Variability in Response to Clozapine: Potential Role of Cytochrome P450 1A2 and the Dopamine D4 Receptor Gene

Abstract

ABSTRACTClozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patieents There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the free plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, investigated the (G)n mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.