A literature-based algorithm for the assessment, management, and monitoring of drug-induced QTc prolongation in the psychiatric population

Figures & data

Table 1 Articles reviewing QTc prolongation assessment and risk stratification among psychiatric patients

Author, year of publication	Summary of findings
Ojero-Senard et al, 2017^Citation18	Notifications from a pharmacovigilance database were collected for patients on SRIs with QTc prolongation. QTc prolongation was only associated with citalopram and escitalopram and was noted as not being a side effect of SRIs.
Barbui et al, 2016^Citation19	This cross-sectional survey showed that antipsychotic poly-pharmacy and antipsychotic dosing were associated with QTc interval prolongation.
Danielsson et al, 2016^Citation20	This matched case-control register study showed that the CredibleMeds^® system of TdP classification risk predicted drug- related risk for mortality in the elderly.
Nose et al, 2016^Citation21	This cross-sectional study was conducted at several psychiatric centers to measure the frequency of QTc prolongation and associated risk factors. Risk factors that were associated with QTc prolongation included female sex, age, heart rate, alcohol and/or substance abuse, cardiovascular disease, cardiovascular drug treatment, drug overdose, and polypharmacy. Data support current guidelines that recommend avoiding the concurrent use of two or more antipsychotics and the link between citalopram and QTc prolongation, which necessitates routine ECG monitoring.
Schächtele et al, 2016^Citation22	Hospital discharge prescriptions in a geriatric cohort were assessed for presence of QT-prolonging medications. A considerable proportion of QTc-prolonging medications with higher risk (as per CredibleMeds^®) could only be detected by using more than one classification system. Adaptation of international classifications can improve identification of patients at risk.
Poncet et al, 2015^Citation23	An analytical model estimating the cost effectiveness of routine ECG screening to identify QTc prolongation in psychiatric hospitals revealed that performing systematic ECG at admission helped reduce the number of sudden cardiac deaths in a cost-effective fashion.
Rabkin, 2015^Citation24	This literature review suggests that the association of increasing age and female sex with greater QT intervals necessitates awareness of the QTc prior to use of psychotropics and to measure QTc after initiation of therapy.
Takeuchi et al, 2015^Citation25	This systematic literature review claims that current evidence does not confirm that antipsychotic poly-pharmacy prolongs QTc, though poly-pharmacy with high-risk QTc-prolonging medications may increase the risk. Authors advise clinicians to remain conservative in prescribing antipsychotic poly-pharmacy considering that the clinical benefit of antipsychotic poly-pharmacy is lacking.
Shah et al, 2014^Citation26	Authors conclude that ECG monitoring when starting an antipsychotic in the absence of cardiovascular risk factors is not necessary. ECG monitoring is recommended if a patient has cardiovascular risk factors, if the antipsychotic is high-risk for TdP or sudden death, or if a patient has overdosed on an antipsychotic.
Girardin et al, 2013^Citation27	This cross-sectional study measured the prevalence of drug-induced QT prolongation as well as associated risk factors in patients admitted to a psychiatric hospital. QTc prolongation and arrhythmia occurrence increase when specific psychotropic drugs are started in patients with hypokalemia, abnormal T-wave morphology, HCV infection, and HIV infection.
Krantz et al, 2013^Citation28	This study suggests that an ECG-based intervention in methadone maintenance can decrease the QTc interval in high-risk patients and that clinical characteristics alone are inadequate to identify patients who need ECG monitoring.
Tran and Dishman, 2012^Citation29	Authors provide a review of citalopram-induced QTc prolongation and how to manage patients at risk, particularly those at high citalopram doses (eg. ≥40 mg in patients older than 60 years, or ≥20 mg in patients younger than 60 years).
Wenzel-Seifert et al, 2011^Citation30	The risk of QTc prolongation and TdP associated with common antipsychotics is reviewed. In addition, patients’ risk factors for QTc prolongation and TdP are reviewed, including age over 65 years, pre-existing cardiovascular disease, bradycardia, female sex, hypokalemia, hypomagnesemia, supratherapeutic/toxic serum concentration, or simultaneous administration of other drugs that delay repolarization or interfere with drug metabolism.
Yang et al, 2011^Citation31	Results of this cross-sectional naturalistic study among hospitalized patients with schizophrenia on long-term antipsychotics, revealed QTc prolongation was higher in women than in men. It was also found that clozapine led to more profound QTc prolongation than atypical antipsychotics and risperidone. Predictors of QTc prolongation identified included comorbid cardiovascular disease, antipsychotic types, sex, and age.

