APA Resource Document on QTc Prolongation and Psychotropic Medications

Margo C. Funk, M.D., M.A.,1 Scott R. Beach, M.D.,2,3 Jolene R. Bostwick, PharmD, BCPS, BCPP,4 Christopher M. Celano, M.D.,2,3 Mehrul Hasnain, M.D.,5 Ananda Pandurangi, M.B.B.S., M.D.,6 Abhisek C. Khandai, M.D., M.S.,7 Adrienne Taylor, M.D.,7
James L. Levenson, M.D.,6 Michelle Riba, M.D.,8 and Richard J. Kovacs, M.D.9

APA OFFICIAL ACTIONS

Objective: Psychiatrists and other clinicians frequently pre- scribe psychotropic drugs that may prolong cardiac repolar- ization, thereby increasing the risk for torsades de pointes (TdP). The corrected QT interval (QTc) is the most widely used and accepted marker of TdP risk. This resource document was created in response to the paucity of strong evidence to guide clinicians in best practice prescription and monitoring of psychotropic medications that may increase risk of TdP.

Method: The American Psychiatric Association (APA) Council on Consultation-Liaison Psychiatry, in collaboration with the American College of Cardiology (ACC), convened a work- group of experts to summarize the current literature and to create this set of clinical considerations for the practicing cli- nician.

Results: This resource document includes a summary of ba- sic electrocardiography, psychopharmacology and drug safety, special practice settings including the intensive care unit and under-resourced clinics, special populations includ- ing children and patients with cardiac implantable electronic devices, and the approach to TdP risk strati cation and miti- gation.

Conclusions: There is no absolute QTc interval at which a psychotropic should not be used, rather a comprehensive risk-bene t analysis should include assessment of pharma- cologic and non-pharmacologic risks for TdP versus the risk of failure to control high-risk psychopathology or of psychi- atric decompensation.

INTRODUCTION

Psychiatrists frequently prescribe psychotropic drugs that may prolong cardiac repolarization, thereby increasing the risk for torsades de pointes (TdP). The heart-rate corrected QT interval (QTc) on the electrocardiogram (ECG) is the most widely used and accepted marker of TdP risk by drug safety boards. Over the past decade, there has been in- creased attention by the medical community about the role of QTc interval monitoring in the prescription of psychotro- pic medications.

The incidence of TdP is di cult to study in a systematic way. Although rigorous testing of new drugs for the tenden- cy to prolong the QTc interval has been in place for more than 10 years, classi cation systems that catalogue medica- tions according to ‘level of risk’ are based on variable levels of evidence, including case reports or retrospective cohorts, which cannot be used to compare drugs and are di cult to generalize into clinical practice. Though TdP is thought to be a fairly rare event, active surveillance systems suggest the incidence of TdP may be 10 to 100-fold higher than estimat- ed by spontaneous report (1). Furthermore, most studies use the Bazett correction. Though it is the most widely used correction formula, it is well established that Bazett overes-

timates the QTc interval at high heart rates, underestimates the QTc interval at low heart rates, and is consistently cited to be the least reliable method of correction.

Given the paucity of strong evidence to guide clinicians in best practice prescription and monitoring of psychotropic medications that may increase risk of TdP, to date there are no practice guidelines endorsed by the American Psychiatric Association (APA) or the American College of Cardiology (ACC). The APA Council on Psychosomatic Medicine, in col- laboration with the ACC, convened this workgroup of ex- perts in the eld to summarize the current literature and to create a set of clinical considerations for the practicing clini- cian. This resource document is not intended to be a practice guideline, rather an educational tool for clinicians to use when prescribing psychotropic medications.

QTC INTERVAL AND TORSADES DE POINTES

Drug-Induced TdP and the Association with QTc Interval

TdP (literally meaning twisting of points) is a very rare form of polymorphic ventricular tachycardia characterized by the twisting of QRS complexes around the isoelectric line (Figure 1.A). The phenomenon was described by Desert-

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QTc PROLONGATION AND PSYCHOTROPIC MEDICATIONS

FIGURE 1. Torsades de Pointes and Use of the Tangent Method for Reliable QT-Interval Measurementa

a Panel A shows an example of torsades de points from surface telemetry monitoring. Panel B shows ECG intervals relevant for QT interval measure- ment and heart-rate correction. The dotted red lines represent the intersec- tion of the tangent to the steepest downward slope of the T-wave and the isoelectric baseline. Use of this intersection to de ne the end of the T-wave is a reliable and well-accepted method for QT interval measurement.

ennes and colleagues in 1966 in a group of patients that ex- hibited a long QT interval, a long cycle/short cycle sequence prior to the arrhythmia, and macroscopic T wave alternans (2). The clinical arrhythmia had also been described in a se- ries of patients exposed to the antiarrhythmic drug quini- dine (3). TdP usually occurs in unsustained bursts that ter- minate spontaneously. These bursts can recur and may progress to a fatal ventricular arrhythmia. When not quickly fatal, it is clinically characterized by palpitation, dizziness, and syncope. Chest pain, shortness of breath, and sweating may be present as non-speci c symptoms.

