title: Antipsychotic Dose Mediates the Association between Polypharmacy and Corrected QT Interval.
abstract: Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = -12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = -2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy.
authors: WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, University of Verona, Verona, Italy.
authors: Corrado
authors: C
authors: Barbui
authors: WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, University of Verona, Verona, Italy.
authors: Irene
authors: I
authors: Bighelli
authors: Division of Psychiatry, University College of London, UK, and Department of Medicine and Surgery, University of Milano Bicocca, Milan, Italy.
authors: Giuseppe
authors: G
authors: Carrà
authors: WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, University of Verona, Verona, Italy.
authors: Mariasole
authors: M
authors: Castellazzi
authors: Department of Mental Health, Siena, Italy.
authors: Claudio
authors: C
authors: Lucii
authors: Department of Neuroscience, Imaging and Clinical Sciences, University of Chieti, Chieti, Italy.
authors: Giovanni
authors: G
authors: Martinotti
authors: WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, University of Verona, Verona, Italy.
authors: Michela
authors: M
authors: Nosè
authors: WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, University of Verona, Verona, Italy.
authors: Giovanni
authors: G
authors: Ostuzzi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000068180:Aripiprazole / Q000009:adverse effects; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006220:Haloperidol / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy; D008875:Middle Aged; D019338:Polypharmacy; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D006220:Haloperidol