Clozapine Response and Adverse Events Differ Based on Gender

Clozapine Better for Comorbid Schizophrenia, Cannabis Use Disorder
Clozapine Better for Comorbid Schizophrenia, Cannabis Use Disorder
Investigators found data that showed in women taking clozapine the risk of developing diabetes was high, among other risks, and that in men there were cardiovascular risks, including a poorer lipid profile.

According to a review published in Psychiatry Research, studies regarding gender-based differences to treatment with clozapine are still lacking in definitive data in some respects. Some studies have indicated that women have a lower response to treatment with clozapine, whereas others indicate the opposite; however, the evidence uniformly supports that women have a higher risk of developing diabetes, and that men are more likely to develop metabolic abnormalities and have higher cardiovascular risks from clozapine treatment.

It is known that men and women can manifest mental illness differently, and respond differently to the same treatment. The investigators of this study evaluated the existing literature to determine the extent and validity of evidence for gender differences in effectiveness and side effects of clozapine as a treatment for psychiatric illness.

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Using a systematic review of research databases, the investigators identified studies that met preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria to compare clozapine effects in men vs women. Only a single published study specifically addressed gender-based differences in treatment response to clozapine, while 10 other studies reported clozapine-related adverse effects by gender. The studies mostly involved patients with schizophrenia: One manuscript did not specify a diagnosis, and in another, the sample included patients with schizophrenia, schizoaffective disorder, bipolar disorder, personality disorder, and other psychiatric disorders.

In the single study that met PRISMA inclusion criteria for this meta-analysis and reported treatment effect for clozapine use and gender, being a woman was associated with more frequent hospital admissions during follow-up (65.8% of women vs 47.6% of men; P =.001) and a shorter time to discontinuation (hazard ratio 1.3; 95% CI, 1.1-1.54; P =.002). Women participants also had a poorer response rate compared with men (34.2% vs 52.5%; P <.001). Regarding safety outcomes from the other studies, men were significantly more likely to develop clozapine-induced hypertension, cardiovascular risk, or metabolic abnormalities, such as a poorer lipid profile. Women were reported to have a higher risk for other adverse effects including weight gain from clozapine exposure, development of diabetes or hyperglycemia, and more frequent need for the use of laxatives.

Limitations to the study included the small number of manuscripts related to gender-based differences in treatment response to clozapine and that the majority of included studies involved patients with schizophrenia, potentially limiting generalizability to other psychiatric illnesses. Furthermore, clozapine is generally prescribed to patients who are resistant to other medications or who have taken or are taking concomitant medications, possibly confounding study results.

The investigators suggest that their findings show that there is still a clear lack of evidence to define gender-based differences in response to clozapine; however, the limited evidence shows that women may be less likely to respond to clozapine treatment and may have more frequent hospital admissions following treatment initiation. Men taking clozapine are likely to experience more metabolic disturbances, which in turn induces greater cardiovascular risk, whereas women taking clozapine are likely to be at higher risk of developing diabetes, weight gain, and treatment-induced constipation.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of the author’s disclosures.


Alberich S, Fernández-Sevillano J, González-Ortega I, et al. A systematic review of sex-based differences in effectiveness and adverse effects of clozapine. [published online August 3, 2019]. Psychiatry Res. doi:10.1016/j.psychres.2019.112506