The burst-pattern of drug-induced TdP makes it very dif- cult to capture on a standard 10 second ECG. Pre-mortem diagnosis by ECG requires prolonged monitoring and some- times a bit of luck. Sudden cardiac death attributable to drug-induced TdP is likewise di cult to adjudicate without concomitant ECG evidence of the arrhythmia. Therefore, surrogate markers and risk models have been used to inform prescribers of drugs that might produce TdP in an individu- al patient. Since TdP is characterized by a prolonged QTc interval by de nition, QTc interval prolongation has been the major surrogate marker for the clinical arrhythmia. In a major Rotterdam prospective population-based cohort study, prolonged QTc interval (as de ned in Table 1) was as-

sociated with a three-fold (8-fold for those ≥68 years age) increased risk of sudden cardiac death over a 6.7-year fol- low-up period (4). The link between drug-induced QTc in- terval prolongation and TdP is so strong that regulatory agencies responsible for drug approval worldwide have mandated that every new drug with signi cant systemic bioavailability be thoroughly tested for the possibility of drug-induced QTc interval prolongation (www.ich.org, product guidelines) (5). The American Heart Association, the American College of Cardiology and other organizations have published strategies to reduce TdP risk in hospitalized patients based on QTc interval prolongation as a surrogate marker for arrhythmia risk (6). These and other similar data have contributed to using QTc interval primarily as the most important (but imprecise) surrogate marker for TdP. Other less researched and less often used surrogate markers in- clude T-wave shape and morphology and J-T interval.

TABLE 1. Bazett-corrected QTc interval measurements (6, 10).

The Genesis of the QTc Interval

Mechanical activity of the heart is linked to electrical activ- ity in a complex interplay between the depolarization and repolarization of excitable tissue and contraction and relax- ation of the myocardium. The ECG represents the body sur- face ndings of the sum of the cardiac cycle of depolariza- tion and repolarization. Figure 2.A shows an ECG lead II waveform with descriptions of ECG intervals and the elec- trophysiological events represented.

Figure 2.B-C provides a simpli ed description of ionic events occurring at a cellular level. Sodium (Na+), calcium (Ca2+), and potassium (K+) ionic movements underlie the processes of depolarization and repolarization. A resting potential is maintained by sodium-potassium pump and other mechanisms resulting in uneven distribution of ions between the interstitium and interior of the cardiac myo- cyte (7). Cellular depolarization (QRS interval on the sur- face ECG; Figure 2.B-C) derives mostly from a net inward ux of sodium and then calcium ions. Cell repolarization (JT/QT interval on the surface ECG; Figure 2.B-C) derives from a net outward ux of potassium ions. Ventricular tis- sue is vulnerable to polymorphic ventricular tachycardia (e.g., TdP) during the latter part of the repolarization phase and the risk increases if ventricular repolarization is pro- longed. The majority of drugs associated with QTc interval prolongation and TdP are linked to pharmacological block- ade of hERG (human-Ether-a-go-Related Gene) potassium channels (Figure 2.D), which produce a repolarizing cur- rent termed the delayed recti er current (IKr) (8). The role

Rating

Adult men (ms)

Adult women (ms)

Normal

< 430

< 450

Borderline

431-470

451-480

Prolonged

> 470

> 480

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FIGURE 2. Electrocardiogram (ECG) Waveforms and Intervals Corresponding to Ionic Activity During Cardiac Depolarization and Repolarizationb

b Panel A shows a surface ECG waveform with intervals relevant to monitoring for TdP. The dotted line demonstrates delayed repolarization manifesting as a prolonged T-wave/U-wave, represented on the ECG as QT prolongation. The solid line shows the tangent to the steepest downward slope of the T-wave, de ning the end of the T-wave by the intersection of the tangent with the baseline. Panel B shows the relationship of sodium (Na+), calcium (Ca2+) and potassium (K+) action potentials to the surface ECG (panel A). Panel C demonstrates the net in ux of sodium (Na+) and calcium (Ca2+) into the cardiac myocyte during depolarization and the net e ux of potassium (K+) during both normal and delayed repolarization. The role of magnesium (Mg2+) is unclear, however it may promote stabilization of the membrane potential during repolarization via interactions with calcium and potassium channels. Panel D compares the rate of potassium e ux through various potassium channels during normal repolarization versus in the presence of a hERG channel blocking drug.

of magnesium (Mg 2+), known to be a rst line intervention for acute TdP, is unclear mechanistically, but may serve to stabilize the cardiac myocyte membrane potential via inter- action with calcium and potassium channels (Figure 2.C).

Correcting QT Interval for Heart Rate

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The duration of QT interval varies depending upon the heart rate, and the QT interval needs to be “corrected” (QTc) for heart rate to make it more consistent and clinically mean- ingful. A number of di erent formulae, each with its own set of limitations, exist to correct the QT interval for heart rate. It is important to recognize there is a lack of consensus as to which technique is optimal, and none are perfect. When do- ing serial comparisons of QTc interval, the same correction technique should be used throughout.

Bazett’s formula (QTcB=QT/RR(Sec.)) (9) is the most common method used to correct QT interval for heart rate, and is programmed into most ECG machines in clinical use. The RR interval, which is a proxy for heart rate, is input into the formula in seconds. The standard “normal” and “at risk” values for QTc interval are studied and based on this formu- la as well (10) (Table 1). A major limitation of Bazett’s formu- la is that it overestimates QTc interval at any heart rate much higher than 60 beats per minute (bpm) and underestimates QTc interval at rates lower than 60 bpm (11). As many pa- tients who are being treated with potentially QTc-prolong- ing medications in the hospital setting are tachycardic due to agitation or systemic medical conditions, this overcorrec- tion becomes clinically meaningful. Bazett’s formula was a standard for pharmaceutical research but the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) recently identi ed it as “an inferior method” and recommended using Frideri- cia’s formula (or another suitable method) instead (www. ich.org). Fridericia’s formula uses a cube root (instead of square root) of HR (QTcF=QT/∛RR) and is less in uenced by extremes of HR. Other formulas (e.g., Framingham’s and Hodges’) or statistical methods (population- or individu- al-corrected QTc interval) are also available but are used less frequently. In some cases of drug-induced QTc interval pro- longation, the uncorrected QT interval may be a better pre- dictor of clinical events (12).

