The effect of body weight changes on total plasma clozapine concentrations determined by applying a statistical model to the data from a double-blind trial

Francisco J. Diaz, Richard C. Josiassen, Jose De Leon

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Purpose/Background Some therapeutic drug monitoring studies suggest that increased weight is associated with small increases in clozapine concentrations. The goal of this study was to reanalyze a US double-blind study using a sophisticated statistical model to test whether weight gains from baseline or increases in percentage of body fat from baseline, computed from a published equation, are associated with increased total plasma clozapine concentrations after controlling for the effects of smoking and sex. Methods/Procedures Using data from a multidosage randomized double-blind US clozapine trial previously published, a random intercept linear model of steady-state total plasma clozapine concentrations was fitted to 424 concentrations from 47 patients. Findings/Results After adjusting for sex and smoking, (1) a 1-kg gain in body weight during clozapine treatment was significantly associated with a 1.4% increase in total plasma clozapine concentrations (95% confidence interval = 0.55 to 2.3) and (2) a 1-point increase in percentage of body fat during clozapine treatment was significantly associated with a 5.4% increase in total clozapine concentration (2.5 to 8.3) in females and 1.4% (-1.1 to 4.0) in males. Implications/Conclusions As hypothesized, weight increases during clozapine treatment, which probably reflect increases in fat tissue, were associated with increases in total plasma concentrations. Pending further replication in other samples, it seems likely that clozapine may deposit in body fat and that this may decrease clozapine clearance. This change may be small in most patients but may be clinically relevant in females with major gains in body fat.

Original languageEnglish
Pages (from-to)442-446
Number of pages5
JournalJournal of Clinical Psychopharmacology
Issue number5
StatePublished - Oct 1 2018

Bibliographical note

Funding Information:
The authors thank Lorraine Maw, MA, at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, who helped in editing this article. The authors are grateful to the reviewers who provided important suggestions for improving the article. Please see Reference 3 for the complete list of acknowledgements for the clozapine trial, which was supported in part by US Public Health Service Grant MI-145190, Novartis Pharmaceuticals Corporation, and a National Alliance for Research on Schizophrenia and Depression Established Investigator Award to George Simpson, MD. Richard C. Josiassen, PhD, was a coinvestigator in the clozapine trial.

Funding Information:
In the last 3 years, Drs Diaz and de Leon had no commercial conflict of interest. In the last 3 years, Dr Josiassen had grants from Lundbeck and National Institute of Mental Health. For the writing of this article and the analyses reported in it, Dr Diaz was supported in part by an Institutional Clinical and Translational Science Award, National Institute of Health/National Center for Advancing Translational Sciences Grant Number UL1TR000001 (awarded to the University of Kansas Medical Center). Dr Diaz did not receive any salary or payment from the institutions that supported the operation of the clozapine trial or from the grants supporting the clozapine trial. The contents are solely the responsibility of the

Publisher Copyright:
© 2018 Wolters Kluwer Health, Inc.


  • adipose tissue
  • clozapine, blood
  • clozapine, pharmacokinetics
  • obesity
  • weight gain

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)


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