Antipsychotic (AP) polypharmacy is common in psychiatric practice, despite concerns about its risks and questions regarding its effectiveness.1-4 One concern when prescribing antipsychotic drugs, whether as monotherapy or in polypharmacy, is the potential for prolongation of the QT interval corrected for heart rate (QTc), which increases the risk of torsades de pointes and ventricular fibrillation.2 The risk of QTc lengthening is dose-dependent and possibly increases with AP polypharmacy (the concurrent use of ≥2 AP drugs), which has been associated with increased cumulative equivalent AP dosage.3   

A recent study by C. Barbui and colleagues sought to determine whether AP dose mediates the association between polypharmacy and QTc interval, using data from a cross-sectional survey that examined the prevalence of QTc lengthening among patients with psychiatric illnesses in Italy. All patients in the study took antipsychotic medication, and ECG examination was also necessary for inclusion. Of the 1776 patients recruited, those with cardiovascular disorders or other risk factors for QTc prolongation were excluded. Of the 725 remaining patients, 186 (26%) were taking ≥2 AP drugs, thereby meeting the study’s definition of polypharmacy, and 539 (74%) were on monotherapy.3 Antipsychotic drug doses were converted into multiples of the Defined Daily Dose (DDD), the international unit of drug utilization. 

The study found that the mean cumulative AP dose (prescribed daily dose/defined daily dose) was significantly higher (2.93, SD 1.31 vs. 0.82, SD 0.77)(z=-12.62, P <.001) and the QTc interval was significantly longer (mean=420.86 milliseconds, SD 27.16 vs. 413.42 milliseconds, SD 31.54; z= -2.70, P=.006) in patients taking ≥2 AP drugs than in those taking only one. The number of AP drugs taken was significantly associated with AP dose (z test for trend =12.135, P<.001) and QTc interval (z test for trend =3.35, P<.001). After mediational analysis and adjustment for confounding variables, the data showed that AP dose mediates the association between polypharmacy and QTc interval.

In a 2004 study by M. J. Sernyak and R. Rosenheck, 1 of the 4 most common reasons for prescribing more than 1 antipsychotic drug was “decreasing total amount of medication,” a rationale cited by 9% of clinicians.5 But as the study by Barbui and colleagues noted, “ since AP polypharmacy is not associated with reduced cumulative dose of AP drugs, but the combined equivalent is significantly higher in those receiving AP polypharmacy compared with those on monotherapy, this may actually worsen the QTc interval.”3 That is, adding a second AP drug may increase the risk of QTc interval prolongation, rather decrease it, as is sometimes assumed.