Technical Aspects of Recording and Measuring QT Interval on the ECG
Since the QT interval is, by de nition, an ECG measure- ment, a properly recorded and measured ECG must be the basis for clinical decision making regarding QTc interval prolonging drugs. Interpretation of the ECG, including quantitation of the electrocardiographic intervals, should be performed according to the local institutional standards. In most hospital settings, board-certi ed cardiologists provide the interpretations, but in many practice settings this may not be feasible. ECG interpretation should be available by a person quali ed by experience or training to interpret the

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QTc PROLONGATION AND PSYCHOTROPIC MEDICATIONS

ECG. Most modern ECG machines provide computer-de- rived interval measurements, as well as interpretive state- ments. These automated measures di er from machine to machine, but most often are derived from “representative complexes” or “median complexes” that take advantage of signal averaging techniques and automated threshold detec- tion. Prescribers need to be aware of the limitations of ma- chine-derived intervals, as well as the di erence of mea- surements from machine to machine (13). In general, if the patient’s ECG pattern is normal and free of artifact, the com- puter-derived intervals, including QTc interval, are reliable. If the patient’s ECG is abnormal the computer-derived in- tervals are less reliable, and prescribers should consider performing manual measurement. Widening of the QRS complex is a common abnormality seen with bundle branch block, ventricular pacing, or use of certain medications (e.g. tricyclic antidepressants) and leads to prolongation of the QT interval without perturbation of repolarization. In such cases, clinicians should not only perform manual measure- ments, but also consider alternative methods to assess for TdP risk. In all cases, manual measurement remains the best approach, and is a skill that should be encouraged among all clinicians involved in caring for patients who may receive ECGs in the course of their clinical care (14).

How to Measure the QT interval

The QT interval is de ned as the distance from the beginning of the QRS complex to the end of the T-wave. A standardized approach to de ne the end of the T-wave is the intersection of the tangent to the steepest downward slope of the T-wave with the isoelectric baseline (Figure 1.B). When using Ba- zett’s or Fridericia’s formulae to correct for heart rate, the RR interval from the preceding cycle length is used (14).

The recommendations above apply to the standard 12- lead ECG, which is a 10 second recording of cardiac electrical activity. Many other techniques capture ECG information in other formats and may have utility in monitoring the QTc in- terval. Hospital telemetry systems record single or multi- lead ECG data continuously from patients. Many of these systems have automated QTc interval measurement algo- rithms, some even providing real time assessment of the QTc interval. The American Heart Association has published standards regarding these systems, and the practitioner should be familiar with the local systems if they are used to make clinical decisions (15). Ambulatory monitors (e.g., Holter, event, and implanted loop) can also provide measure- ments of the QTc interval, but similar to the 12-lead ECG, re- quire noise-free signals and are more reliable in patients with normal ECGs. The use of ambulatory monitors for measure- ment of the QTc interval is discouraged because of the di – culty obtaining a noise-free signal in the ambulatory patient. Similarly, single-lead measurement with a mobile device is not a substitute for a 12-lead ECG. Ambulatory monitors and single-lead mobile devices may be useful for monitoring/ screening at-risk patients for arrhythmias, however.

Non-drug Risk Factors for QTc Interval Prolongation
and TdP
Medications are only one of the several possible risk factors for QTc interval prolongation and these increase the risk of TdP independently. Well-established non-drug risk factors based on literature are included in Table 2.

TABLE 2. Risk for TdP (16-18)

Non-modi able risk factors

Modi able risk factors

• Female sex

• Advanced age

• Congenital long QT syn-
drome (LQTS)

• Personal history of drug-induced QTc interval prolongation

• Personal history of struc- tural or functional cardiac disease (e.g., heart failure with reduced ejection fraction)

• Metabolizer status

• Concurrent use of more than one QTc interval prolonging drug

• Pharmacokinetic drug-drug interactions

• Drug toxicity

• Rapid intravenous infusion of QTc interval prolonging drugs

• Severe acute illness

• Bradycardia

• Starvation

• Inadequate dose adjustment of
hepatically-metabolized drugs in patients with hepatic cirrhosis

• Inadequate dose adjustment
of renally-eliminated drugs in patients with acute kidney injury or chronic kidney disease

• Risk or presence of hypoka- lemia, hypomagnesemia, or hypocalcemia

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Combinations of these risk factors have been shown to correlate with subsequent prolongation of the QTc interval in at-risk patients (19); therefore, potential cumulative ef- fects must be seriously considered. The odds of provoking TdP with a non-cardiac drug alone are very low, but co-ex- isting risk factors can increase the odds dramatically (20, 21). It is essential to be aware of these risk factors to assess and monitor patients accordingly if a drug with a risk to pro- long QTc interval is being considered or prescribed.

Most of the non-modi able risk factors are self-explana- tory and can be documented through clinical interview or past clinical records. Prior unexplained syncope should be investigated thoroughly as to the cause. While abnormal QT behavior in the absence of other risk factors may suggest congenital LQTS, it is important to recognize that some pa- tients will show no evidence of LQTS until exposed to a QTc interval prolonging agent or clinical situation (22). If in doubt, a cardiologist can be consulted.

