Genetic determinants of variable metabolism have little impact on the clinical use of leading antipsychotics in the CATIE study

Purpose: To evaluate systematically in real clinical settings whether functional genetic variations in drug metabolizing enzymes influence optimized doses, efficacy, and safety of antipsychotic medications. Methods: DNA was collected from 750 patients with chronic schizophrenia treated with five antipsychotic drugs (olanzapine, quetiapine, risperidone, ziprasidone, and perphenazine) as part of the Clinical Antipsychotic Trials of Intervention Effectiveness study. Doses for each of the medicines were optimized to 1, 2, 3, or 4x units in identically appearing capsules in a double-blind design. We analyzed 25 known functional genetic variants in the major and minor metabolizing enzymes for each medication. These variants were tested for association with optimized dose and other relevant clinical outcomes. Results: None of the tested variants showed a nominally significant main effect in association with any of the tested phenotypes in European-Americans, African-Americans, or all patients. Even after accounting for potential covariates, no genetic variant was found to be associated with dosing, efficacy, overall tolerability, or tardive dyskinesia. Conclusion: There are no strong associations between common functional genetic variants in drug metabolizing enzymes and dosing, safety, or efficacy of leading antipsychotics, strongly suggesting merely modest effects on the use of these medicines in most patients in typical clinical settings.