The Potential Role of POR*28 and CYP1A2*F Genetic Variations and Lifestyle Factors on Clozapine and N-DesmethylClozapine Plasma Levels in Schizophrenia Patients.

BACKGROUND: Despite its advantages over other antipsychotics, for treatment-resistant schizophrenia, clinical use of Clozapine (CLZ) is challenging by its narrow therapeutic index and potentially life-threatening dose-related adverse effects. RESEARCH DESIGN AND METHODS: As the potential role in CLZ metabolism is assigned to CYP1A2 enzyme and consequently Cytochrome P450 oxidoreductase (POR) their genetic variations might help to determine CLZ levels in schizophrenia patients. For this purpose, 112 schizophrenia patients receiving CLZ were included in the current study. Plasma CLZ and N-desmethylclozapine (DCLZ) levels were analyzed by using HPLC and genetic variations were identified with the PCR-RFLP method. RESULTS: The patients' CYP1A2 and POR genotypes seemed to not affect plasma CLZ and DCLZ levels whereas in the subgroup analysis, POR *28 genotype significantly influenced simple and adjusted plasma CLZ and DLCZ levels concerning smoking habit and caffeine consumption. CONCLUSIONS: The findings of the present study highlight the importance of both genetic and non-genetic factors (smoking and caffeine consumption) for the individualization of the CLZ treatment. In addition to that, it suggests that the added utility of not only the CLZ metabolizing enzymes but also POR, which is crucial for proper CYP activity, to guide CLZ dosing might be useful for clinical decision-making.

The relationship between the serotonin 2A receptor gene -1438A/G and 102T/C polymorphisms and citalopram/sertraline-induced nausea in major depressed patients.

OBJECTIVE: The aim of the present study was to determine the relationship between the polymorphisms of -1438A/G and 102T/C in the 5-HT2A receptor (HTR2A) gene and nausea/vomiting as a side effect induced by sertraline (SERT) or citalopram (CIT) in patients with major depressive disorder. METHODS: A total of 128 patients were enrolled, 63 patients received CIT, whereas 65 patients were treated with SERT. Nausea/vomiting were assessed with the UKU Side-effects Rating Scale at baseline and at the end of the second and fourth weeks. Polymerase chain reaction-restriction fragment length polymorphism technique was employed to determine genetic differences. RESULTS: We have found that, in the patients treated with CIT, there was a nominally significant difference in the genotypic distribution associated with -1438A/G polymorphism between patients with and without nausea (X2  = 6.15, p = 0.041). Moreover, logistic regression analysis revealed a significant association between nausea/vomiting as a side effect and -1438A/G polymorphism. That is, patients with the G allele were at a higher risk for developing nausea/vomiting (p = 0.044, odds ratio = 2.213). The 102T/C polymorphism in the HTR2A gene had no significant effect on the nausea/vomiting as a side effect among participants treated with either CIT or SERT. CONCLUSION: The present study suggests the association of the HTR2A gene -1438A/G polymorphism with nausea/vomiting as a side effect related to CIT treatment.