Pharmacodynamic and pharmacokinetic drug-drug in- teractions are probably the most common risk factors that can be easily modi ed (or prevented) in many instances. The pharmacodynamic interaction would result when drugs with a potential to prolong QTc interval are pre- scribed concurrently. A pharmacokinetic interaction would occur if a drug or a substance (e.g., nicotine, drug of abuse)

is added or removed resulting in a metabolic interaction that results in slow or inhibited metabolism and consequent higher plasma concentrations of the drug associated with QTc interval prolongation. Given the vastness of possible drug-drug interactions, the best clinical approach would be to consult with a pharmacist.

Toxic drug plasma concentrations can result from a slow (or rapid, i.e., if a parent drug requires activation via CYP en- zymes to an active drug) metabolizer status, pharmacokinet- ic drug-drug interaction, or from an intentional or accidental overdose. Patients in such a situation will need to be moni- tored depending upon the level of toxicity and extent of oth- er risk factors for QTc interval prolongation. Dose-related QTc interval prolongation is an important consideration, so medications administered intravenously that achieve higher plasma concentrations more rapidly, may increase this risk compared with oral administration. Presence of hepatic cir- rhosis and/or renal insu ciency will add to the QTc interval prolonging e ect of the drug by impairing its metabolism and/or excretion, resulting in higher than usual (or toxic) drug plasma concentrations. In states of mild insu ciency, the e ect may be negligible for one drug, but the risk will be cumulative if more than one drug associated with QTc inter- val prolongation is prescribed concurrently.

Hypokalemia, hypomagnesemia and hypocalcemia can add to the risk of TdP. Several medications and/or proce- dures (e.g., diuretics and dialysis) can potentially disrupt electrolyte balance, and patients taking them will need to be monitored in this regard (23). Maintaining communication with the physician prescribing such drugs and establishing responsibility about electrolyte monitoring will facilitate the process and minimize duplication. Acute medical condi- tions (e.g., gastroenteritis, endocrinopathies), physiological conditions (e.g., gravida emesis, strenuous exercise), or fast- ing can also cause electrolyte disruption. Furthermore, cer- tain diagnoses can be accompanied by behaviors (e.g., purg- ing and/or dietary restriction in eating disorders, binge drinking in alcohol use disorder, use of dietary supplements) that would pose a risk for electrolyte derangement; these need to be considered during risk strati cation.

PSYCHOPHARMACOLOGY

It is worth noting that the following discussion of psycho- tropic medication classes, and in some cases, individual medications, is meant to highlight the importance of per- forming a comprehensive risk-bene t evaluation through the application of current data, knowledge of the clinical relevance of absolute QTc interval calculations, and consid- eration of historical regulatory recommendations in the context of other non-medication risk factors.

CredibleMeds publishes a widely used, freely available online list of drugs known to prolong the QTc interval, divid- ed into four categories (https://crediblemeds.org/) (24): drugs with known risk of TdP; drugs with possible risk of

TdP; drugs with conditional risk of TdP (i.e., can cause TdP under certain conditions); and drugs to be avoided by pa- tients with congenital long QT. The lists are produced by consensus of a board of experts who utilize available data from product labeling, the FDA, published literature, and other sources. A link to the website is included in many guidelines of the American Heart Association and American College of Cardiology. However, the inclusion and classi ca- tion are not systematic, as it is based on evidence of quite variable quality, ranging from double blind, randomized pla- cebo-controlled trials with intensive ECG monitoring to sin- gle case reports that often include other risks that may ac- count for the reported association. In some cases, supporting citations provide no actual evidence of the association. In our opinion, the classi cation on crediblemeds.org should not be accepted uncritically, but considered as a general list of drugs with possible potential for causing TdP. For all drugs that have a potential to prolong QTc interval, the risk of QTc in- terval prolongation and TdP increases when other risk fac- tors for QTc interval prolongation are also present.

Several other points are important to remember when re- viewing studies related to QTc interval prolongation. First, it is critical to understand the population being studied (e.g., healthy vs. medically or psychiatrically ill), the method of QTc interval measurement used (e.g., Bazett, Fridericia, use of a nomogram), the timing of QTc interval measurement (e.g., following a single dose of a medication vs. at steady- state), the dose of the medication, and the presence of other medications that might alter the metabolism of the medica- tion being studied. These vary widely among studies and can impact the degree of QTc interval prolongation reported. Second, while most studies report mean QTc interval pro- longation, this arguably is less important than the percent- age of participants who experience clinically meaningful QTc interval prolongation, since, in these instances, a change in medication can make a substantial impact on QTc inter- val. Finally, it is important to recognize the strengths and weaknesses of di erent study types. Case reports, for exam- ple, are important for identifying potentially important side e ects, but they often are fraught with confounders and may be in the setting of overdose, which limits their utility. Thor- ough QTc interval studies, in contrast, can clearly illustrate causal relationships between medications and QTc interval prolongation; however, these are performed in healthy adults with minimal QTc interval risk factors and so have limited generalizability. Given the wide variability in meth- odology and study samples, we have chosen to refrain from providing mean QTc interval prolongation for speci c med- ications in table form. Instead, we hope to highlight relevant studies that provide guidance for making recommendations regarding medication selection in patients at risk for QTc in- terval prolongation. It is important clinicians understand the inherent limitations of available data and how this ap- plies to their own practice as well as how this may impact guidance provided by regulatory agencies.

