Future Studies on the Interaction Between Clozapine and Valproic Acid Should Aspire to Include Longitudinal Designs and Free Valproate Concentrations, and Should Consider that Inducer and/or Inhibitory Effects May Vary With Time, the Individual, and the Auto-Induction of Valproic Acid

To the Editor: I would like to congratulate Smith et al1 for their study, the fourth and largest therapeutic drug monitoring study replicating the finding that valproic acid (VPA) may induce clozapine metabolism. In 2008, Diaz et al2 modeled 415 trough steady-state total clozapine concentrations from 255 Italian patients, including 17 receiving VPA. VPA significantly decreased total (clozapine and norclozapine) concentration by 22% only in smokers. For clozapine concentrations, the effect was the same (22% decrease), indicating that dosing should be increased by a correction factor of 1.3. In 2014, Diaz et al3 used the same model for 353 steady-state total clozapine concentrations from 151 Swiss patients, including 28 patients showing 102 VPA concentrations. VPA significantly decreased total clozapine concentration by 27%, implying a correction factor of 1.53. However, the effect was minimal on clozapine concentrations (correction factor of 1.15), implying that induction was mostly explained by decreased norclozapine concentration. In 2018, Hommers et al4 compared the most recent trough steady-state concentrations in 45 patients receiving VPA with 45 controls matched by sex, smoking status (49% smokers), and age, finding lower median concentration/dose (C/D) ratios for norclozapine, 0.44 versus 0.78 (ng/mL per mg/d). In 2019, Smith et al1 selected 687 patients showing 8589 concentrations of clozapine in Norway and 76 (86% smokers) comedicated with 357 VPA concentrations. The norclozapine C/D ratio was reduced by 1.4% per 100 mg/d of VPA. The 4 therapeutic drug monitoring studies were compatible with the inductive effects of VPA mainly influencing norclozapine. Smith et al1 proposed that VPA may increase the activity of the enzymes involved in norclozapine clearance. They suggested presystemic mechanisms, including the induction of cytochromes (CYPs), uridine 59-diphosphoglucuronosyltransferases (UGTs), and p-glycoprotein. Our understanding5 of norclozapine elimination is limited, but it seems to occur mainly through the kidney, possibly by a combination of the elimination of free norclozapine by an unknown renal transporter and the elimination of norclozapine conjugates by UGT and sulfates.6 Next, after reviewing the literature, this letter proposes that the effects of VPA on clozapine metabolism may be much more complex than currently believed (Table 1).1,2,6,7–13 Future studies should consider: (1) careful longitudinal designs; (2) the possible inhibitory effect of VPA; (3) the effect of free VPA concentrations; and (4) the autoinductive effects of VPA.