REVIEW

Clinical update

Risk of arrhythmia induced by psychotropicmedications: a proposal for clinical managementSøren Fanoe1, Diana Kristensen2, Anders Fink-Jensen2, Henrik Kjærulf Jensen3,Egon Toft4, Jimmi Nielsen5, Poul Videbech6, Steen Pehrson1,and Henning Bundgaard1*

1Department of Cardiology, The Unit for Inherited Cardiac Diseases, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen2100, Denmark; 2Psychiatric Centre Copenhagen and Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark; 3Department of Cardiology, AarhusUniversity Hospital Skejby, Aarhus, Denmark; 4Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; 5Aalborg Psychiatric Hospital, Aalborg UniversityHospital, Aalborg, Denmark; and 6Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

Received 7 November 2013; revised 19 January 2014; accepted 16 February 2014; online publish-ahead-of-print 18 March 2014

Several drugs used in the treatment of mental diseases are associated with an increased risk of sudden cardiac death (SCD). A general cause-relationship between the intake of these drugs and SCD is unattainable, but numerous case reports of drug-induced malignant arrhythmiaand epidemiological studies, associating the use of specific drugs with SCD, strongly support the presence of an increased risk. Whereas theabsolute risk of drug-induced life-threatening arrhythmia may be relatively low, even small increments in risk of SCD may have a major healthimpact considering that millions of patients are treated with psychotropics. In subgroups of pre-disposed patients, e.g. patients with cardiac dis-eases or other co-morbidities, the elderly or patients treated with other negatively interacting drugs, the absolute risk of drug-induced arrhythmiamaybeconsiderable. On the other hand, severalof the majormental disorders areassociated with a large riskof suicide if untreated. The observedriskof malignant arrhythmia associated with treatment with psychotropic drugs calls for clinical guidelines integrating the riskof the individual drugand other potentially interacting risk factors. In this review, data from various authorities on the risk of arrhythmia associated with psychotropicmedications were weighted and categorized into three risk categories. Additionally, we suggest a clinically applicable algorithm to reduce the riskof malignant arrhythmia in patients to be treated with psychotropic medications. The algorithm integrates the risk categories of the individualdrugs and pre-disposing risk factors and suggests a prudent follow-up for patients with an increased risk. We believe this clinically manageableguideline might improve safety in the many and rapidly increasing number of patients on psychotropic drugs.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Acquired long QT † Pro-arrhythmia † Psychotropics † Torsade de Pointes ventricular tachycardia † Drug-induced

† Sudden cardiac death

IntroductionSeveral studies have reported an increased incidence of suddencardiac death (SCD) in patients treated with anti-psychotic or anti-depressant drugs.1 –3 Ray et al.4 demonstrated a two-fold increasein the incidence–rate ratio for SCD in current users of antipsychoticscompared with non-users and former users and Weeke et al.5

showed that treatment with certain anti-depressants was associatedwith up to a 5- to 6-fold increase in the incidence of out-of-hospitalcardiac arrest. On the other hand, untreated depression per semore than doubles the risk of SCD,6,7 which adds to the overallrisk of SCD in these patients. In the study by Whang et al.1 depression

was associated with an increased risk of fatal ischaemic heart diseaseeven when controlling for cardiovascular risk factors, although an un-favourable cardiovascular risk profile is frequent in several subgroupsof patients with psychiatric disorders.8,9 Most recently, Khan et al.10

reported a three–four-fold increased mortality risk associated withschizophrenia, major depression, and bipolar mood disorder.

Mentaldisordersaccount foraboutone-thirdofnon-communicablediseases in Europe, and in the EU population the estimated cumulativerisk for developing a mental disorder up to the age of 65 years is about50%11 and others have shown that about one-third receive pharmaco-therapy.12 Thus, even a small risk of SCD associated with psychotropicmedications may be a major health issue.

* Corresponding author. Tel: +45 35 45 05 12; Fax: +45 35 45 26 28, Email: henningbundgaard@dadlnet.dk

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: journals.permissions@oup.com

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Several drugs associated with SCD have the propensityof prolong-ing the QT interval,13–15 which is considered a substrate for the po-tentially life-threatening ventricular tachycardia, Torsade de Pointes(TdP). Therefore, drug-induced QT prolongation is generally used asa proxy for an increased risk of TdP, i.e. risk of SCD. Torsade dePointes may also present as palpitations, dizziness, or syncope.Drug-induced QT-interval prolongation is most often due to a dose-dependent inhibition of the cellular Ikr current through channelscoded by the hERG gene.16,17

In 2005, the International Conference on Harmonisation of Tech-nical Requirements for Registration of Pharmaceuticals for HumanUse (ICH) published guidelines to evaluate QT interval prolongationand pro-arrhythmic potential of non-Antiarrhythmic Drugs(ICH-E14).18 With few exceptions, all new drugs have to undergo a‘thorough QT study’ (TQT) defined by the ICH-E14. However, themajority of the presently used drugs were marketed before TQTstudies were mandatory. Additionally, even a well-performed TQTstudy cannot rule out pro-arrhythmia when the drug is used inlarge scale in the clinical situation, where patients often receive mul-tiple drugs, have co-morbid substance abuse or even existing heartdiseases. Most importantly, several antipsychotics and antidepres-sants on the market are known to induce QT prolongation. On thisbasis, psychiatrists and other physicians need to be able to assessand handle a potential risk of drug-induced QT prolongation.