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Regulatory Agencies and Drug Safety Monitoring

Agencies in many countries regulate the drug (and thera- peutic devices) approval process through establishing e – cacy and safety of the drug (device) and monitoring them for any potential concerns after they become available for use. A few examples of such agencies include the Food and Drug Administration (FDA) in the USA, Medicines and Health- care Products Regulatory Agency (MHRA) of the United Kingdom, Health Canada, and the Therapeutic Goods Ad- ministration (TGA) of Australia. Over the last decade, these agencies have issued safety warnings related to the risk of QTc interval prolongation and TdP associated with some psychotropic drugs. In some cases, the warnings followed data based on thorough QTc interval studies and in other in- stances warnings were based on data from post-marketing reports and surveillance. While some degree of general con- sensus exists between various agencies, they tend to di er in ne details and occasionally more dramatically. The di er- ences stand out more noticeably when data are limited and/ or di cult to interpret reliably. This is the case with regards to the risk of QTc interval prolongation and TdP associated with psychotropic drugs, as we highlight with a few exam- ples below.

Citalopram and escitalopram underwent a thorough QTc interval study after post-marketing reports of QTc interval prolongation and TdP associated with citalopram emerged (25, 26). A dose-dependent QTc interval prolongation was observed both for citalopram (mean 8.5 ms with 20 mg/day dose and mean 18.5 ms with 60mg/day dose) and escitalo- pram (mean 4.5 ms with 10 mg/day dose and mean 10.7 ms with 30mg/day dose). The increase, based on prede ned terms, was signi cant for citalopram but not for escitalo- pram. Following these data, all four regulatory agencies mentioned above issued a safety warning for citalopram. The MHRA considered the data for escitalopram concern- ing enough to issue a safety warning for escitalopram as well. This highlights that safety of psychotropics (or lack thereof ) is not a dichotomous matter (21). Interestingly, in the aforementioned thorough QTc interval study (25), QTc interval was calculated using Bazett’s method, which now is considered an “inferior method” and Fridericia’s method (or another suitable method) is recommended for use in such studies (27).

The FDA and the TGA both have issued safety warning about quetiapine based on post-marketing data. The evi- dence was not strong or clear enough for the FDA to issue a “boxed” safety warning, however, a warning is included within the text of the FDA label for quetiapine. The FDA la- bel notes “there were cases reported of QTc interval prolon- gation in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QTc inter- val” (28). The TGA safety warning is based on a very similar observation and notes “Post-marketing reports of QTc inter- val prolongation associated with quetiapine treatment have occurred not only in the context of overdose, but also with

concomitant illness and in patients taking other drugs known to cause electrolyte imbalances or increase the QTc interval” (29). A recent comprehensive review has substan- tiated these concerns noticing that while quetiapine toxicity is associated with QTc interval prolongation, all three cases of TdP (out of 16 case reports of QTc interval prolongation) reported up till 2013 had occurred at therapeutic doses of quetiapine (21).

This document does not speci cally cover safety warn- ings issued by various regulatory agencies. Above we have only provided a few examples to draw attention to this mat- ter. Our understanding of psychotropic drug associated QTc interval prolongation and TdP is evolving. Further safety warnings and/or modi cation of existing warnings is ex- pected as data emerge. We advise clinicians to stay informed and follow the safety warnings pertinent to their country of practice.

Selective Serotonin Reuptake Inhibitors (SSRIs)

For many years, SSRI antidepressants were considered safe from a QTc interval prolongation perspective, despite occa- sional case reports of QTc interval prolongation for all agents in this class. To date, studies examining QTc interval prolongation e ect for uoxetine, uvoxamine, and paroxe- tine have provided no compelling evidence of QTc interval prolongation (30). Sertraline remains the agent with the best-established track record in cardiac populations (31, 32).

As previously stated, on August 2011, the FDA issued a warning for QTc interval prolongation with citalopram based on a thorough QTc interval study demonstrating pro- longation of 8.5ms at doses of 20mg and 18.5ms at doses of 60mg (25). Subsequent studies, including a meta-analysis, a large retrospective study of an ECG database, and a random- ized placebo-controlled study, have suggested that citalo- pram may be more likely than other SSRIs to cause QTc in- terval prolongation, and may prolong the QTc interval at a similar magnitude to that demonstrated in the FDA study (33-36). The FDA currently advises practitioners to not uti- lize doses of citalopram greater than 40mg in all patients, and to use doses of 20mg or lower in patients over the age of 60 years or with liver dysfunction. Though most studies suggest that the risk of QTc interval prolongation and TdP increases with higher doses, at least one large study found higher doses to be associated with fewer adverse outcomes, though QTc interval was not speci cally examined and the authors did not control for other known risk factors (37).

Several studies have suggested that escitalopram may have QTc interval prolonging properties, with a thorough QTc interval study estimating prolongation of 4.5ms at 10mg and 10.7ms at 30mg daily (30). However, a large meta-analy- sis of nearly 3300 patients demonstrated a mean prolonga- tion of only 3.5ms for all doses (38).

When applying these results to real-life clinical practice, it is essential to consider that QTc interval changes in the range of 10-20ms, as found in the citalopram studies, are be- low the limits of detection on an individual ECG and may

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only yield a signal in large samples. QTc interval changes in the range of 30-60ms would be considered potential signals; changes >60ms should be considered unusual and signals of concern. Hence, though the QTc interval changes with cit- alopram separate out from the other SSRIs, the clinical im- pact in isolation of other risk factors is insigni cant.

