Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels
Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.
KeywordsSchizophrenia Clozapine Drug interaction Minocycline
We would like to acknowledge the participants in this study for their contributions to advances in schizophrenia treatment. In addition, we acknowledge Dr. Christine Tran for her contributions to this paper.
Compliance with Ethical Standards
Conflict of Interest
Deanna L. Kelly, PharmD, is a consultant for Lundbeck and XOMA. Joseph P. McEvoy, MD, is a consultant for Ameritox, Alkermes, Envivo, Jazz, Otsuka, and Merck. Robert P. McMahon, PhD, is a consultant for Amgen, Inc. Robert W. Buchanan, MD, is a Data Safety Monitoring Board member for Otsuka and Pfizer. He consulted with Abbott and is affiliated with Amgen, Bristol-Meyers Squibb, EnVivo, Omeros, and Pfizer. He is also part of the advisory boards of Abbott; Amgen; EnVivo; Janssen Pharmaceutical, Inc.; NuPathe, Inc.; Pfizer; Roche; and Takeda. The remaining authors declare no conflicts of interest.
Sources of Funding
1R21MH091184-01A1 (PI Deanna L. Kelly), funded by the National Institute of Mental Health, Bethesda, MD.
K23DA034034 (PI Heidi J. Wehring), funded by the National Institute on Drug Abuse, Bethesda, MD.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research boards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Research Involving Human Participants
This study was approved by the University of Maryland, Baltimore, the State of Maryland Department of Health and Mental Hygiene, and Duke University IRBs and performed in compliance with Declaration of Helsinki.
Informed consent was obtained from all individual included participants.
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