Evidence Insufficient for Greater Diabetes Risk with Clozapine vs. Other Antipsychotics

For patients with schizophrenia, the evidence was inconclusive as to whether clozapine was associated with a higher rate of new-onset diabetes when compared with other antipsychotics, concluded a new study.

“Our main analysis does not show a difference in risk of diabetes between clozapine and other antipsychotics,” Peter FJ Schulte, MD, PhD, Mental Health Services North-Holland-North, Alkmaar, the Netherlands, and fellow researchers wrote in the study. “To the best of our knowledge, this study has the longest follow-up of a sizeable cohort of clozapine users in comparison to matched controls.”

According to study background, previous data had indicated that clozapine was linked to the largest diabetic effects of all atypical antipsychotics. This led Dr Schulte and colleagues to retrospectively evaluate the risk for new-onset diabetes in long-term clozapine treatment vs. treatment with other antipsychotics.

The study included a matched control population with schizophrenia or schizoaffective disorder. In all, researchers enrolled 94 patients who had schizophrenia or schizoaffective disorder and had been treated with clozapine for 5 years or longer and matched them according to age, diagnosis, and sex with 94 patients who had not taken clozapine.

During follow-up, which lasted for as long as 20 years (mean, 12.3 years), the clozapine group had a cumulative rate of new detection of diabetes of 22.3% (absolute risk difference, 6.3%; 95% confidence interval, −4.9% to 17.5%).

Furthermore, in an additional analysis of 83 matched pairs with normal glucose measurement before endpoint, there was a significant risk difference between the two arms (clozapine, 21.7% vs. control, 8.4%). However, Dr Schulte and colleagues observed that this analysis may have been biased against clozapine because more patients in the control group showing hyperglycemia at inclusion subsequently developed diabetes. 

In light of the new data and prior studies, “we conclude that definitive evidence showing a clinically significant larger risk for new-onset diabetes after long-term treatment with clozapine in comparison to other antipsychotics is lacking,” Dr Schulte and colleagues wrote. “Nevertheless, on the basis of results from this and earlier studies, clinicians should focus on the prevention and detection of diabetes in all patients with schizophrenia and schizoaffective disorder and routinely monitor weight and metabolic parameters as recommended.”


Schulte PFJ, Bocxe JTH, Doodeman HJ, et al. Risk of new-onset diabetes after long-term treatment with clozapine in comparison to other antipsychotics in patients with schizophrenia. J Clin Psychopharmacol. 2016; doi:10.1097/jcp.0000000000000465.