It is also important to keep in mind that, for some pa- tients, the risk of QTc interval prolongation with 60mg of citalopram is not as signi cant as the risk of psychiatric de- compensation with a lower dose. There is evidence to sug- gest that the FDA warning has not reduced all-cause or car- diac mortality, but has led to increased rates of psychiatric hospitalizations for patients whose dose was reduced re- exively (39). Another study found that patients who had their dose of citalopram re exively reduced were more like- ly to be prescribed sedatives or anxiolytics and had higher healthcare utilization (40). These studies highlight the im- portance of comprehensively considering all factors con- tributing to the risk-bene t ratio when prescribing “at-risk” medications.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Among SNRIs, venlafaxine, the oldest agent in this class, has the most evidence to support concerns with the risk for dose-related QTc interval prolongation, in both therapeutic doses (150 mg or 300 mg daily) and in overdose situations (41-44), some of which have proven fatal (45, 46). With that stated, the overall risk of QTc interval prolongation and TdP at therapeutic doses and in overdose situations is low (47), though elderly patients may be at greater risk (48). One study comparing the risk of sudden cardiac death or near death when venlafaxine was compared to other antidepres- sants found no increase in risk with the use of venlafaxine (49).

The paucity of data on the remaining available SNRIs, in- cluding duloxetine, desvenlafaxine, and levomilnacipran, limit any conclusions regarding the QTc interval prolonga- tion risk among these agents (41). Duloxetine’s e ects on the QTc interval have been studied in therapeutic and su- pratherapeutic doses. Overall, studies have found a decrease in the QTc interval when studied in healthy adults (50, 51). When corrected for heart rate, there is a slight increase in QTc interval values, however, study authors deemed this is not clinically signi cant (51).

One published study, reviewing overdoses of desvenla- faxine identi ed no cases of QTc interval prolongation in doses up to 3500 mg (52). In a systematic review and me- ta-analysis of levomilnacipran, this agent was found to in- crease QTc interval compared to placebo when Bazett’s for- mula, but not when Fridericia’s formula, was used (53), suggesting these ndings may have been driven by increases in heart rate. Among users of levomilnacipran, no patients experienced a QTc interval greater than 500 ms (53). Nota- bly, some studies evaluating the QTc interval risk of levom- ilnacipran were further limited by the exclusion of patients with a baseline abnormal ECG (54, 55).

Tricyclic and Tetracyclic Antidepressants (TCAs)

TCAs are known to prolong the QTc interval via blockade of sodium channels leading to QRS widening, in addition to ef- fects on the delayed potassium recti er current. Clinically signi cant QTc interval prolongation tends to occur at ther- apeutic doses only in the setting of pre-existing cardiac dis- ease, or in overdose (56). A meta-analysis suggested the av- erage QTc interval prolongation associated with TCAs is 13 ms compared to placebo (31). Among TCAs, amitriptyline and maprotiline have been most commonly associated with TdP in case reports (57).

Other Antidepressants

At therapeutic doses, the use of bupropion has demonstrat- ed a reduction in QTc interval (33, 58, 59) and may be consid- ered a reasonable option in patients at high risk for ventric- ular arrhythmias (60). On the other hand, similar to venlafaxine, bupropion has been linked to QTc interval pro- longation, particularly in overdoses (61-64). Reports of QTc interval prolongation with bupropion may be confounded by tachycardia and reported concomitant medications or substances (41). Importantly, in one key study, none of the patients that exhibited prolonged QTc interval experienced any type of arrhythmia (62).

Evaluating the risk of QTc interval prolongation with mirtazapine, studies have demonstrated a greater risk of mirtazapine for cardiac sudden death and ventricular ar- rhythmias in elderly patients when compared with paroxe- tine or citalopram (65, 66). However, other studies demon- strate low risk of mirtazapine for cardiovascular adverse drug reactions, including arrhythmia, when compared to other antidepressants (60, 67) or in overdose (68, 69). Given these con icting results, mirtazapine should be used cau- tiously in patients at risk for QTc interval prolongation, which is in alignment with the FDA warning in product la- beling.

Continuing on with newer antidepressants, data on the risk of QTc interval prolongation with use of vilazodone is very limited, however initial data does not support an in- crease in risk (41, 70, 71). With regard to vortioxetine, data fail to demonstrate a risk associated with therapeutic and supratherapeutic doses in healthy adult males (72). Further, in short-term studies of adults with major depressive disor- der treated with vortioxetine, changes in QTc interval (Frid- ericia) were similar to that of placebo (73). It is important to keep in mind that broader exposure is limited due to the novelty of these two agents.

Antipsychotic Medications

Both typical and atypical antipsychotic medications also have been associated with QTc interval prolongation and its sequelae of TdP and sudden cardiac death (SCD). Among the typical antipsychotics, low-potency phenothiazines–es- pecially thioridazine–lead to the greatest risk of QTc inter- val prolongation and sudden cardiac death (74-76). In a ran- domized trial of six antipsychotic medications, thioridazine

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led to 30.1 ms of QTc interval prolongation, which was nu- merically greater than the prolongation associated with hal- operidol (7.1 ms), ziprasidone (15.9 ms), quetiapine (5.7 ms), olanzapine (1.7 ms), or risperidone (3.6 to 3.9 ms) (74).

