Antipsychotic agents and QT changes

R. Welch, BSc(Pharm); P. Chue, MRCPsych

Welch - Alberta Hospital Edmonton, Edmonton, Alta.; Chue- Psychopharmacology Research Unit, University of Albertaand Alberta Hospital, Edmonton

Recently, antipsychotic medications of the novel or atypical classes have received increased attentionbecause of concerns with respect to potential lengthening of the QT interval, yet the currently availableand commonly prescribed conventional antipsychotics are significantly more cardiotoxic, particularly agentsin the butyrophenone and phenothiazine classes. Lengthening of the QT interval can be associated with afatal paroxysmal ventricular arrhythmia known as torsades de pointes. The specific duration of the QTinterval at which the risk of an adverse cardiac event is greatest, is not established. There is not only sig-nificant variation in the applied definition of an abnormal interval, but the maximal QT interval in healthyvolunteers is greater than the currently accepted standards. The QT interval is influenced by normal phys-iological and pathologic factors, but the mechanisms remain unclear. Using recombinant technology,haloperidol and sertindole have been demonstrated to be high-affinity antagonists of a human cardiacpotassium channel encoded by the human ether-a-go-go-related gene. Pimozide, however, has been shownto act principally through calcium channel antagonism, and chlorpromazine may affect sodium channels.Nevertheless, it is possible that these effects are significant only in the presence of predisposing factors,either genetic or acquired. Despite proven efficacy in clinical trials and subsequent supervised use inEurope, a number of recently developed antipsychotic medications are not available to patients in NorthAmerica. Yet, conventional antipsychotic medications that would not be approved by current safety stan-dards continue to be widely used.

Les neuroleptiques nouveaux ou atypiques attirent de plus en plus d'attention depuis quelque temps acause des preoccupations soulevees par la possibilite de prolonger l'intervalle QT, mais les neuroleptiquesactuellement disponibles et prescrits couramment sont beaucoup plus cardiotoxiques, en particulier lesbutyrophenones et les phenothiazines. L'allongement de l'intervalle QT peut entrainer une arythmie ven-triculaire paroxystique fatale (torsade de pointes). La duree precise de l'intervalle QT a laquelle le risqued'incident cardiaque indesirable est le plus eleve n'est pas etablie. Non seulement il existe des variationsimportantes de la definition appliquee d'un intervalle anormal, mais on constate egalement que l'intervalleQT maximal chez des volontaires en bonne sant6 est plus long que les normes courantes acceptees. Desfacteurs physiologiques et pathologiques normaux agissent sur l'intervalle QT, mais les mecanismes ne sonttoujours pas clairs. Au moyen de la technologie recombinante, on a demontr6 que l'haloperidol et le sertin-dole sont des antagonistes i grande affinite d'un canal potassique cardiaque humain code par le genehumain apparente au gene dit ((ether-a-go-go)). On a toutefois demontre que le pimozide agit principale-

Correspondence to: Dr. P. Chue, Psychopharmacology Research Unit, 10-126 CSB, 8440-112th St., Edmonton AB T6G 2B7; fax 780407-3329; pchue@ualbertaca

Medical subject headings: action potentials; antipsychotic agents; arrhythmia; death, sudden; electrocardiography; ion channels; torsades de pointes

J Psychiatry Neurosci 2000;25(2):154-60.

Submitted Jan. 15, 1999Revised Oct. 18, 1999Accepted Nov. 1, 1999

© 2000 Canadian Medical Association

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ment par antagonisme des canaux calciques et que la chlorpromazine peut avoir une incidence sur les canauxsodiques. 11 se peut neanmoins que ces effets ne soient importants qu'en presence de facteurs predisposants,genetiques ou acquis. Meme si leur efficacite a ete demontree par des etudes cliniques et s'ils sont utilises depuissous supervision en Europe, de nombreux neuroleptiques mis au point recemment ne sont pas disponibles enAmerique du Nord. Or, on continue d'utiliser beaucoup de neuroleptiques classiques qui ne seraient pas approu-ves en fonction des normes de securite en vigueur.

