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Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels

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Abstract

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.

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Acknowledgements

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.

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Author notes

  1. Heidi J. Wehring and Teresa Elsobky contributed equally to this work.

Authors and Affiliations

  1. Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD, 21228, USA

    Heidi J . Wehring, Gopal Vyas, Charles M. Richardson, Robert P. McMahon, Fang Liu, Robert W. Buchanan, Stephanie Feldman, Elizabeth M. McMahon & Deanna L. Kelly

  2. Bernard J. Dunn School of Pharmacy, Shenandoah University, Ashburn, VA, USA

    Teresa Elsobky

  3. Medical College of Georgia, Augusta University, Augusta, GA, USA

    Joseph P. McEvoy

  4. Spring Grove Hospital Center, Baltimore, MD, USA

    Gopal Vyas & Charles M. Richardson

  5. University of Maryland School of Pharmacy, Baltimore, MD, USA

    Bethany A. DiPaula

  6. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kelli Sullivan

Authors
  1. Heidi J . Wehring
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  2. Teresa Elsobky
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  3. Joseph P. McEvoy
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  4. Gopal Vyas
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  6. Robert P. McMahon
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  7. Bethany A. DiPaula
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  8. Fang Liu
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  9. Kelli Sullivan
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  10. Robert W. Buchanan
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  13. Deanna L. Kelly
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Corresponding author

Correspondence to Heidi J . Wehring.

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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.

Ethical Approval

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

Informed consent was obtained from all individual included participants.

Additional information

Dr. Heidi Wehring and Dr. Teresa Elsobky share first authorship of this paper.

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Wehring, H.J..., Elsobky, T., McEvoy, J.P. et al. Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels. Psychiatr Q 89, 73–80 (2018). https://doi.org/10.1007/s11126-017-9515-x

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  • DOI: https://doi.org/10.1007/s11126-017-9515-x

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