The Superiority of Clozapine Over Second-Generation Antipsychotics in Patients With Treatment-Resistant Schizophrenia: Room for Doubt.

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.