The issue of QT prolongation has gained increasingattention, particularly in recent years, because of itsassociation with a potentially lethal paroxysmal ven-tricular arrhythmia known as torsades de pointes (Tdp;Fig. 1).1A Fatalities associated with patients taking terfe-nadine and astemizole,'-7 as well as QT changes noted inpatients taking mibefradil and cisapride,>'0 led to regu-latory bodies restricting, relabelling or removing thesemedications from markets. The antipsychotic medica-tion, sertindole (a substituted indoyl piperidine) wasrecently withdrawn from the European market becauseof QT prolongation. In France, The Society ofPharmacovigilance requires hospital initiation foradministration of sultopride (a substituted benzamide)and urges caution with the concomitant administrationof specific medications, or when the patient is experi-encing hypokalemia or bradycardia. In light of theseissues (which only become apparent at relatively latestages in drug development when larger numbers ofpatients are studied), the Food and Drug Admini-stration now requires specific safety data from clinicaltrials reflective of the potential problems found in clini-cal practice, particularly any drug-drug interactionsthat could affect parameters such as the QT interval.Such studies are currently ongoing with ziprasidone (abenzisothiazolyl piperazine).QT prolongation is associated with various ventricu-

lar arrhythmias, syncope and sudden death. Although

Fig. 1: Electrocardiogram illustrating torsade de pointes.

marked QT prolongation increases the risk of arrhyth-mia, the specific duration at which the risk of arrhyth-mia is greatest (the critical QT interval) is not well estab-lished. The clinically significant measure of QT prolon-gation, the corrected QT (QTc) interval, is inverselyrelated to heart rate and may be calculated by a numberof different regression formulae, the most common ofwhich is Bazzet's formula."' However, differences existin the methods of measurement, and there are inherentdifficulties in the measurement of the end of the Twave."1-3 Fig. 2 represents a normal electrocardiogram(ECG) with associated intervals.'4The age- and sex-adjusted standard for a prolonged

interval has been defined at different lengths over thecourse of time," ranging from greater than 370 millisec-onds in males and 400 milliseconds in females, increas-ing to greater than 460 milliseconds in males and 490milliseconds in females, and then declining to greaterthan 420 milliseconds in males and 430 milliseconds infemales. More recently, the upper limit of normal hasbeen defined as an interval ranging from 420 to 500 mil-liseconds,1""16 whereas the clinically significant QT inter-

Fig. 2: Normal electrocardiogram and the associatedintervals.

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val, as reported by pharmaceutical companies, has beendefined as an interval greater than 500 milliseconds."7 Ina study of 6693 patients undergoing 24-hour ambulato-ry ECG, a QTc interval in excess of 440 milliseconds wasassociated with more than double the incidence of sud-den death.'8 However, there was not only greater mor-

bidity in the deceased patients versus controls, includ-ing a history of previous ischemic cardiac disease, butconfoundingly, there was a similar incidence of suddendeath when the QTc interval was less than 400 millisec-onds.'8 A study of healthy volunteers demonstratedconsiderable diurnal variability in the QTc interval,with an average maximal interval of 495 (standard devi-ation 21) milliseconds.19 The maximum QTc intervalequalled or exceeded 490 milliseconds in more than halfof the individuals, and was longest and most variable atwakening, the period of greatest risk for sudden cardiacdeath. In addition, a gender effect was found, with sig-nificantly longer QTc intervals found in women.'9 TheQT interval has also been shown to vary with foodingestion in healthy volunteers, with post-prandial pro-

longation ranging from 16 to 23 milliseconds.20The length of the QT interval does not strictly reflect

repolarization of the ventricles, the event associatedwith the induction of Tdp. It is the summation of all theelectrophysiological events, from the time of initialdepolarization of the ventricles (beginning of the Qwave) to their subsequent repolarization (end of the Twave), in a given lead. Drugs such as the tricyclic anti-depressants, which increase depolarization (increasethe QRS interval) as well as repolarization, make theevaluation of a true prolonged QTc interval difficult."'2'The development of malignant ventricular arrhythmiasis often preceded by T wave alternans (inversion of theT wave), which reflects a failure in the recovery of theion channels before the next action potential and isrelated to particularly prolonged QTc intervals." Sincethe QT interval is a surface manifestation of actionpotential duration (Fig. 322), it has been suggested thatthe underlying cellular mechanism of Tdp-induction isthe development of early-after depolarizations (EADs)in the conducting system of the Purkinje fibres. EADsare oscillations occurring during repolarization inPhase 2 (early/plateau) and Phase 3 (late) of the actionpotential, which, in vitro, give rise to triggered actionpotentials leading to premature beats if propagatedthroughout the entire heart. EADs follow inhibition ofrepolarization either through decreased potassium (K+)efflux (e.g., by antiarrhythmic drugs) and/or through

increased calcium (Ca2+) or sodium (Na+) influx. EAD-triggered activity may initiate or maintain Tdp througha number of complex processes.23