Aside from thioridazine, haloperidol’s QTc interval pro- longing properties have received the most attention. Halo- peridol is available in oral, intramuscular, and intravenous formulations, and each formulation is typically used in dif- ferent clinical situations. While oral and intramuscular hal- operidol are typically used for the management of psychosis or agitation in medically stable patients, intravenous halo- peridol is often used for the management of delirium in medically ill patients. As noted above, in individuals without signi cant medical illness, orally administered haloperidol 15mg daily is associated with a mild (~7 ms) increase in QTc interval at steady state (34). Intravenous haloperidol may cause a greater degree of QTc interval prolongation and con- fer a greater risk for TdP than orally administered haloperi- dol (77), though the di erence between these medications may be explained–at least in part–by their uses in di erent clinical populations, as noted above (78). Due to its links to QTc interval prolongation and TdP, the FDA recommends cardiac monitoring of patients in the setting of intravenous haloperidol use (79).

Other typical antipsychotic medications also prolong the QTc interval. Both chlorpromazine and pimozide are associ- ated with clinically signi cant QTc interval prolongation (77, 80, 81), and pimozide has been linked to TdP in overdose (82). Loxapine appears to be less likely to cause signi cant QTc interval prolongation, as two recent thorough QTc in- terval studies found that inhaled loxapine leads to mild (~5ms) increases in the QTc interval (83, 84). Finally, while the e ects of perphenazine on QTc interval have not been studied, a retrospective cohort study found that per- phenazine was associated with a similar risk of sudden death / ventricular arrhythmia and a lower risk of all-cause mortality compared to olanzapine (85).

Like the typical antipsychotics, nearly all atypical anti- psychotic medications have been associated with QTc inter- val prolongation to some degree. While it is di cult to rank atypical antipsychotic medications based on QTc interval risk due to di ering study methodologies (21), ziprasidone appears to carry a particularly high risk of QTc interval pro- longation (86). Thorough QTc interval studies suggest that ziprasidone leads to 10-21 ms increases in the QTc interval on average (74, 87), with over 20% of individuals experienc- ing >60 ms increases in QTc interval, a substantial and clini- cally meaningful increase (88).

The remaining atypical antipsychotic medications pro- long QTc interval to a lesser degree. Iloperidone has been linked to Fridericia-corrected QTc interval increases of 8.5 ms (at a dose of 8mg BID) to 15.4 ms (at a dose of 24mg daily) in cardiovascular healthy adults (87). As previously high- lighted, thorough QTc interval studies suggest that queti- apine leads to small to moderate (1.3-14.5 ms) increases in QTc interval at doses of up to 750mg daily, and the FDA has

issued a warning due to quetiapine’s propensity to prolong QTc interval (74, 87-90). These same trials found olanzapine to prolong QTc interval by 1.7-6.8 ms at up to 20mg/day and risperidone to prolong QTc interval by 3.6-11.6 ms at doses of 6-16mg/day (74, 88). QTc interval prolongation from pali- peridone, lurasidone, and asenapine range from 4.5 ms (asenapine) to 12.3ms (paliperidone) (91), and a recent me- ta-analysis found that these three medications did not cause signi cant QTc interval prolongation compared to placebo (86). Though the e ect of clozapine on QTc interval has been studied rarely, a retrospective review of patients who had switched treatment from another antipsychotic (>80% were atypical antipsychotics) to clozapine found no signi – cant changes in QTc interval following the switch, suggest- ing that the risk of QTc interval prolongation between clozapine and other atypical antipsychotic medications is similar (92). Finally, aripiprazole appears to be the least likely atypical antipsychotic medication to cause QTc inter- val prolongation, with a recent meta-analysis nding that aripiprazole led to signi cant reductions in QTc interval compared to both placebo and active controls (93).

The link between atypical antipsychotics and TdP is less clear. While these medications have only been linked to TdP in case reports and FDA adverse events reports (21, 94), atypical antipsychotics have been associated with an in- creased risk of sudden death in population-based studies (95, 96), which may be explained by the association between these medications and ventricular arrhythmias. Further- more, in elderly patients with dementia, they have been as- sociated with mortality related to cardiac events, which has led the FDA to issue a boxed warning related to this compli- cation.

Other Psychotropics

Lithium

There have been con icting reports concerning lithium’s ef- fect on QTc interval prolongation. A retrospective study showed lithium had no signi cant association with QTc in- terval prolongation (97). However, another report showed lithium in concentrations above 1.2 mmol/L can markedly prolonged the QTc interval (98). Multiple regression analy- sis revealed that sex, lower serum potassium concentration, and, especially, higher serum lithium concentration were determinants for the prolongation of the QTc interval (99).

Antiepileptic Drugs

Major antiepileptic drugs have not been found to signi – cantly precipitate prolongation of QTc interval. Valproate was found to lower QTc interval dispersion, which might indicate that valproate may have some preventative e ects and stabilization in cardiac conduction (100). Studies with lamotrigine or topiramate have not shown any clinically sig- ni cant changes on individual QTc interval, except for slight decreases in QTc intervals with lamotrigine (101, 102). Though carbamazepine has sodium-channel blocking prop-

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erties, at least one study suggests decreasing QTc interval with increasing carbamazepine concentrations (103). In a double-blind, placebo- and active-controlled trial, gabapen- tin enacarbil, a transported prodrug of gabapentin, was not associated with QTc interval prolongation in healthy adults (104).

Stimulants

Stimulants have multifactorial potential in addition to just QTc interval prolongation. The increase of catecholamines by CNS stimulants results in a rise in heart rate (HR) and blood pressure (BP), which would be expected to increase the risk of ventricular arrhythmia or sudden cardiac death (105). Clinical trials have found no statistically or clinically signi cant changes to the QTc interval over short and long- term treatment with methylphenidate and amphetamine drugs (106, 107). Atomoxetine has been shown to be associ- ated with life-threatening long QT syndrome (108). Evi- dence shows that atomoxetine inhibits cardiac potassium channel currents causing action potential prolongation and increasing risk of acquired long QT syndrome (109). How- ever, a pooled analysis of ve randomized double-blind tri- als showed no clinically signi cant increase in QTc interval prolongation (110).

