Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia

Abstract

Background: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-Ndesmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking.Methods: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N + -glucuronides, and metabolite-toparent ratios in cases versus controls.Results: After adjusting for covariates, the N-DMC (−40%, P < 0.001) and N + -glucuronide C/Ds (−78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged ( P > 0.7). In contrast, the 5Nglucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls.Conclusions: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.

Effect of smoking habits and concomitant valproic acid use on relapse in patients with treatment‐resistant schizophrenia receiving clozapine: A 1‐year retrospective cohort study

“…This study found that the risk of relapse in patients with both smoking habits and concomitant VPA use was higher than that in patients without either. Patients with both smoking habits and concomitant VPA use accounted for approximately 10% of our sample, which is consistent with that in previous studies 15–17 …”

“…Patients with both smoking habits and concomitant VPA use accounted for approximately 10% of our sample, which is consistent with that in previous studies. [15][16][17]…”

Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment

“…Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last intake of clozapine, and (3) detectable levels of N -desmethylclozapine, clozapine -N -oxide, clozapine-5 N -glucuronide, and clozapine- N + - glucuronide. Patients comedicated with the unselective CYP inducers carbamazepine, phenytoin, or phenobarbital, the CYP1A2 inhibitor fluvoxamine, or valproic acid, which has multiple effects on clozapine metabolism, 30 , 31 were excluded. For the nonswitchers (reference group), a stable trial of clozapine for at least 90 days between the first and last TDM analysis of clozapine in the database was required for inclusion.…”

Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits

“…It has been shown that sex, age, and smoking habits explain only about 50% of variability in plasma clozapine levels, 12,13 with tobacco smoking being the key environmental factor that leads to 30%-40% reduction in clozapine serum levels 14 by inducing the expression of CYP1A human isoforms and UDP-glucuronosyltransferases. 15,16 However, clozapine is subjected to complex hepatic metabolism, where CYP1A2 and CYP3A4 are the main enzymes responsible for demethylation of clozapine into its major metabolite N-desmethylclozapine, which may mediate both favorable and unfavorable effects. 17 Although smoking has a large impact on clozapine levels, much of the unexplained pharmacokinetic variability likely occurs due to drug-drug interactions and polymorphisms in genes encoding drug metabolism and transport.…”

“…However, clozapine serum levels exhibit extensive interindividual variability and, consequently, the patients may experience different treatment outcomes at similar dosing. It has been shown that sex, age, and smoking habits explain only about 50% of variability in plasma clozapine levels, 12,13 with tobacco smoking being the key environmental factor that leads to 30%–40% reduction in clozapine serum levels 14 by inducing the expression of CYP1A human isoforms and UDP‐glucuronosyltransferases 15,16 . However, clozapine is subjected to complex hepatic metabolism, where CYP1A2 and CYP3A4 are the main enzymes responsible for demethylation of clozapine into its major metabolite N ‐desmethylclozapine, which may mediate both favorable and unfavorable effects 17 …”