It is important to note that lengthening of the QTinterval is not necessarily associated with Tdp.Antiarrhythmic drugs such as amiodarone can cause

relatively benign increases of over 600 milliseconds,whereas others such as procainamide have an increasedpropensity to cause Tdp at considerably shorter inter-vals.24 Thus, the exact mechanism underlying the gener-

ation of Tdp remains unclear. In addition, the signifi-cance of QTc prolongation in patients taking antipsy-chotic medications is unknown with respect to pre-

dictability of adverse outcomes, especially when QTcdispersion (the difference between the longest andshortest QTc interval) is unchanged.'6

In addition to the congenital causes, a number ofpathophysiologic conditions are associated with alteredrepolarization of the ventricles and prolongation of theQT interval. They include Parkinson's disease and othercentral nervous system (CNS) disorders, diabetes,hypothyroidism, electrolyte disturbances (especiallyhypokalemia and hypomagnesemia), obesity, anorexia,hypoalimentation, cirrhosis and myocardial dis-ease.1221,2"3 Drugs, however, account for the largestgroup of acquired causes that can induce Tdp."224 Table1 summarizes the growing list of drugs that can pro-

duce QT prolongation and/or Tdp.i"2A number of risk factors are associated with drug-

induced Tdp. These include sex, age, cardiac disease,comorbid electrolyte disturbances, metabolic or

endocrine abnormalities, CNS insult, toxins and con-

genital long QT syndromes (LQTS). LQTS are charac-

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terized by prolonged QT intervals, QT interval labilityand polymorphic ventricular tachycardia. Mutationscausing LQTS have now been identified in 4 genes, eachencoding an ion channel and linked to chromosome 3(SCN5A; Na'channel), chromosome 7 (HERG; K'chan-nel), chromosome 11 (KVLQT1; K' channel) and chro-mosome 21 (KCNE1; KI channel). There has been a fifthgene implicated in LQTS identified on chromosome 4,however, the specific mutation in the gene has yet to beidentified2.' The potential for a comorbid-inheriteddiathesis is conceivable given that cytogenetic studieshave implicated several genes on chromosomes 3 and11 with schizophrenia.'-" Lastly, QTc interval prolonga-tion is related to the class of antipsychotic medication(particularly butyrophenones and phenothiazines),dosage (especially greater than 2000 mg of chlorpro-mazine equivalents16) and drug-drug interactions.Cardiovascular morbidity'6 and mortality has been

well documented with administration of many antipsy-chotic medications, including the older agents haloperi-dol, droperidol, pimozide, chlorpromazine and thiori-dazine,36-4 as well as the novel antipsychotic medica-tions such as risperidone.4' Although there is limitedinformation available in the medical literature regard-ing QTc intervals and the novel antipsychotic medica-tions, the presentation of the data also makes it difficultto make meaningful comparisons. For example, somestudies express data as the percent incidence greaterthen 450 milliseconds or 500 milliseconds, frequentlytermed the "clinically significant QTc prolongation."Fig. 4 compares the mean QTc intervals of ziprasidone,risperidone, quetiapine, sertindole and olanzapine,derived from thie available data.9'4The mechanisms by which both conventional and

Drug class Medication

Psychotropic Phenothiazines antipsychotdcs, haloperidol,pimozide, tricyclic antidepressants, lithium,chloral hydrate

Antiarrhythmic Disopyramiide. Procarnaffide, quinidine,amiodaron.e, bretylium, sotalol

