The heart of psychotropic drug therapy

Abstract

J G Reilly and colleagues1Reilly JG Ayis SA Ferrier IN Jones SJ Thomas SHL QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients.Lancet. 2000; 355: 1048-1052Summary Full Text Full Text PDF PubMed Scopus (550) Google Scholar report an association between QTc lengthening and the use of tricyclic antidepressants, droperidol and thioridazine, in psychiatric patients. Age over 65 years and female sex were significantly associated with QTc lengthening in their study, but cardiovascular disease and diuretic use were not. However, the presence of any of these risk factors in patients taking drugs that lengthen QTc is known to increase the likelihood of torsade de pointes. Reilly and colleagues point out that the mechanism underlying QTc lengthening by thioridazine is blockade of the delayed rectifier cardiac potassium channel (IK). This channel, specifically the rapidly activating component (IKr), plays a central part in arrhythmogenesis. Its malfunction, either through blockage by drugs or through genetic defects (eg, in congenital long QT syndrome), impairs cardiac repolarisation resulting in QT prolongation and serious ventricular arrhythmias, such as torsade de pointes. The gene which encodes IKr has been identified as the human-ether-a-go-go-related gene (HERG).2Sanguinetti MC Jiang C Curran ME Keating MT A mechanistic link between an inherited and an acquired cardiac arrhythmia. HERG encodes the Ikr potassium channel.Cell. 1995; 81: 299-307Summary Full Text PDF PubMed Scopus (2118) Google Scholar Work from several groups, including our own,3Walker BD Singleton CB Bursill JA et al.Inhibition of the human ether-a-go-go related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.Br J Pharmacol. 1999; 127: 243-251Crossref PubMed Scopus (52) Google Scholar using HERG-transfected cell lines, have established that drugs that prolong the QT interval (eg, antipsychotics, antihistamines, macro-lide antibiotics, and cisapride) all have in common blockade of HERG potassium channels as the underlying cellular mechanism. Indeed, we have studied thioridazine as well as the tricyclic antidepressant amitriptyline in our model of HERG channels stably expressed in Chinese Hamster Ovary cells.3Walker BD Singleton CB Bursill JA et al.Inhibition of the human ether-a-go-go related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.Br J Pharmacol. 1999; 127: 243-251Crossref PubMed Scopus (52) Google Scholar We found that both drugs blocked HERG tail current in a concentration-dependent manner, with clinically relevant 50% inhibition concentrations (IC50s; figure). Our finding of concentration-dependent HERG channel blockade at the cellular level correlates well with Reilly and colleagues' clinical observation of a dose-related increase in QTc lengthening by these drugs. We have also examined chlor-promazine and found that it too caused concentration-dependent inhibition of HERG channel currents (figure). Likewise, Suessbrich and colleagues have reported potent blockade of HERG potassium channels by haloperidol.4Suessbrich H Schonherr R Heinemann SH Attali B Lang F Busch AE The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus Oocytes.Br J Pharmacol. 1997; 120: 968-974Crossref PubMed Scopus (202) Google Scholar Despite these findings, and case reports of QTc prolongation in patients receiving therapeutic doses of chlorpromazine and haloperidol, neither drug was significantly associated with QTc lengthening in the series by Reilly and colleagues. Several limitations that the investigators highlighted may have resulted in an underestimate of the true prevalence of QTc lengthening in their study. Differential protein binding of the various drugs in vivo is another factor contributing to their varying propensity to lengthen QTc. The atypical antipsychotic agent sertindole has been withdrawn from the market by its manufacturer (H Lundbeck A/S, Copenhagen, Denmark) due to concerns about adverse cardiac events. Low doses of sertindole produce QT lengthening and this adverse effect has been shown to be due to potent HERG channel blockade by the drug.5Rampe D Murawsky MK Grau J Lewis EW The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG.J Pharmacol Exp Tlier. 1998; 286: 788-793PubMed Google Scholar These data support the concept that psychoactive drugs, with a high affinity for HERG potassium channels, can cause serious ventricular arrhythmias, particularly during overdoses or in combination with other risk factors that lengthen QTc. We propose that in-vitro testing of the wide range of antipsychotic agents for their effects on HERG channels would be another useful screening procedure to predict relative risk for QTc prolongation, ventricular arrhythmias, and sudden death.