Clinical Factors Associated with New-Onset Glucose Intolerance among Patients with Schizophrenia during Clozapine Treatment: All-Case Surveillance in Japan

Clinical Factors Associated with New-Onset Glucose Intolerance among Patients with Schizophrenia during Clozapine Treatment: All-Case Surveillance in Japan

MIKIKO ISHIBASHI,¹ KENTARO MATSUI,^1,2,3 MASAHIKO KAWANO,⁴ HIDEHIRO OSHIBUCHI,¹ JUN ISHIGOOKA,⁵ KATSUJI NISHIMURA¹ and KEN INADA¹

¹Department of Psychiatry, Tokyo Women's Medical University, Tokyo, Japan
²Department of Clinical Laboratory, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
³Department of Sleep-Wake Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
⁴Miyakonojo Shinsei-Hospital, Miyakonojo, Miyazaki, Japan
⁵Institute of CNS Pharmacology, Tokyo, Japan

Clozapine (CLZ), an antipsychotic with a unique mechanism of action, is known to be superior to any other antipsychotic for schizophrenia. However, CLZ is also known to be associated with the development of lethal side effects, which include agranulocytosis and glucose intolerance (GI). Regular measurement and registration of blood test results have been mandatory for all CLZ users; however, these risks may still prevent therapists from prescribing CLZ. While CLZ-induced agranulocytosis has been well documented, CLZ-induced GI in the real world has not been fully investigated. Therefore, in this study, we used data registered in monitoring systems to investigate background factors associated with new-onset GI after CLZ administration and changes in HbA1c levels during CLZ treatment. Data of all patients with schizophrenia who were using CLZ from July 29, 2009 to January 20, 2016 were used for the analysis. Of the 3,746 patients enrolled in the study, 92 (2.5%) had GI at baseline; of the remaining 3,654 patients, 428 (11.7%) developed new-onset GI. Multivariate logistic regression analysis revealed that the development of new-onset GI was significantly associated with older age, higher baseline HbA1c levels, and longer treatment duration. In patients with GI at baseline, HbA1c levels were maintained or improved over 18 months, while in the other patients, CLZ administration gradually elevated HbA1c levels. The findings of this study suggest that, although adequate monitoring and intervention is required, CLZ induction and maintenance therapy may be safe, even for patients with impaired glucose tolerance.

Keywords —— clozapine; drug-induced hyperglycemia; glucose intolerance; HbA1c; schizophrenia

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Tohoku J. Exp. Med., 2020 , 252, 177-183.

Correspondence: Ken Inada, M.D., Ph.D., Department of Psychiatry, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan.

e-mail: inada.ken@twmu.ac.jp

*These two authors contributed equally to this work.