Abbreviations: ECG, electrocardiogram; FDA, US Food and Drug Administration; HCV, hepatitis C virus; QTc, corrected QT; SRIs, serotonin reuptake inhibitors; TdP, torsades de pointes.

Table 2 Articles describing guidelines and protocols for assessing, monitoring, preventing or managing drug-induced QTc prolongation in the psychiatric population

Author, year of publication	Summary of findings
Wahidi et al, 2016^Citation32	Two case reports of TdP in patients on parenteral antipsychotics were reviewed and authors proposed practice guidelines for dosing parenteral antipsychotics in order to avoid TdP during the control of agitation at psychiatric hospitals.
Chou et al, 2014^Citation33	This guideline, based on a systematic review of methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge on use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.
Fanoe et al, 2014^Citation34	In this review, data from various authorities on the risk of arrhythmia associated with psychotropic medications were categorized into three risk categories. A clinical algorithm to reduce the risk of fatal arrhythmia in patients treated with psychotropics is proposed. The algorithm integrates the risk categories and risk factors and suggests follow-up parameters and timelines.
Pacciardi et al, 2013^Citation35	Authors summarized evidence-based safety considerations during the treatment of acute agitation with intramuscular antipsychotic medications in psychiatric patients.
De Heart et al, 2011^Citation36	This review evaluated the quality and content of various screening guidelines published between 2000 and 2010 for cardiovascular risk in schizophrenia.
Martin et al, 2011^Citation37	A multidisciplinary expert panel concluded that treatment programs should have a cardiac risk management plan incorporating clinical assessment, ECG assessment, risk stratification, and prevention of drug interactions and should strongly consider risk minimization strategies that are patient-specific (eg, patient monitoring, ECG, adjusting methadone dosing).
Nielsen et al, 2011^Citation38	This article reviewed the mechanisms of QTc prolongation and the risk with antipsychotics, along with several clinical recommendations.
Fishman et al, 2010^Citation39	Six broad recommendations based on evidence were developed by a working group of experts jointly convened by the National Heart, Lung and Blood Institute and the Heart Rhythm Society to address and recommend research directions and strategies in prediction and prevention of sudden cardiac death.
Modesto-Lowe et al, 2010^Citation40	Retrospective analyses found that patients who develop TdP often have multiple risk factors, including high methadone doses, use of other medications that cause QTc prolongation, and electrolyte abnormalities. As such, guidelines are presented for initiating methadone in opioid treatment and pain populations.

Abbreviations: ECG, electrocardiogram; TdP, torsades de pointes; QTc, corrected QT.

Table 3 Review articles about QTc prolongation (not specifically in the psychiatric population) included in the development of the algorithm

