title: A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition.
abstract: Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.
authors.affiliation: Pfizer Global Research and Development, New London, CT 06320, USA.
authors.forename: Edmund P
authors.initials: EP
authors.lastname: Harrigan
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Miceli
authors.forename: Richard
authors.initials: R
authors.lastname: Anziano
authors.forename: Eric
authors.initials: E
authors.lastname: Watsky
authors.forename: Karen R
authors.initials: KR
authors.lastname: Reeves
authors.forename: Neal R
authors.initials: NR
authors.lastname: Cutler
authors.forename: John
authors.initials: J
authors.lastname: Sramek
authors.forename: Thomas
authors.initials: T
authors.lastname: Shiovitz
authors.forename: Michelle
authors.initials: M
authors.lastname: Middle
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects*; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D000069348:Quetiapine Fumarate; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D013881:Thioridazine / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D001189:Aryl Hydrocarbon Hydroxylases; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D013881:Thioridazine; D000077152:Olanzapine