2026 ECNP Congress

PS03-3212

How many patients with schizophrenia spectrum disorders need sustained clozapine treatment to save one life? A population-based cohort study

Vicent Llorca-Bofí — V. Oliva, G. Anmella, M. De Prisco, M. Bioque, E. Vieta, D. Hidalgo-Mazzei · Hospital Clínic Barcelona, Department of Psychiatry, Barcelona, Spain

2026 ECNP Congress

Introduction: People with schizophrenia spectrum disorders (SSD) face a life expectancy reduced by 10–20 years compared to the general population [1]. Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia and has been associated with lower all-cause mortality across multiple cohort studies [2,3]. To the best of our knowledge, no previous study has quantified how many patients need sustained clozapine treatment to prevent one death, nor whether sustained exposure is required to achieve this survival benefit.

Aim: To investigate the association between clozapine exposure intensity and all-cause mortality in a large population-based cohort of patients with SSD, and to provide an NNT-based quantification of clozapine’s survival benefit (number of patients needed to treat to prevent one death) .

Methods: Population-based cohort study using the PADRIS-PRESTO Cohort, comprising linked electronic health records from the Catalan public health system (2015–2019). Patients with SSD (ICD-10: F20–F25) using mental health services were included. Clozapine exposure intensity was quantified using the medication possession ratio (MPR) derived from pharmacy dispensing data. Patients were classified as sustained exposure (MPR ≥80%), non-sustained exposure (MPR <80%), or non-exposed. All-cause mortality was the primary outcome, identified through linked mortality records. Cox proportional hazards models with left truncation estimated adjusted hazard ratios (HRs), controlling for age, sex, SSD type, somatic comorbidity burden, and prior psychiatric hospitalisations. NNT was derived from Kaplan–Meier absolute risk differences at 1, 3, and 5 years. Sensitivity analyses included restriction to incident users, inverse probability of treatment weighting, and alternative MPR thresholds.

Results: A total of 34,644 patients (164,795 person-years) and 1,752 deaths were included. Of these, 3,085 (8.9%) had sustained clozapine exposure and 1,604 (4.6%) non-sustained exposure. In fully adjusted models, sustained exposure was associated with a 50% lower mortality risk (HR 0.50, 95% CI 0.37–0.67), whilst non-sustained exposure was associated with a threefold higher mortality risk compared to non-exposed patients (HR 3.01, 95% CI 2.54–3.57). An exposure–mortality gradient was observed across MPR categories, with the greatest survival benefit observed at MPR ≥80%. The NNT to prevent one death was 189 at 1 year (95% CI 150–288), 64 at 3 years (95% CI 51–98), and 39 at 5 years (95% CI 31–60). Results were robust across all sensitivity analyses, with stronger effects observed when restricting to incident clozapine users (HR 0.32, 95% CI 0.13–0.76).

Conclusions: Sustained clozapine exposure is associated with substantially lower mortality in SSD, with an NNT of 64 at 3 years providing a clinically meaningful and directly interpretable measure for clinical practice and health policy. Previous NNT estimates for clozapine have addressed hospitalisation but not mortality [4], underscoring the novelty of this finding. Non-sustained exposure was associated with markedly increased mortality risk, highlighting the critical importance of strategies supporting treatment continuity to reduce premature mortality in schizophrenia.

References

  1. Vermeulen, J.M., Van Rooijen, G., Van De Kerkhof, M.P.J., Sutterland, A.L., Correll, C.U., De Haan, L., 2019. Clozapine and long-term mortality risk in patients with schizophrenia: a systematic review and meta-analysis of studies lasting 1.1–12.5 years. Schizophr. Bull. 45 (2), 315–329.
  2. Taipale, H., Tanskanen, A., Mehtälä, J., Vattulainen, P., Correll, C.U., Tiihonen, J., 2020. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 19 (1), 61–68.
  3. Correll, C.U., Solmi, M., Croatto, G., Schneider, L.K., Rohani-Montez, S.C., Fairley, L., Smith, N., Bitter, I., Gorwood, P., Taipale, H., Tiihonen, J., 2022. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry 21 (2), 248–271.
  4. Masuda, T., Misawa, F., Takase, M., Kane, J.M., Correll, C.U., 2019. Association with hospitalisation and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: a systematic review and meta-analysis of cohort studies. JAMA Psychiatry 76 (10), 1052–1061.