Management of clozapine-resistant schizophrenia

The ANZJP 2026 schizophrenia guideline appropriately emphasises the importance of identifying treatment-resistant schizophrenia and the timely initiation of clozapine. However, despite clear guidance on when to commence clozapine, there remains comparatively limited direction regarding the systematic assessment and management of individuals who show an inadequate response to clozapine, commonly termed clozapine-resistant schizophrenia. The absence of consistent, operationalised guidance contributes to variability in clinical practice and uncertainty regarding optimal management strategies. In this perspective article, we summarise practical, evidence-informed recommendations to assist clinicians in the assessment and management of clozapine-resistant schizophrenia. Current evidence supports the early use of clozapine once treatment-resistant schizophrenia is established, with delayed clozapine use associated with poorer outcomes. In individuals with persistent symptoms despite clozapine treatment, systematic assessment is required to exclude pseudoresistance, including non-adherence, drug interactions, altered metabolism, and subtherapeutic plasma clozapine concentrations. Therapeutic drug monitoring is therefore a core component of care. Optimisation of clozapine should prioritise individualised adjustment of plasma concentrations guided by clinical response, adverse effects, and tolerability, rather than reliance on fixed concentration thresholds alone. Where an adequate trial of optimised clozapine has failed, augmentation strategies may be considered, with preference given to interventions supported by meta-analytic findings and real-world effectiveness data, while recognising the modest and inconsistent benefits observed across studies. Augmentation trials should be time-limited, systematically evaluated and if no meaningful improvement occurs, should be discontinued rather than continued indefinitely. Despite decades of research, no augmentation strategy has demonstrated consistent efficacy in clozapine-resistant schizophrenia. Future research should prioritise adequately powered, placebo-controlled trials and standardised definitions of treatment-resistant schizophrenia and clozapine-resistant schizophrenia to enable clearer treatment algorithms and more reliable clinical pathways for this patient group.