In the TQT studies, the drug-induced QT-interval prolongation isused as a surrogate risk marker and the threshold level of regulatoryconcern is an increaseof around5 msabovebaseline,while aQTdur-ation above 500 ms or an increase ≥60 ms above baseline are com-monly used as threshold values in clinical practice. The exact criteriafor the evaluation in the TQT study depends on the indication for thetested drug.19,20

Several common cardiovascular conditions including ischaemicheartdisease, arterial hypertension, heart failure, andbrady-arrhythmias,butalsoabroadrangeof lesscommonconditions likecardiomyopathiesand primary arrhythmia disorders, predispose to the developmentof drug-induced arrhythmia. Interactions with other concomitantlyused drugs, including potassium- and magnesium-wasting diuretics,CYP3A4 inhibitors, and other QT prolonging drugs, e.g. antibioticsand antifungals may also increase the likelihood of serious arrhythmia.In order to improve patient safety, clinical guidelines integrating thesemany potentially interacting factors are warranted and collaborationbetweenpsychiatrists andcardiologists needed.Weproposeaclinicallymanageable guideline for reduction of the riskof arrhythmia induced bydrugs administered to patients with psychiatric disorders (Figure 1).The guideline also suggests a balanced risk–benefit relation in patientsin great need of using these drugs. The proposal was developed incollaboration between the Danish Society of Cardiology and theDanish Psychiatric Society21 (see Appendix).

Figure 1 An algorithm for lowering the risk of cardiac arrhythmia during treatment with psychotropic medications. When a class B or B* drug(Table 2) is chosen, assessment of the cardiac risk profile is recommended. If cardiac risks are identified—the cardiac risk factors should be optimizedand/or a drug with a more favourable risk profile should be chosen. Re-evaluation of the ECG and symptoms should take place within 1 to 2 weeksafter (� 5 half lives) initiation of treatment with class B/B* drugs.

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MethodsIn order to assess the risk of arrhythmia associated with psychotropicmedications, we classified each drug according to the reported effectsat therapeutic levels on the QT interval, induction of arrhythmia, andcardiac conduction disturbances. Data were collected from the followingfive sources:

(i) European Medicines Agency, EU (EMEA),22

(ii) The US Food and Drug Administration (FDA),23

(iii) The Maudsley prescribing guideline,24

(iv) The independent databases Micromedex (TuvenHealth Analytics),25

and(v) The Arizona Center for Education and Research on Therapeutics

(http://crediblemeds.org) (26 February 2014, date last accessed).

Cardiac data from these five sources were reviewed and additionally, foreach drug we reviewed the accessible publications of thorough QTstudies. For each drug, the findings reported in each of these sourceswere carefully reviewed and the combined data weighted; the main—and most important—distinction was made between drugs without anassociated risk of arrhythmia (Class A drug) and drugs with such a risk(Class B drug). The latter group was further subdivided into Class B* drugs.These three categories (Table 1) are modified from qtdrugs.org—nowhttp://crediblemeds.org: drugs with neither QT-prolongation nor TdPrisk corresponds to Class A. The category ‘possible TdP risk’ correspondsto Class B. The categories ‘drugs to be avoided by congenital long QT’,‘Drugs with conditional TdP risk’, and ‘drugs with known TdP risk’ aremerged into Class B*. In Table 2, psychotropic drugs are classified accordingto these categories.

The accessibilityofTQTstudieswas investigated foreachdrug throughsearching the following sources: the summeryofproducts characteristics,www.clinicaltrials.gov (26 February 2014, date last accessed), and the USNational Library of Medicine National Institutes of Health.

The class of recommendation (Table A1) and class of evidence (TableA2) for the present guideline recommendations are given in Table A3(see Appendix).

