Valproic acid is an
anticonvulsant, which is also widely used for treating
psychiatric disorders. Some clinical trials have demonstrated benefits of
valproic acid augmentation
therapy in
schizophrenia. Interindividual variability in
valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing
enzymes. The aim of this study was to determine the relationship between serum concentrations of
valproic acid and single nucleotide polymorphisms of the
cytochrome P450 (CYP) 2C19 gene in patients with
schizophrenia. All patients had been receiving fixed dose of
valproic acid for at least 2 weeks. The daily doses were 0.5-1.5 g. No other drugs except
olanzapine were coadministered. Serum concentrations of
valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The
CYP2C19 (
CYP2C19*2 G681A rs4244285 and
CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of
valproic acid were significantly higher in patients with
CYP2C19 *1/*2 genotype (P < 0.01) or
CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of
valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for
CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 - β) = 0.8486 at type I level of 0.05) to support the observed significant associations for
CYP2C19 SNPs and serum C/D ratios of
valproic acid. The findings of this study suggest that the genetic polymorphisms of
CYP2C19 significantly affect the steady-state serum concentrations of
valproic acid in Chinese Han population. The determination of the
CYP2C19 genotypes may be useful for dosing adjustment in
schizophrenia patients on
valproic acid therapy.