Author, year of publication	Summary of findings
Institute for Safe Medication Practices Canada^®, 2017^Citation41	Institute for Safe Medication Practices Canada^® (ISMP Canada) developed an evidence-based tool to help pharmacists evaluate and communicate QT prolongation risk.
Tisdale, 2016^Citation42	This article described the important role that pharmacists play in minimizing the risk of drug-induced QTc prolongation and TdP. This article reviews clinical assessment of risk of QTc prolongation (via the QTc interval prolongation risk score), drug interactions that increase risk of TdP, and dose reductions of renally eliminated QTc-prolonging drugs in patients with kidney disease.
Jardin et al, 2014^Citation43	This retrospective analysis assessed risk factors for TdP in hospitalized patients receiving ≥1 QTc-prolonging medication. The following risk factors were associated with significant QTc prolongation: female sex, LVEF <40%, and cardiac arrest.
Tisdale et al, 2014^Citation44	The authors described a computerized clinical decision support system developed to alert pharmacists to drugs that lead to QTc prolongation among patients admitted to coronary care units at moderate/high risk of QTc prolongation. When alerted, pharmacists were to contact prescribers to decrease risk of TdP. The use of this system resulted in a significant reduction in the prescribing of QT-prolonging medications.
Haugaa et al, 2013^Citation45	This institution-wide QT alert system was used to alert prescribers to patients with a QTc of over 500 ms. Mortality was increased among those with increasing pro-QTc scores, which was an independent predictor of mortality.
Tisdale et al, 2013^Citation46	A prospective observational study was conducted on 900 patients admitted to cardiac care units to develop and validate a risk scoring system that could predict patients at highest risk of developing QTc prolongation. The tool is used to distinguish whether patients are at low, medium, or high risk of QTc interval prolongation based on a score that is obtained by number of risk factors and their weighting.
Nachimuthu et al, 2012^Citation47	This article reviewed the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention, and monitoring of prolonged drug-induced QT prolongation and treatment strategies.
Drew et al, 2010^Citation48	This scientific statement reviewed the risk, ECG monitoring, and management of drug-induced LQTS. Authors reviewed signs of arrhythmia, mechanisms of acquired LQTS, drug combinations known to cause TdP, risk factors/exacerbating conditions, methods to monitor QT intervals, and management of QT prolongation and TdP.

Abbreviations: LQTS, long QT syndrome; LVEF, left ventricular ejection fraction; QTc, corrected QT; TdP, torsades de pointes.

Figure 1 A literature-based algorithm for the assessment, management and monitoring of drug-induced QTc prolongation.

Notes: *As per CredibleMeds^®. ^aAs per Tildale et al.⁴⁶
Abbreviations: cLQTS, congenital long QT syndrome; ECG, electrocardiogram; EF, ejection fraction; QTc, corrected QT; TdP, torsades de pointes.

Ojero-SenardABeneventJBondon-GuittonEA comparative study of QT prolongation with serotonin reuptake inhibitorsPsychopharmacology2017234203075308128770276

 PubMed Web of Science ®Google Scholar

BarbuiCBighelliICarràGAntipsychotic Dose Mediates the Association between Polypharmacy and Corrected QT IntervalPLoS One2016112e014821226840602

 PubMed Web of Science ®Google Scholar

DanielssonBCollinJJonasdottir BergmanGBorgNSalmiPFastbomJAntidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults – a Swedish nationwide studyBr J Clin Pharmacol201681477378326574175

 PubMed Web of Science ®Google Scholar

NosèMBighelliICastellazziMPrevalence and correlates of QTc prolongation in Italian psychiatric care: cross-sectional multicentre studyEpidemiol Psychiatr Sci201625653254026467074

 PubMed Web of Science ®Google Scholar

SchächteleSTümenaTGaßmannKGFrommMFMaasRCo-prescription of QT-interval prolonging drugs: an analysis in a large cohort of geriatric patientsPLoS One2016115e015564927192430

 PubMed Web of Science ®Google Scholar

PoncetAGencerBBlondonMElectrocardiographic screening for prolonged QT interval to reduce sudden cardiac death in psychiatric patients: a cost-effectiveness analysisPLoS One2015106e012721326070071

 PubMed Web of Science ®Google Scholar

RabkinSWImpact of age and sex on QT prolongation in patients receiving psychotropicsCan J Psychiatry201560520621426174524

 PubMed Web of Science ®Google Scholar

TakeuchiHSuzukiTRemingtonGUchidaHAntipsychotic polypharmacy and corrected QT interval: a systematic reviewCan J Psychiatry201560521522226174525

 PubMed Web of Science ®Google Scholar

ShahAAAftabACoverdaleJQTc prolongation with antipsychotics: is routine ECG monitoring recommended?J Psychiatr Pract201420319620624847993

 PubMed Web of Science ®Google Scholar

GirardinFRGex-FabryMBerneyPShahDGaspozJMDayerPDrug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry studyAm J Psychiatry2013170121468147624306340