Antihistamine Astemizole, terfenadineAntimicrobial Erythromnycin, trimethoprim-sulfamethoxazole,

tetracyclineGastrointestinal CisaprideprokinetlcAntimalarial or Chloroquine, halofantrine, mefloquine,antiprotozoal pentamidine, quinineMiscellaneous Amantadine, pro'hucol, tacrolimus, vasopressin

atypical antipsychotic medications influence the QTinterval is complex, but there is increasing evidence toimplicate certain subtypes of myocardial ion channels.Haloperidol and sertindole have been proposed to exerttheir arrhythmogenic side effects through antagonismof the human ether-a-go-go-related gene (HERG) thatencodes for a protein associated with a cardiac KI chan-nel involved in the rapid delayed rectifier current I/'I,. is involved in repolarizing currents, inhibition ofwhich prolongs the duration of the action potential.Studies of cloned human cardiac KI channels transfect-ed into mammalian cell lines suggests that this channelmay also be involved in acquired QTc interval prolon-gation. Haloperidol binds to the open or inactivatedHERG channel with an IC-, value of approximately 1jimol/L, whereas the primary active metabolite ofhaloperidol, reduced haloperidol, binds with an IC,,value of 2.6 gimol/L. Sertindole, however, producesantagonism at 14 nmol/L.44 This high affinity antago-nism of the HERG KI channel is the putative mecha-nism underlying the prolongation of the QT intervalobserved with this drug and is comparable to the classHII antiarrhythmic medications. Indeed, the blockade isso potent that it has been suggested that this moleculemay have a role as a cardiovascular medication.Interestingly, because HERG was originally clonedfrom human brain," it has been suggested that some ofthe antipsychotic effects result from the blockade ofsimilar channels in the CNS. This idea remains specula-tive, however, since no CNS functions have thus farbeen associated with HERG channels, and mutations inthe gene are not associated with neurologic abnormali-ties." Nevertheless, the voltage-dependent KI channelKv2-1 has been cloned from human brain and fluspiri-

Fig. 4: The mean QTc interval prolongation of selected

novel antipsychotic drugs.

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lene has been shown to be a relatively potent antagonistof this channel.46 Additionally, sex hormone effects(estradiol and dihydrotestosterone) causing prolonga-tion of the QT interval through downregulation of repo-larizing K+ channels, have been described in rabbit ven-tricular cells.4 Again, although speculative at this point,the actions of hormones may directly impact cardiacregulation, since women have longer baseline QT inter-vals than men, and being a woman has been identifiedas a predisposing factor for drug-induced Tdp.48HERG K+ channel actions may not account for the

effect of all antipsychotic medications on the QT inter-val. Studies, particularly in animal models, need to beinterpreted with caution and may account for the incon-sistency among findings. A study of feline myocardiumexposed to haloperidol, risperidone, sertindole, cloza-pine and olanzapine, showed that all of these drugsprolonged QT intervals in a concentration-dependentmanner, with haloperidol and risperidone being themost potent. This finding is not consistent with thecloned human cardiac channel data with sertindole.49Pimozide (a diphenylbutylpiperidine), which was

associated with sudden cardiac death in young adults inEurope in the 1980s (which led to recommended ECGmonitoring), is a potent Ca2+ channel antagonist.5"Pimozide has been shown to potently block L-type Ca2+channels in rat ventricular myocytes in a voltage-depen-dent manner, producing a negative ionotropic effect.Two other diphenylbutylpiperidines, penfluridol andfluspirilene, also block the KCl-induced response at sim-ilar concentrations. These actions resemble the conven-tional cardiovascular drugs diltiazem, verapamil andnifedipine, which are used clinically to treat hyperten-sion, arrhythinias and angina pectoris.'' Interestingly,pimozide is also distinctive in its ability to block a pop-ulation of Ca2+ channels, the low-threshold rapidly-inactivating T channel, in sinoatrial cells, as well as inGH4Cj pituitary cells in the brain;"' Ca2+ movementthrough these T channels in rabbit sinoatrial cells has aneffect on pacemaker potential and heart rate.Chlorpromazine is associated with cardiac arrhyth-

mias such as ventricular and atrial tachycardia, prema-ture atrial beats, heart block and ventricular fibrillation.In addition, alterations in PQ, QRS and QTc intervals, aswell as T-wave changes and ST-segment depression,have been reported.5' Chlorpromazine has been shown toblock a variety of K+-dependent channels in heart musclecells in rats, but the potency of this inhibition is signifi-cantly less than that reported for Na+-dependent chan-

