Given the findings that olanzapine and risperidone may be as good as clozapine in TRS, it may be worth trialing these drugs before clozapine in patients with TRS. These and related issues, including nuances, are discussed.
精神分裂症是一种主要的精神疾病，各项研究显示其终生患病率的中位数为0.5%。在对治疗抵抗的不同定义中，约37%的精神分裂症患者对治疗无反应，约24%从首发起就存在治疗抵抗。治疗抵抗通过试用不同的抗精神病药物以及采用抗精神病药物增效策略来解决；使用何种增效剂取决于目标症状是什么。1988年的一项具有里程碑意义的研究证明了氯氮平在难治性精神分裂症（TRS）中的疗效。随后的验证性研究和荟萃分析，使氯氮平在全球精神分裂症治疗指南中成为TRS的首选药物。2016年至2025年期间，两项网状荟萃分析（NMA）和一项个体参与者数据荟萃分析（IPD-MA）对氯氮平与其他抗精神病药物在TRS中的随机对照试验（RCT）进行了研究。NMA发现氯氮平优于第一代抗精神病药物；然而，氯氮平在总体症状、阳性症状或阴性症状方面并非排名第一，并且在成对分析中，氯氮平与奥氮平以及氯氮平与利培酮在总体症状、阳性症状和阴性症状方面几乎没有差异。IPD-MA发现，在短期、中期和长期内，就总体症状、阳性症状和阴性症状而言，氯氮平并不比单独或联合使用的对照第二代抗精神病药物更好。这些发现与临床经验和治疗指南建议相悖。在可能的解释中，值得注意的是，当不考虑由奥氮平制造商赞助的RCT时，氯氮平明显优于对照药物。氯氮平会带来许多不便、令人痛苦且严重的不良反应，这些反应可能罕见或常见。鉴于有研究发现奥氮平和利培酮在TRS中可能与氯氮平效果相当，对于TRS患者，在使用氯氮平之前先试用这些药物可能是值得的。本文将讨论这些及相关问题，包括细微差别。