Psychotropic drugs

AntipsychoticsAn association between treatment with the older, typical anti-psychotic drugs and development of QT-interval prolongation,TdP, and SCD was established several years ago.26,27 The newer atyp-ical antipsychotic drugs were considered safer, but in a registry studyRay et al.4 found that users of typical and atypical antipsychotic drugshad similarly increased risks of SCD. For both groups, the riskincreased dose dependently with adjusted incidence-rate ratiosfrom 1.31 to 2.42 and from 1.59 to 2.86 in users of typical and atypicalantipsychotics, respectively. For individual drugs, the highest

incidence-rate ratio was 5.05 (thioridazine). Importantly, formerusers had no increased risk. The risk was twice as high in men. Forpersons 70–74 years of age, the risk was 10-fold higher than inthose 30–35 years of age. A meta-analysis of randomized trialsdemonstrated a higher death rate in patients with Alzheimerdisease randomized to antipsychotic drugs compared with placebo(OR ¼ 1.54). There were no differences in death rates betweentreatment groups among patients dropping out of these trials.28

The mortality associated with different antipsychotics has beenexplored in head to head randomized trials of sertindole vs. risperi-done in the SCoP study29 (n ¼ 14 147 patient-years) and of ziprazi-done vs. olanzapine in the ZODIAC study30 (n ¼ 18 154 patientsfollowed for 1 year). No difference in all-cause mortality was foundin the two studies. However, treatment with sertindole was asso-ciated with an increased cardiac mortality compared with risperi-done (HR: 2.84; CI: 1.45–5.55).

Haloperidol is widely used and prolongs the QTc interval �5 ms,but it is the drug with most documented cases of TdP-VT. This mayreflect the extensive use of haloperidol in somatic settings in patientswith concurrent somatic conditions, predisposing to the develop-ment of arrhythmias.15,31,32

AntidepressantsTricyclic anti-depressants (TCAs)Most tricyclic anti-depressants (TCAs) seem to prolong the QTinterval, but reports of TdP are few and especially related to treat-ment with amitriptylin and maprotillin.33 Tricyclic anti-depressantshave been shown to delay the AV-node conduction resulting in AVblock.34 In a registry study, treatment with TCA was associated withan increased risk of cardiac arrest (OR¼ 1.69).5 The mean age of thispopulation was 67 years (95% CI 58–75) and several had serioussomatic comorbidity.

Selective neurotransmitter re-uptake inhibitors(SSRI and SNRI)Selective serotonin re-uptake inhibitors (SSRI) and serotonin–norepinephrine reuptake inhibitors (SNRI) are widely used. Thesingle most commonly used antidepressant, the SSRI citalopramreached about 452.6 million defined daily doses in the UK in2009.35 These drugs are generally regarded as safe even in over-doses.36– 38 However, as a consequence of recently reported QTstudies, both FDA39 and EMA40 have limited the recommendedmaximum doses of citalopram and escitalopram. For patients olderthan 60 years of age, the maximum recommended dose is furtherreduced. A QT-interval prolonging effect of certain antidepressantswas most recently confirmed in a large-scale pharmacovigilancestudy.41 In a Danish nationwide registry study, Weeke et al.5 assessedthe treatment with anti-depressants and the risk of out of hospitalcardiac arrest. Overall, the treatment with any antidepressant wassignificantly associated with cardiac arrest (OR ¼ 1.23). Tricyclicanti-depressants and SSRIs significantly increased the risk of cardiacarrest (OR 1.69 and 1.21, respectively), whereas no association wasobserved for SNRI. Patients treated with SSRI were older than thoseon TCA (74 vs. 67 years).

Table 1 Classification of psychotropic medicationsaccording to the risk of QT prolongation and arrhythmia

Class A A drug considered to be without any risk of QTprolongation or TdP

Class B A drug with a propensity of inducing QT prolongation

Class B* A drug with pronounced QT prolongation, documentedcases of TdP, or other serious arrhythmias

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Table 2 Categorization of psychotropic medications according to the reported risks for induction of cardiac arrhythmia

Drug EMA FDA Micromedex Maudsley Arizona Thorough QT study Theweightedrecommendations