nels. It is likely that the cardiovascular effects of chior-promazine are caused by its effect on Na+-dependentchannels.5" At higher concentrations, inhibition of K+-currents is associated with a class III antiarrhyffimiceffect.5'There are relatively few studies directly linking drug-

induced ECG changes with electrophysiologicalchanges. Such a study with sultopride, droperidol,thioridazine and clozapine on Purkinje fibres demon-strated class IH effects with droperidol and sultopride.Class I effects were seen with higher concentrations ofdroperidol alone and when thioridazine and clozapinewere used together. EADs developed early with admin-istration of droperidol and sultopride and were influ-enced by extracellular K+ or Mg2+ concentrations andmodification of Ca2+ entry by nifedipine or isopro-terenol.52 The guidelines for the clinical use of sulto-pride in France reflect this data.

It is apparent that the regulatory approval of medica-tions with proven clinical efficacy becomes an issue ofrisk-benefit analysis. Although QTc prolongation maybe less of a problem with the more recently marketedatypical antipsychotic medications, the larger numberof pharmaceutical options currently available, includ-ing clozapine, risperidone, olanzapine, quetiapine andremoxipride (special status), as well as an increasedsensitivity of regulatory agencies to potential sideeffects, have complicated and delayed the approvalprocess. This dilemma exists despite technologicadvances, particularly in the area of cloned human car-diac channels. Indeed, a senior researcher in this arearecommended in 1997 that such data be included in thepreclinical data package for regulatory approval, sincestandard cardiovascular safety profiling did not detectcardiotoxicity, even at relatively late stages in drugdevelopment."3 However, it is less clear that QT prolon-gation is accounted for solely by specific ion channelchanges or, more importantly, whether this phenome-non is the only cause of morbidity and mortality associ-ated with medication. It may well be that destabiliza-tion of the action potential by a number of mechanismsmay account for cardiotoxicity, of which QT prolonga-tion is but 1 manifestation. Regardless, many valuablemedications can be used safely with adherence toappropriate monitoring requirements; for example,mandatory blood monitoring with clozapine or recom-mended ECG monitoring with pimozide (for dosesabove 16 mg in Europe and 20 mg in North America).Despite many recent technologic advances, much of

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the practical understanding of antipsychotic medica-tions continues to be derived from clinical use. Thenewer antipsychotic medications have unique proper-ties that distinguish them pharmacologically from othercurrently available antipsychotic medications. It isimperative that the issue of cardiotoxicity is addressedto establish whether the preclinical efficacy of theseagents can be safely translated into clinical practice.Psychiatric patients possess many of the acquired riskfactors for ischemic cardiac disease (e.g., smoking, inac-tivity), which in the presence of a potential geneticdiathesis and medications that can affect ion channelsand/or the QT interval, may lead to an increased sus-ceptibility for adverse cardiac events. It is clear that thecommonly prescribed conventional antipsychotic med-ications, notwithstanding their long-term neurotoxiceffects, are associated with a significant potential forcardiovascular morbidity and would not be approved ifsubmitted under current restrictions and guidelines.

Acknowledgements

The authors thank Professor Glen Baker for his carefulreview of the manuscript.

References

1. Perotti-Amoroso A, Manceau A, Goulet A, Bisaillon C,MacKenzie J, Fearo M, et al. Serlect recommended by the FDAadvisory committee for schizophrenia. Doctors Guide to Medicaland Others News. 1996;July 15.

2. FDC Reports. FDA letter poses hurdle for new antipsychotic:Pink Sheet; 1998;July.

3. FDC Reports. Zeldox Swedish contraindications include pro-longed QT interval: Pink Sheet; 1998;July. p. 13.

4. Huzzar RJ. Basic dysrrhythmias: interpretation and management.Los Angeles: C.V. Mosby; 1995. p. 173.

5. Josefson D. Hay fever drug to be banned by the FDA. BMJ1997;314:248.

6. FDA announces plan to halt marketing of terfenadine [news].Am J Health Syst Pharm 1997;54:342.

7. Wise J. Hay fever drug to become prescription only. BMJ1997;314:1299.

8. Gray VS. Syncopal episodes associated with cisapride and con-current drugs. Ann Pharmacother 1998;32:648-51.

9. FDC Reports. Pfizer zeldox awaits QTc comparison to risper-

dal, zyprexa. Pink Sheet; 1998;Aug:21.

