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Am J Psychiatry. 2017 Oct 1;174(10):990-998. doi: 10.1176/appi.ajp.2017.16091097. Epub 2017 Jul 28.

Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia.

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From the National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus BSS, Aarhus University, Aarhus, Denmark; the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus and Copenhagen, Denmark; the Centre for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark; the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London; the Research Unit, Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and the Department of Public Health, Biostatistics, Aarhus University, Aarhus, Denmark.



This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia.


A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates.


The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16-3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50-4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86-2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47-4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04-1.78).


The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.


Antipsychotics; Epidemiology; Mortality; Schizophrenia; Treatment resistance

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