Antipsychotic drugs

Amisulpride Yes – Yes Little – No B

Aripiprazole No No No No – No A

Chlorprothixen Yes – No – – No B

Clozapine No No No Little Possible No B

Flupenthixol Yes – No Little No B

Haloperidol Yes Yes Yes Much Yes No B*

Levomepromazine Yes – – – – No B

Olanzapine Yes No Yes Some – No A

Paliperidone Yes Yes Yes No Possible Yes104 B

Perphenazine Yes – No Little – No A

Pimozide Yes Yes Yes Much Yes No B*

Quetiapine Yes No No Some Possible Yes105 B

Risperidone Yes No Yes Little Possible No B

Sertindole Yes – Yes Much Possible No B*

Sulpiride Yes – No – – No B

Ziprasidone Yes Yes Yes Some Possible Yes105 B*

Zuclopenthixole Yes – No – – No A

TCA and MAO inhibitors

Amitriptyline Block – Yes Some Conditional risk No B

Clomipramine Yes No No Some Conditional risk No B

Doxepin Block No No Some Conditional risk Yes106 B

Imipramine Yes – Yes Some Conditional risk No B

Isocarboxazid No No – No – No A

Moclobemide Yes No – – No B

Nortriptyline Yes Block Yes Some Conditional risk No B

Neurotransmitter uptake inhibitors

Citalopram Yes Yes Yes Little Conditional risk Yes39 B

Escitalopram Yes Yes Yes – – Yes39 B

Fluoxetine No No No – Conditional risk No A

Paroxetine No No No No Conditional risk No A

Sertraline No No No No Conditional risk No A

Duloxetine No No No – – Yes107 A

Reboxetine No No No – Yes108 A

Venlafaxine Yes No Yes Little Possible No B

Mianserin No – No – – No A

Mirtazapine No No No No – No A

Agomelatine No – – – – Yes109 A

Bupropion No No No – – No A

Mood stabilizers

Lithium Block Block No Little Possible No Ba

Carbamazepine No Block No No – No A

Lamotrigine No No No No – Yes110 A

Valproate No No No No – No A

Anxiolytic drugs

Benzodiazepines No No No – No A

Gabapentin No No No – Yes111 A

Pregabaline No No No – – No A

Continued

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Mood stabilizersCarbamazepine, lamotrigene, valproate, and lithium are used asmood stabilizers. The anti-convulsants have generally not been asso-ciated with severe arrhythmia. Lithium has been used in the treat-ment of bipolar disorders for many years and it is well-known thattreatment should be monitored.42 Caution should be taken inpatients treated concomitantly with anti-arrhythmic drugs.43 Regard-ing a QT prolonging effect of lithium, reports are divergent,44,45 butbradycardia, T wave changes and AV-block have been described.46

Anxiolytic agentsBenzodiazepines and pregabalin, which are bound more selectivelyto the GABA receptors, are widely used in treatment of anxiety. Ben-zodiazepines comprise a heterogeneous group of drugs. In vitrostudies have shown both inhibition and activation of potassium cur-rents during exposure to benzodiazepines,47,48 but no changes inQT duration have been reported in clinical use.

Medications for treatment of opioid addictionMethadone causes pronounced QT-prolongation49– 51 and severalcases of TdP have been reported.52 The Substance Abuse & MentalHealth Services Administration (SAMHSA) has proposed a cardiacrisk management plan for methadone maintenance treatment pro-grams.53 SAMHSA recommends that a baseline ECG be recorded ifthe patient has risk factors and that ECGs for such patients shouldbe recorded annually or when the daily dose exceeds 120 mg.However, both methadone dose and baseline QT length are predic-tors of QT prolongation.54 Thus, we recommend (Figure 1) baselineand follow-up ECG’s, including an additional evaluation if the dailydosage exceeds 100 mg, as recommended in the guideline byKrantz et al.55

Compared with methadone, the alternativebuprenorphine causesfar less prolongation of the QT interval56 and TdP has not beenreported. Unfortunately, buprenorphine is a partial m-receptoragonist, which makes it less effective compared with methadone inpatients requiring high doses.57

PolypharmacyIn North America and Europe, �20% of patients treated for schizo-phrenia receive more than one antipsychotic drug.58,59 The efficacyand safety of combination therapy regimens have only to a verylimited extent been evaluated in randomized trials.60 Concomitantuse of different drugs with the propensity of prolonging the QT inter-val may lead to unpredictable QT prolongation and should, from adrug safety point of view, be avoided if possible.61 Similarly, it is im-portant to recognize that drugs interacting with the metabolism ofa QT-prolonging drug can result in higher plasma concentrationsand thereby increase the risk of arrhythmia. Thus, it has been shownthat concomitant use of erythromycin and other inhibitors of thehepaticCYP3A isoenzyme is associatedwith ahigher riskof SCD.62 Fur-thermore, a number of other legal or illegal substances, e.g. alcohol andcocaine, may also affect the repolarization.63,64 It is therefore importantto know all co-medications, including over-the-counter medications,and it is generally recommended to avoid concomitant use of morethan one drug with the propensity of prolonging the QT interval ordrugs with pharmacokinetic interactions.61

Heart diseases pre-disposing toarrhythmiaIschaemic heart disease is the most prevalent heart disease in devel-oped countries and attributable to �15% of all deaths.65,66 Bothacute and chronic ischaemic heart diseases, including previous myo-cardial infarcts, are associated with SCD.67 The substrate for arrhyth-mia is considered to be re-entry due to changes in conductionvelocities and abnormal automaticity.68