10. SoRelle R. Withdrawal of posicor from market. Circulation1998;98:831-2.

11. Moss AJ. Measurement of the QT interval and the risk associ-ated with QTc interval prolongation: a review. Am J Cardiol1993;72:23B-25B.

12. Moss AJ. Prolonged QT-interval syndromes. JAMA1986;56:2985-7.

13. Woosley RL, Sale M. QT interval: a measure of drug action. AmJ Cardiol 1993;72:36B-43B.

14. Spence AP, Mason EB. Human anatomy and physiology.California: The Benjamin/Cummings Publishing Company;1985. p. 495.

15. Perkins DO, Lieberman JA. Medical complications and selec-tivity of therapeutic response to atypical drugs. Am J Psychiatry1998;155:272-6.

16. Wamer JP, Bames TR, Henry JA. Electrocardiographic changesin patients receiving neuroleptic medication. Acta PsychiatrScand 1996;93:311-3.

17. Litherland S. Drug treatment and schizophrenia in the 1990's.Drugs 1997;54:794.

18. Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. QT intervalvariables from 24 hour electrocardiography and the two yearrisk of sudden death. Br Heart J 1993;70:43-8.

19. Molnar J, Zhang F, Weiss J, Ehlert FA, Rosenthal JE. Diumalpattern of QTc interval: How long is prolonged? Possible rela-tion to circadian triggers of cardiovascular events. J Am CollCardiol 1996;27:76-83.

20. Nagy D, DeMeersman R, Gallagher D, Pietrobelli A, Zion AS,Daly D, et al. QTc interval (cardiac repolarization): lengtheningafter meals. Obes Res 1997;6:531-7.

21. Scott JL, Walls RM. QT interval prolongation. J Emerg Med1985;3:221-5.

22. Lipman BC, Lascio T. ECG assessment and interpretation.Philadelphia: F.A. Davis; 1994.

23. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbi J, Vincent,GM. Multiple mechanisms in the long-QT syndrome. Currentknowledge, gaps, and future directions. The SADS foundationtask force on LQTS. Circulation 1996;94:1996-2012.

24. Singh BN. When is QT prolongation antiarrhythmic and whenis it proarrhythmic? Am J Cardiol 1989;63:867-9.

25. Bernardi M, Calandra S, Colantoni A, Trevisani F, RaimondoML, Sica G, et al. Q-T interval prolongation in cirrhosis: preva-lence, relationship with severity, and etiology of the disease

VoL 2$---o Zq th2O%X)L':Lfa4

9-*v,Y

and possible pathogenetic factors. Hepatology 1998;27:28-34.

26. Carella MJ, Mantz SL, Rovner DR, Willis PW, Gossain VV,Bouknight RR, et al. Obesity, adiposity, and lengthening of theQT interval: improvement after weight loss. Int J Obes RelatMetab Disord 1996;20:938-42.

27. Cooke RA, Chambers JB, Singh R, Todd GJ, Smeeton NC,Treasure J. QT interval in anorexia nervosa. Br Heart J1994;72:69-73.

28. El-Gamal A, Gallagher D, Nawaras A, Gandhi P, Gomez J,Allison DB, et al. Effects of obesity on QT, RR, and QTc inter-vals. Am J Cardiol 1995;75:956-9.

29. Ishizaki F, Harada T, Yoshinaga H, Nakayama T, Yamamura Y,Nakamura S. Prolonged QTc intervals in Parkinson's disease- relation to sudden death and autonomic dysfunction. No ToShinkei 1996;48:448-9.

30. Oka H, Mochio S, Sato H, Katayama K. Prolongation of QTcinterval in patients with Parkinson's disease. Eur Neurol1997;37:186-9.

31. Sawi PT, Dahne R, Bender R, Berger M. Prolonged QT intervalas a predictor of mortality in diabetic nephropathy. Diabetologia1996;39:77-81.

32. Springuel P. Drugs causing prolongation of QT interval andtorsades de pointes. CMAJ 1998;158:103-4.

33. Tentolouris N, Katsilambros N, Papazachos G, PapadogiannisD, Linos A, Stamboulis E, et al. Corrected QT interval in rela-tion to the severity of diabetic autonomic neuropathy. Eur JClin Invest 1997;27:1049-54.

