Can valproic acid be an inducer of clozapine metabolism?

F. J. Diaz, C. B. Eap, N. Ansermot, S. Crettol, E. Spina, J. De Leon

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Introduction: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). Discussion: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

Original languageEnglish
Pages (from-to)89-96
Number of pages8
Issue number3
StatePublished - May 2014


  • clozapine
  • drug interactions
  • enzyme induction
  • metabolism
  • pharmacokinetics
  • random-effects linear model
  • smoking
  • therapeutic drug monitoring
  • tobacco
  • valproic acid

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)


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