The prevalence of heart failure is �2% in Western countries69 andthese patients are pre-disposed to malignant arrhythmia. A largeproportion of the patients with heart failure die suddenly (SCD)due to arrhythmia.70 This is especially the case in patients withheart failure due to ischaemic heart disease.71 Subgroups of patientswith inherited cardiomyopathies, e.g. hypertrophic cardiomyopathy,arrhythmogenic right ventricular cardiomyopathy, and dilatedcardiomyopathy, are at increased risk of SCD.72,73

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Table 2 Continued

Drug EMA FDA Micromedex Maudsley Arizona Thorough QT study Theweighted recommendations

Anticholinergic drugs

Biperiden No No – – No A

Orphenadrine No No – – No A

Opioid substitution No

Buprenorphine No No No – – No A

Methadone Yes Yes Yes – Yes No B*

The cardiac risk reported from the selected sources.‘Yes’ indicates that the source in question has reported a risk of arrhythmia or QT prolongation, ‘No’ indicates that no such risk has been reported. ‘Block’ indicates that the AV blockhas been reported. ‘Conditional risk’ indicates that these drugs prolongQTandhave a riskof inducing TdP undercertain conditions. ‘ThoroughQT study’ indicateswhethera thoroughQT study has been published or described in the summery of product characteristics for the particular medicament. The weighted recommendations represent the classification ofpsychotropic medications according to Table 1.aRegarding a QT prolonging effect of lithium, reports are divergent,44,45 but bradycardia, T wave changes and AV block have been described.46

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In the structural congenital heart diseases, the abnormalities aswell as chirurgical sequelae may predispose to development of ar-rhythmia.74 Pre-existing QT-interval prolongation is seen in patientswith genetically determined changes in ion-channel function, i.e.inherited long QT syndrome.75 The degree of prolongation of theQT interval is in general considered to reflect the risk of seriouscardiac events in patients with inherited long QT syndrome.75–77

There is a considerable overlap between the QT of healthy indivi-duals and the QTof carriers of a long QT mutation.78,79 The inheritedarrhythmic syndromes, e.g. Brugada syndrome and long QT syn-drome, may be triggered by electrolyte disturbances or exposureto specific drugs.80,81 In addition to the arrhythmia associated withseveral heart diseases per se, the medical treatment of these diseasesmay add to the risk for development of arrhythmias. This may relateto diuretic-induced hypokalaemia, effects of CYP-system inhibitors,e.g. verapamil, drugs with intrinsic pro-arrhythmic side effects, e.g. fle-cainide, or drugs with the propensity of prolonging the QT-interval,e.g. sotalol or drugs associated with TdP.

Cardiac risk factors in thepsychiatric patientHeart diseases are more prevalent in patients with psychiatric dis-eases.82 This has in part been attributed to life style factors likesmoking, poor treatment, and poor treatment compliance,8 butseveral other factors have been proposed including genes commonfor both disease groups.83 On the other hand, the prevalence of de-pression is high among patients with ischaemic heart disease and isassociated with a higher mortality.84 Most importantly, a large pro-portion of the patients treated with psychotropic medications arethe elderly, and the risk of ischaemic heart disease increases dramat-ically with age.69 Elderly people with ischaemic heart disease have thehighest rate of SCD—and must be considered to be a high-risk groupwhen exposed to drugs with a pro-arrhythmic potential.

Management of the individualpatientA rational approach to reduce the risk of serious arrhythmia in apatient considered for treatment with a pro-arrhythmic drug is tomake a structured risk assessment before commencement of treat-ment. The assessment needs to include a medical history of heartdisease, present and former cardiac symptoms with focus on chestpain, dyspnoea, palpitations, near-syncopes or syncopes, and familyhistory of SCD; a list of medications to assess for possible drug inter-actions and other QT-prolonging drugs or potassium-wasting drugs;an ECG for assessment of signs of heart disease, conduction disor-ders, or prolonged QT interval.

The decision to commence treatment with psychotropic medica-tions includes several steps: evaluation of the severity of the psychi-atric condition and the need for pharmaco-therapy; selection ofthe appropriate psychotropic medication—at the recommendeddose; assessment of the cardiac risk associated with the chosen medi-cation; if a class A drug has been chosen (Table 2), the treatment canbe commenced without any further cardiac risk assessment. If a classB or B* drug (Table 2) is chosen, assessment of the cardiac risk is

needed according to the proposed algorithm (Figure 1); if cardiacrisks are identified, the cardiac risk factors should be optimizedand/or a drug with a more favourable risk profile should be chosenif possible. In case of structural heart disease, QT prolongation, elec-trolyte disturbances, or cardiac symptoms referral to a cardiologistshould be considered. Follow-up should be organized according tothe algorithm (Figure 1). Re-evaluation of the ECG and symptomsshould take place within 1 or 2 weeks (i.e. at steady-state .5 drughalf lives) after initiation of treatment with class B/B* drugs. Similarly,a significant increase in dose of these drugs necessitates re-evaluatingsymptoms and a new ECG. A QTc-interval above 500 ms or an incre-ment above 60 ms when compared with baseline are generally con-sideredassociated with adefinitely increased riskof TdP85 and shouldin most cases lead to discontinuation of the drug (Figure 1).