34. Wojciech Z, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL,Priori SG, et al. Influence of the genotype on the clinical courseof the long-QT syndrome. N Engl J Med 1998;339:960-5.

35. Tsuang MT, Faraone SV. Genetic heterogeneity of schizophre-nia. Seishin Shinkeigaku Zasshi 1995;97:485-501.

36. Jackson T, Ditmanson L, Phibbs B. Torsade de pointes and low-dose haloperidol. Arch Intern Med 1997;157:2013-5.

37. Lawrence KR, Nasraway SA. Conduction disturbances associ-ated with administration of butyrophenone antipsychotics inthe critically ill: a review of the literature. Pharmacotherapy1997;17:531-7.

38. Ochiai H, Kashiwagi M, Usui T, Oyama Y, Tokita Y, IshikawaT. Torsade de pointes with T wave altemans in a patient receiv-ing moderate dose of chlorpromazine: report of a case. KokyuTo Junkan 1990;38:819-22.

39. Paoloni P, Ciliberti D, Blasi N, Capone P. Iatrogenic torsade depointes induced by thioridazine. Minerva Cardioangiol1992;40:245-9.

40. Sharma ND, Rosman HS, Padhi D, Tisdale JE. Torsades depointes associated with intravenous haloperidol in critically illpatients. Am J Cardiol 1998;81:238-40.

41. Ravin DS, Levenson JW. Fatal cardiac event following initia-tion of risperidone therapy. Ann Pharmacother 1997;31:867-70.

42. Tran PV, Hamilton SH, Kuntz AJ, Potvin JH, Andersen SW,Beasley C, et al. Double-blind comparison of olanzapine versusrisperidone in the treatment of schizophrenia and other psy-chotic disorders. J Clin Psychopharmacol 1997;17:407-18.

43. Litherland S, Fleischhacker WW, Hummer M. Drug treatmentand schizophrenia in the 1990s. Drugs 1997;54:794.

44. Rampe D, Murawsky MK, Grau J, Lewis EW. The antipsychot-ic agent sertindole is a high affinity antagonist of the humancardiac potassium channel HERG. J Pharmacol Exp Ther1998;286:788-93.

45. Suessbrich H, Schonherr R, Heinemann SH, Attali B, Lang F,Busch AE. The inhibitory effect of the antipsychotic drughaloperidol on HERG potassium channels expressed inXenopus oocytes. Br J Pharmacol 1997;120:968-74.

46. Wible B, Murawsky MK, Crumb WJ, Rampe D. Stable expres-sion and characterization of the human brain potassium chan-nel Kv2.1: blockade by antipsychotic agents. Brain Res1997;761:42-50.

47. Drici MD, Burklow TR, Haridasse V, Galzer RI, Woolsey RL.Sex hormones prolong the QT interval and downregulatepotassium channel expression in the rabbit heart. Circulation1996;94:1471-4.

48. Makkar RR, Fromm BS, Steinman RT, Meissner MD, LehmannMH. Female gender as a risk factor for torsades de pointesassociated with cardiovascular drugs. JAMA 1993;270:2590-7.

49. Drici MD, Wang WX, Liu XK, Woosley RL, Flockhart DA.Prolongation of QT interval in isolated feline hearts by antipsy-chotic drugs. J Clin Psychopharmacol 1998;18:477-81.

50. Enyeart JJ, Dirksen RT, Sharma VK, Williford DJ, Sheu SS.Antipsychotic pimozide is a potent Ca2+ channel blocker inheart. Mol Pharmacol 1990;37:752-7.

51. Kon K, Krause E, Gogelein H. Inhibition of K+ channels bychlorpromazine in rat ventricular myocytes. J Pharmacol ExpTher 1994;271:632-7.

52. Adamantidis MM, Kerram P, Dupuis BA. In vitro electrophys-iological detection of iatrogenic arrhythmogenicity. FundamClin Pharmacol 1994;8:391-407.

53. Rampe D. Voltage-dependant potassium channels cloned fromhuman heart: new tools to predict the pro-arrhythmic potentialof drugs. Ion Channel Modulators 1997;2:331-7.

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