 PubMed Web of Science ®Google Scholar

KatzDFSunJKhatriVQTc interval screening in an opioid treatment programAm J Cardiol201311271013101823820570

 PubMed Web of Science ®Google Scholar

TranEDishmanBCitalopram-induced QTc prolongation: a brief review of the dataMent Health Clin201226139141

 Google Scholar

Wenzel-SeifertKWittmannMHaenEQTc prolongation by psychotropic drugs and the risk of Torsade de PointesDtsch Arztebl Int20111084168769322114630

 PubMed Web of Science ®Google Scholar

YangFDWangXQLiuXPSex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychoticsPsychopharmacology2011216191621301815

 PubMed Web of Science ®Google Scholar

WahidiNJohnsonKMBrenzelAde LeonJTwo sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychoticsCase Rep Psychiatry2016201694068131427597919

 PubMedGoogle Scholar

ChouRCrucianiRAFiellinDAMethadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm SocietyJ Pain201415432133724685458

 PubMed Web of Science ®Google Scholar

FanoeSKristensenDFink-JensenARisk of arrhythmia induced by psychotropic medications: a proposal for clinical managementEur Heart J201435201306131524644307

 PubMed Web of Science ®Google Scholar

PacciardiBMauriMCargioliCIssues in the management of acute agitation: how much current guidelines consider safety?Front Psychiatry201342623675355

 PubMedGoogle Scholar

de HertMVancampfortDCorrellCUGuidelines for screening and monitoring of cardiometabolic risk in schizophrenia: systematic evaluationBr J Psychiatry201119929910521804146

 PubMed Web of Science ®Google Scholar

MartinJACampbellAKillipTQT interval screening in methadone maintenance treatment: report of a SAMHSA expert panelJ Addict Dis201130428330622026519

 PubMed Web of Science ®Google Scholar

NielsenJGraffCKantersJKToftETaylorDMeyerJMAssessing QT interval prolongation and its associated risks with antipsychoticsCNS Drugs201125647349021649448

 PubMed Web of Science ®Google Scholar

FishmanGIChughSSDimarcoJPSudden cardiac death prediction and prevention: report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society WorkshopCirculation2010122222335234821147730

 PubMed Web of Science ®Google Scholar

Modesto-LoweVBrooksDPetryNMethadone deaths: risk factors in pain and addicted populationsJ Gen Intern Med201025430530920087676

 PubMed Web of Science ®Google Scholar

Institute for Safe Medication Practices Canada®Pharmacist Evaluation of QT Prolongation Risk and Recommendation. [Internet]2017 Available from: https://www.ismp-canada.org/ToolQit_QTprolongation/Accessed September 03, 2018

 Google Scholar

TisdaleJEDrug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and managementCan Pharm J20161493139152

 Web of Science ®Google Scholar

JardinCGPutneyDMichaudSAssessment of drug-induced torsade de pointes risk for hospitalized high-risk patients receiving QT-prolonging agentsAnn Pharmacother201448219620224301687

 PubMed Web of Science ®Google Scholar

TisdaleJEJaynesHAKingeryJREffectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patientsCirc Cardiovasc Qual Outcomes20147338139024803473

 PubMed Web of Science ®Google Scholar

HaugaaKHBosJMTarrellRFMorlanBWCaraballoPJAckermanMJInstitution-wide QT alert system identifies patients with a high risk of mortalityMayo Clin Proc201388431532523541006

 PubMed Web of Science ®Google Scholar

TisdaleJEJaynesHAKingeryJRDevelopment and validation of a risk score to predict QT interval prolongation in hospitalized patientsCirc Cardiovasc Qual Outcomes20136447948723716032

 PubMed Web of Science ®Google Scholar

NachimuthuSAssarMDSchusslerJMDrug-induced QT interval prolongation: mechanisms and clinical managementTher Adv Drug Saf20123524125325083239

 PubMedGoogle Scholar

DrewBJAckermanMJFunkMPrevention of Torsade de Pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation, endorsed by the American Association of Critical-Care Nurses and the International Society for Computerized ElectrocardiologyCirculation201012181047106020142454

 PubMed Web of Science ®Google Scholar