If the psychiatric condition is invalidating or life threatening, ahigher cardiac risk may be accepted, but necessitates reductions ofall reversible risk factors and a close follow-up.

DiscussionSeveral drugs used in the treatment of mental diseases are associatedwith an increased risk of SCD, even though a direct causative linkbetween the drug intake and SCD is difficult to prove. However,the association has repeatedly been reported from various sourcesand therefore, the risk need to be taken into consideration in dailyclinical practice. The incidence of drug-induced long-QT has beenestimated to about 11/1 000 000 in France. This is probably an under-estimate, since fatal cases were excluded.86

The magnitude of the SCD risk is of major importance, but thetrue incidence of SCD in the general population is not known. Theestimated US annual incidence of SCD varies from 180 000 to.450 00087 out of a total of around 2.5 million deaths per year,88

i.e. 7–18% (or 60–150 per 100 000 person-years) of all deathsacross all age-groups are categorized as SCD. In most of thesecases, the cause of death is ischaemic heart disease in older patients,where the annual incidence of SCD for 75 years old men reaches800 per 100 000.73 Additionally, it has been estimated thatout-of-hospital cardiac arrest occurs in about80per 100 000 person-years in subjects without heart disease.69 In children and in youngadults (1–35 years), the SCD rate is generally considered to bemuch lower, i.e. 2–3 per 100 000 person-years.89 Thus, the SCDrate increases considerable with age and in the study by Ray et al.,4

the unadjusted rate for persons from 30 to 74 years of age (mean45 years) was 179 per 100 000 person-years, and 10-fold higherin the age-group 70–74 years. The incidence was twice as high formen when compared with women. The rate of 179 SCD per 100000 person-years represents the average for the group, but in a het-erogeneous group of patients some may have had co-morbidities, e.g.ischaemic heart disease, heart failure, pre-existing long QT-interval,or electrolyte disturbances and these patients would have beentreated at a much higher risk of SCD. Identification and optimizedmanagement of such high-risk patients could probably decrease theSCD rate significantly. Thus, in the otherwise healthy young a doub-ling of the risk of SCD may represent a very rare event since theabsolute risk is low, whereas in older patients and in patients withpre-existing risk factors for SCD the absolute risk associated withtreatment with psychotropic medications may reach a dramatic level.

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In severely ill patients suffering from psychiatric diseases suchas schizophrenia, depression, or bipolar disorders, a treatment-associated risk of SCD may be considered to be unavoidable.90 Fur-thermore, some of these conditions may, if left untreated themselves,increase the risk for heart diseases or death, but all possible precau-tions to reduce the cardiac risk should be taken, including administer-ing the lowest effective dose, optimization of the treatment ofco-morbidities, if possible discontinuation or reduction of dosagesof negatively interacting drugs, reduction of the administration of un-documented combination regimens to a minimum—and establishinga prudent follow-up for detection of side effects in time.

The recent study by Khan et al.10 of adult patients (mean age of37–45 years) with psychiatric diseases included in clinical placebo-controlled trials by pharmaceutical companies for US FDA showedthat 3–4 months exposure to modern psychotropic agents did notworsen the mortality risk. The exposure period was 23.711 and2.183 years for psychotropic agents and placebo, respectively. Atotal of 265 patients died, 109 (41.1%) from suicide. Suicide rateswere generally lower in patients on active treatment—with patientson heterocyclic antidepressants as the only exception. However, itshould be noted that in the actively treated groups, 44 patients(18%) died due to cardiovascular causes and additional 20 (8%)died suddenly. Comparable figures for the placebo groups werenot given. Thus, the authors concluded that psychotropic agentsdid not increase all-cause mortality, but no conclusions were maderegarding the risk of drug-induced SCD. Additionally, old patients,patients with cardiac co-morbidities, patients treated simultaneouslywith more than one psychotropic agent etc. are generally less likely tobe included in such trials. This reduces the generalizability of thesetrials.

Generally, we are as physicians obliged to inform the patient aboutknown side effects including a risk of SCD to the extent the patient iscapable of understanding the message. If the patient is not capable ofunderstanding the risk and especially in the few compulsory treatedpatients the necessary acute therapy should be prioritized and thecardiac assessment and follow-up postponed until the patient isable to cooperate and capable of understanding the information.

