caa a22 4500 388095962 CHVBK 20180307125304.0 cr unu---uuuuu 161130e199906 xx s 000 0 eng 10.1017/S109285290001186X doi S109285290001186X pii (NATIONALLICENCE)cambridge-10.1017/S109285290001186X Variability in Response to Clozapine: Potential Role of Cytochrome P450 1A2 and the Dopamine D4 Receptor Gene [Elektronische Daten] Clozapine 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. Copyright © Cambridge University Press 1999 Özdemir Vura Masellis Mario Basile Vincenzo S. Kalow Werner Meltzer Herbert Y. Lieberman Jeffrey A. Kennedy James L. CNS Spectrums Cambridge University Press 4/6(1999-06), 30-34, 47-56 1092-8529 4:6<30 1999 4 CNS https://doi.org/10.1017/S109285290001186X text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1017/S109285290001186X text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Özdemir Vura NATIONALLICENCE 700 1- Masellis Mario NATIONALLICENCE 700 1- Basile Vincenzo S. NATIONALLICENCE 700 1- Kalow Werner NATIONALLICENCE 700 1- Meltzer Herbert Y. NATIONALLICENCE 700 1- Lieberman Jeffrey A. NATIONALLICENCE 700 1- Kennedy James L. NATIONALLICENCE 773 0- CNS Spectrums Cambridge University Press 4/6(1999-06), 30-34, 47-56 1092-8529 4:6<30 1999 4 CNS CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-cambridge