Diagnostic heterogeneity and clozapine use among patients referred for suspected treatment-resistant schizophrenia

Patients referred for suspected treatment-resistant schizophrenia (TRS) may constitute a diagnostically heterogeneous population. We retrospectively studied 392 patients referred to an outpatient service for suspected TRS. Electronic clinical records were reviewed, and patients classified according to ICD-10 after specialist reassessment.

Treatment patterns and factors associated with clozapine exposure were examined across diagnostic groups. A substantial proportion of patients were classified outside schizophrenia (F20), particularly as organic psychotic disorders (F06) or unspecified psychosis (F29). Patients with schizophrenia (F20) and schizoaffective disorder (F25) showed higher clozapine exposure and greater antipsychotic burden, whereas F06 and F29 groups showed lower pharmacological intensification.

F29 diagnosis was independently associated with lower odds of clozapine exposure compared with F20. Patients referred for suspected TRS are diagnostically and therapeutically heterogeneous. Diagnostic reassessment is important, and clozapine exposure should be interpreted within the diagnostic and treatment context rather than as a stand-alone marker of TRS status.

This work received Portuguese national funding from FCT – Fundação para a Ciência e a Tecnologia, I.P., through the Research Center for Psychological Science of the Faculty of Psychology, University of Lisbon (UID/04527/2025: Research Center for Psychological Science), and DOI identifier https://doi.org/10.54499/UID/04527/2025. Consulta de Esquizofrenia Resistente (CER), and Homeless Outreach Psychiatric Engagement for Lisboa (HOPE 4 Lisboa). Hospital Júlio de Matos (HJM), Unidade Local de Saúde São José (ULSSJ), Centro Clínico Académico de Lisboa (CCAL), Lisboa, Portugal Clínica Universitária de Psiquiatra e Psicologia Médica (CUPPM), and PsyLab Instituto de Saúde Ambiental (ISAMB), Faculdade de Medicina, Universidade de Lisboa (FMUL), Centro Académico de Medicina de Lisboa (CAML), Lisboa, Portugal Centro de Investigação em Ciência Psicológica (CICPSI), Faculdade de Psicologia, Universidade de Lisboa (FPUL), Lisboa, Portugal João Gama-Marques & Joana Henriques-Calado Independent Research, Sissach, Switzerland The authors declare no competing interests.

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