Lethal arrhythmia does not leave traces and cannot be diagnosedpost mortem91 and often autopsy is not even performed to rule outmore common causes of death such as myocardial infarction. As aresult, the exact incidence of death caused by arrhythmia will be un-attainable. The QT/QTc is currently generally accepted as a riskmarker for arrhythmia. However, the risk related toQT prolongationis difficult to predict since a certain prolongation induced by one drugmay not be associated with the same risk as when the QT prolonga-tion was induced by another drug. Forexample amiodarone is knownto prolong the QT interval, but amiodarone-induced TdP is relativelyrare.92 This demonstrates that the QT interval is only an imperfectsurrogate for measuring the risk of arrhythmia and clearly showsthe limitations of an even well-conducted TQT study.

At present, several drugs on the market are capable of prolongingthe QT interval far beyond the limits formulated by the ICH-E14.Some of these drugs might not have been approved and marketedtoday. The risks associated with these drugs should ideally be evalu-ated in phase IV studies. The responsibility to conduct such studies isdifficult to place since patents may have expired, and heavy financialburdens on producers of older drugs might close the production, and

reduce the spectrum of available pharmacological treatments.However, some post-marketing trials have been carried out. Thus,in 1998, sertindole was temporarily suspended from the Europeanmarked due to suspected treatment-associated unexplained deathsand as an authority demand for returning to the market in 2001, a ran-domized trail comparing sertindole and risperidone was performedand published in 2010.29 A total of 9858 patients were randomizedand after 14 147 person-years no effect on all-cause mortality wasidentified between the two groups, but an independent committeeblinded to treatment groups identified higher incidence of SCD inthe sertindole group (HR:2.84 CI: 1.45–5.55), irrespective onlysertindole-treated patients were needed to be ECG monitoredand withdrawn if QTc exceeded 500 ms. Therefore, safe treatmentwith sertindole demands similar ECG monitoring as in the SCoPstudy.

Whereas the association between psychotropic medications andrisk of malignant arrhythmia has been known for many years, theknowledge about the extent and prevention of such pro-arrhythmiaseem to be limited. At present, only guidelines concerning safe use ofanti-depressants and drugs for heroin addiction have been pro-posed.53,93 Finding the optimal psychotropic drug for the patientshould always include evaluation of the perceived effectiveness andside-effects. Risk of suicide and psychotropic-induced life shorteningconditions, such as obesity and diabetes, should be included in theevaluation.94

In the absence of precise knowledge about the individual drugspropensity of inducing arrhythmia and precise risk markers, the clas-sification of psychotropic medications in this review must be consid-ered more as a consensus than based on high-class evidence.

This reviewprovides the first overview including acoordinatedriskclassification of all psychotropic drugs. Additionally, we provide thefirst clinically manageable guideline to increase the safety in the ad-ministration of these drugs.

Conflict of interest: J.N. has received research support from Pfizerand Hemocue and received honoraria from Astra-Zeneca, BMS,Hemocue and Lundbeck. P.V. reports no biomedical financial inter-ests or potential conflicts of interest in relation to the topic of thisarticle. S.P. received honorario from Lundbeck, Eli Lilly, Servier, andJanssen Pharmaceuticals. Other authors have no conflicts of interestto report. S.F., D.K., A.F., H.J., E.T. and H.B. have no conflicts ofinterest.

Appendix A

The development of the guidelineThe spark initiating this work was experiences of serious cardiacevents in patients treated with psychotropics—and the realizationof a striking lack of clear clinical recommendations within the field.

In order to establish the most useful recommendations, wedecided at an early stage to establish a formal working groupbetween the two national specialties—cardiology (Danish CardiacSociety, DCS) and psychiatry (Danish Society of Psychiatry, DPS).A short description of the purpose was agreed on formally by theboards of the two specialties and members from both specialtieswere elected to the working group. The working group had a total

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of four meetings. Before each meeting, each member was given atopic to describe in writing and all the proposals were emailed tothe other members of the working group before the next meeting.At the meeting, the proposals were presented, discussed, and con-sensus reached. The specific topic was accordingly rephrased bythe member covering this special topic—and then presented againon the next meeting. This processwas continued until final consensuswas reached. During the process, the individual proposals wereincluded in the report document. Following the final acceptance ofthe report by the working group, the report was formally inhearing among all members of the two specialties (DCS – 1300,DPS 900 members) before the final and formal approval by theboards of the two specialties. Thus, the process for developing therecommendations was a combination of a modified Delphi processand consensus.

Evaluation of the QT intervalThe QT interval is defined as the time from the start of depolarization(the beginning of QRS) to the end of repolarization of the ventricles(the end of the T-wave). The end of the T-wave can be difficult to de-termine, not least when there is a partial superimposition of the T-and U-waves.95 Physiologically, the duration of the QT intervalmainly depends on the concerted action of sodium (Na+), potassium(K+), and calcium (Ca2+) ion channels. Certain drugs may affect the

QT-interval length and T-wave morphology (Figure A1). The end ofthe T-wave can be difficult to determine, not least when there is apartial superimposition of the T- and U-waves95 (Figure A2).

