A Global Perspective on Clozapine


How widely used is this “gold-standard” antipsychotic?



Clozapine is the “gold-standard” antipsychotic for treatment-resistant schizophrenia. Despite its robust efficacy, there is evidence that clozapine is underutilized.1

Several potential factors likely contribute to this phenomenon, including the physician’s level of experience with clozapine, requirements for routine hematologic monitoring, and concerns about potential adverse effects, such as agranulocytosis, myocarditis, bowel obstruction, seizures, and metabolic syndrome risk. It is important to note, however, that treatment with clozapine is associated with decreased mortality in patients with schizophrenia.2

International trends

Given the international variation in licensing, prescription regulation, attitudes toward clozapine, and patterns in use, Bachmann and colleagues3 compared trends in clozapine use across 17 countries. They aimed to access the prevalence of clozapine use and time trends in utilization across different age groups in countries from Europe, Asia, North and South America, and Oceania.

The study authors approached pharmacoepidemiological research groups and database providers from 32 countries, of whom 17 responded with the required data. They included patients registered continuously in the database of their country for at least 1 year during the period from 2005 to 2014. Annual prevalence (per 100,000 persons per year) was defined as the proportion of individuals with at least one clozapine prescription or dispensing. For the first and last years of the study period, the authors also calculated age- and sex-stratified prevalence data, and trends in clozapine use. The prevalence of clozapine use in each country was age-standardized against the World Health Organization world standard population.

In 2014, overall age-standardized clozapine use was greatest in Finland (173/100,000 persons) and a publicly insured US cohort (123), and lowest in Japan (1) and a privately insured US cohort (12). During the study period, there was a significant increase in the annual prevalence of clozapine use in most countries, with the highest prevalence ratio in the privately insured US cohort. A significant decrease in clozapine use was found in Colombia and the publicly insured US cohort. The largest absolute increase in clozapine use occurred in Finland (+49/100,000) and in the Netherlands (+40). In most countries, overall clozapine use was highest in the 40- to 59-year-old age group. Clozapine use was more common in males, with a median male/female clozapine use ratio of 1.5.

The bottom line

The authors found that although the prevalence of clozapine use increased in most countries, there was an almost 200-fold variation in use. In most populations, clozapine was more commonly used in males, and use peaked at age 40 to 59. An important study limitation is that in order to standardize study methodology, information on clinical characteristics, including indication; clozapine dose, treatment duration, and adherence; and other medications was not available. The authors concluded that future research should address the implementation of interventions designed to facilitate increased clozapine utilization.


Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.


1. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374:620-627.

2. Remington G, Lee J, Agid O, et al. Clozapine’s critical role in treatment resistant schizophrenia: ensuring both safety and use. Expert Opin Drug Saf. 2016;15:1193-1203.

3. Bachmann CJ, Aagaard L, Bernardo M, et al. International trends in clozapine use: a study in 17 countries. Acta Psychiatr Scand. 2017;136:37-51.

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