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.
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.
Authors: Del D Miller; Joseph P McEvoy; Sonia M Davis; Stanley N Caroff; Bruce L Saltz; Miranda H Chakos; Marvin S Swartz; Richard S E Keefe; Robert A Rosenheck; T Scott Stroup; Jeffrey A Lieberman Journal: Schizophr Res Date: 2005-09-19 Impact factor: 4.939
Authors: Jeffrey A Lieberman; T Scott Stroup; Joseph P McEvoy; Marvin S Swartz; Robert A Rosenheck; Diana O Perkins; Richard S E Keefe; Sonia M Davis; Clarence E Davis; Barry D Lebowitz; Joanne Severe; John K Hsiao Journal: N Engl J Med Date: 2005-09-19 Impact factor: 91.245
Authors: Sarah K Tate; Chantal Depondt; Sanjay M Sisodiya; Gianpiero L Cavalleri; Stephanie Schorge; Nicole Soranzo; Maria Thom; Arjune Sen; Simon D Shorvon; Josemir W Sander; Nicholas W Wood; David B Goldstein Journal: Proc Natl Acad Sci U S A Date: 2005-04-01 Impact factor: 11.205
Authors: Jun-Sheng Wang; Ying Ruan; Robin M Taylor; Jennifer L Donovan; John S Markowitz; C Lindsay DeVane Journal: Int J Neuropsychopharmacol Date: 2004-12 Impact factor: 5.176
Authors: Alessia Bogni; Mario Monshouwer; Anna Moscone; Mats Hidestrand; Magnus Ingelman-Sundberg; Thomas Hartung; Sandra Coecke Journal: Toxicol In Vitro Date: 2005-08 Impact factor: 3.500
Authors: Christina L Aquilante; Taimour Y Langaee; Larry M Lopez; Hossein N Yarandi; Jennifer S Tromberg; Dagmara Mohuczy; Katherine L Gaston; Cassandra D Waddell; Mark J Chirico; Julie A Johnson Journal: Clin Pharmacol Ther Date: 2006-02-28 Impact factor: 6.875
Authors: T Scott Stroup; Jeffrey A Lieberman; Joseph P McEvoy; Marvin S Swartz; Sonia M Davis; Robert A Rosenheck; Diana O Perkins; Richard S E Keefe; Clarence E Davis; Joanne Severe; John K Hsiao Journal: Am J Psychiatry Date: 2006-04 Impact factor: 19.242
Authors: Anna C Need; Richard S E Keefe; Dongliang Ge; Iris Grossman; Sam Dickson; Joseph P McEvoy; David B Goldstein Journal: Eur J Hum Genet Date: 2009-01-21 Impact factor: 4.246
Authors: Rebecca N Jerome; Jill M Pulley; Nila A Sathe; Shanthi Krishnaswami; Alyssa B Dickerson; Katherine J Worley; Consuelo H Wilkins Journal: Ethn Dis Date: 2020-04-02 Impact factor: 1.847
Authors: Alexander J Thompson; Jacques Fellay; Keyur Patel; Hans L Tillmann; Susanna Naggie; Dongliang Ge; Thomas J Urban; Kevin V Shianna; Andrew J Muir; Michael W Fried; Nezam H Afdhal; David B Goldstein; John G McHutchison Journal: Gastroenterology Date: 2010-06-12 Impact factor: 22.682
Authors: Huei-Ting Tsai; Stanley N Caroff; Del D Miller; Joseph McEvoy; Jeffrey A Lieberman; Kari E North; T Scott Stroup; Patrick F Sullivan Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2010-01-05 Impact factor: 3.568
Authors: Virginia L Stauffer; Jennifer L Sniadecki; Kevin W Piezer; Jennifer Gatz; Sara Kollack-Walker; Vicki Poole Hoffmann; Robert Conley; Todd Durell Journal: BMC Psychiatry Date: 2010-11-03 Impact factor: 3.630