The QT interval prolongs with decreasing heart rate and shortensat higher heart rates and therefore measurements of the QT-intervallength are often normalized or ‘corrected’ to a heart rate of 60 bpmdenoted as the corrected QT or QTc. Several formulas for correc-tion of QT intervals measured at higher or lower heart rates havebeen developed. Usually, the QT is corrected using either Bazett’sformula96 or Fridericia’s formula:97

Bazett: QTcB =����QTRR

√

Fridericia: QTcF =����QTRR

3

√

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table A3 Recommendations for treatment with drugswith the propensity of prolonging the QT interval

Class I

If the QT-interval or QTc reaches a length .500 ms or increases by.60 ms compared with baseline, treatment with the particulardrug should be ceased or dose reduced (Level of Evidence: C)

Hypokalaemia should be avoided during treatment with drugscapable of prolonging the QT interval (level of evidence: C)

Concomitant treatmentwithmore thanonedrugwith thepropensityof prolonging theQT interval shouldbe avoided if possible (levelofevidence: C)

Class IIa:

Before initiation of treatment, assessment of cardiac risk is needed(level of evidence: C)

The QT interval should be evaluated before initiation of treatmentand during titration of dose (level of evidence: C)

In elderly, treatment should be done with caution (level of evidence:C)

If cardiac risks are identified, the cardiac risk factors should beoptimized and/or a drug with a more favourable risk profile shouldbe preferred if possible in the clinical situation (level of evidence:C)

In case of structural heart disease, QT prolongation or cardiacsymptoms referral to a cardiologist should be considered (level ofevidence: C)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table A1 Class of recommendation112

Classes ofrecommendations

Definition Suggestedwording to use

Class I Evidenceand/orgeneralagreement that agiven treatment orprocedure isbeneficial, useful,effective

Is recommended/is indicated

Class II Confliction evidenceand/or a divergenceof opinion about theusefulness/efficacy ofthe given treatmentor procedure

Is recommended/is indicated

Class IIa Weight of evidence/opinion is in favour ofusefulness/efficacy

Should beconsidered

Class IIb Usefulness/efficacy isless well establishedby evidence/opinion

May beconsidered

Class III Evidence or generalagreement that thegiven treatment orprocedure is notuseful/effective, andin some cases may beharmful

Is notrecommended

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table A2 Level of evidence112

Level ofevidence A

Data derived from multiple randomized clinical trialsor meta-analyses

Level ofevidence B

Data derived from a single randomized clinical trial orlarge non-randomized studies

Level ofevidence C

Consensus of opinion of the experts and/or smallstudies, retrospective studies, registries

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Bazett’s formula is simplest to use, but overcorrects at higher heartrates (.�80 bpm) and undercorrects at lower heart rate.91 Especiallyathighheart rates, theuseofFridericia’s formula is recommended.98Thenormal upper QTc value in men is 450 ms, in women 460 ms,99,100 andin children ,440 ms.101 However, it isofmajor importance tonote thatthese limits represent the 95th percentile values.100 QTc values from440 to 470 ms are considered ‘grey zone’ due to a considerableoverlap between affected and controls in this range.100

A validation study comparing automated QT-interval measure-ments with approved measurements from previous QT-studies

suggests that automated methods are feasible.102 In principle,the American Food and Drug Administration (FDA) accepts theuse of fully automatic methods to measure the QT interval inTQT studies as long as the sensitivity is confirmed by including apositive control.103 It is essential to emphasize that this is aspecial situation with ECGs recorded in healthy subjects. In theclinical routine, it is only recommended to rely on automatedQT interval measuring if the ECG is otherwise normal. Therefore,all physicians need to be able to measure the QT interval manually(Figure A2).

Figure A1 Two cases of drug-induced QT prolongation. Patient A: A 24-year-old woman with prolongation of the QT-interval (QT ¼ 405 ms,QTcB ¼ 510 and QTcF ¼ 489) (correction according to Bazett’s (B) or Fridericia’s (F) formula) during treatment with sertindole at a dose of 16 mgper day. After sertindole treatmentwasceased, theQT interval normalized (QT ¼ 370 ms, QTcB ¼ 455and QTcF ¼ 425). Patient B: A 53-year-oldman with prolongation of the QT interval (QT ¼ 500 ms, QTcB ¼ 495 and QTcF ¼ 497) during the treatment with methadone at a dose of 180 mgper day. The QT interval normalized after treatment with methadone was ceased (QT ¼ 400 ms, QTcB ¼ 396 and QTcF ¼ 397). Standard limblead II (left) and pre-cordial lead V2 (right) are shown.

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