Moda nil has been shown to cause infrequent signi cant increases in BP and HR. However, there has been no evi- dence that it has any clinically signi cant e ect on QTc in- terval prolongation (111). While not considered stimulants, it is worth noting there are also no statistically or clinically signi cant increases in QTc interval associated with cloni- dine and guanfacine (112).

Although the cardiovascular impact of stimulant use is minimal in healthy patients, prescribers should use caution in patients with underlying heart disease, other atrial or ventricular arrhythmias, symptoms of undiagnosed disease (e.g., syncope), or prescription of other like cardiac medica- tions. Given their e ects on the sympathetic nervous sys- tem, patients receiving stimulants should have routine mon- itoring of HR and BP.

Trazodone

Trazodone has rarely been associated with QTc interval prolongation (113). However, there have been a few case re- ports highlighting risk of transient QTc interval prolonga- tion in the setting of trazodone overdose, especially in pa- tients taking other QTc interval prolonging agents or with underlying cardiovascular disease (113, 114).

Benzodiazepines and Buspirone

Although there may be e ects on other cardiac parameters, there appears to be little e ect on QTc interval from benzo- diazepines and none reported with buspirone (115).

Acetylcholinesterase Inhibitors and Amantadine

Medications commonly used in dementias also have a rela- tionship with prolonged QTc interval. Acetylcholinesterase

inhibitors, such as donepezil, have cholinergic e ects which may lead to adverse reactions in the cardiovascular system. Cardiac arrhythmias, QTc interval prolongation and TdP in patients prescribed donepezil have been highlighted in case reports (116). However, these case reports include patients age 80 years or older, with several medical comorbidities. The dopaminergic activity of amantadine has potential for induction of malignant arrhythmias resulting in amanta- dine-induced TdP in the setting of overdose and co-inges- tions (117, 118).

Methadone

Methadone is well-known to be strongly associated with both QTc interval prolongation and TdP (119-121). TdP asso- ciated with methadone use was rst reported in a retrospec- tive case series of 17 patients receiving high dose treatment (119). Several case-control, cross-sectional, and prospective cohort studies have assessed the incidence of methadone-as- sociated QTc interval prolongation and shown signi cant e ects on the QTc interval (120). Unfortunately, the preva- lence of QTc interval prolongation and TdP in metha- done-treated patients is not clear; this gap in knowledge represents a major public health concern, especially in light of the burgeoning opioid epidemic. Guidelines from the American Pain Society can be helpful in identifying ap- proaches to mitigating the risk of QTc interval prolongation associated with methadone, which may include dose reduc- tion and discontinuation of other agents that may prolong the QTc interval (122). Concomitant use with other medica- tions with known risk for prolonging the QTc interval (e.g., citalopram) or in the context of electrolyte disturbances warrants cautious consideration of augmented risk for TdP (123). Further, as newer agents are developed in the manage- ment of opioid addiction, risks associated with these medi- cations and how they compare with the QTc interval prolon- gation risks of methadone will be important.

Buprenorphine

In general, QTc interval prolongation is not considered a consequence of the use of other narcotics. Buprenorphine has been found to be less likely to cause QTc interval prolon- gation than methadone (124). However, some studies have shown that induction with buprenorphine was still followed by an increase in QTc interval (125).

Special Population: Children and Adolescents

Our workgroup has chosen to limit our review to studies in- volving adults over the age of 18. While psychotropic medi- cations can cause QTc interval prolongation in children and adolescents, there are few studies evaluating these e ects. Importantly, additional research is necessary within this population to guide clinical decision-making and avoid “overcautious interpretation” of ECGs among children and adolescents, which may lead to non-treatment (126). Fur- ther, extrapolation of adult data is not appropriate. One ex- ample includes data surrounding the use of methadone

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among pediatric patients and young adults, which suggest methadone may be safe, though additional prospective data are needed (127, 128). Antipsychotic medications have re- ceived the greatest attention in the pediatric population, where a systematic review found ziprasidone to be linked to the greatest degree of QTc interval prolongation and aripip- razole to lead to a signi cant reduction in QTc interval, con- sistent with studies in adults (129). Use of antipsychotic medications or other medications that may prolong the QTc interval in the context of eating disorders within this popu- lation requires speci c consideration. One article highlights the importance of additive risk in the context of anorexia related to bradycardia and/or electrolyte abnormalities and the impact correction equations may have on normalizing the QTc interval, thereby underestimating the true severity of the repolarization abnormality (130). Additional monitor- ing is recommended in this population as well as those with bulimia who may purge and be pre-disposed to electrolyte abnormalities. Caution and repeat ECGs are advised as med- ications posing risk for QTc interval prolongation are added or doses are adjusted, or additional risk factors for QTc in- terval prolongation arise over the course of treatment.

In contrast, there are very few studies evaluating the ef- fects of antidepressants or mood stabilizers on QTc interval in pediatric populations (101, 131). Pediatric patients repre- sent a special challenge to the measurement and correction of the QTc interval. Pediatric patients may not be able to maintain the quiet supine posture needed for good quality ECG recording. The QTc interval varies with age and sex, and there is a sharp in ection in the relationship between age and QTc interval around puberty. Heart rate and the ef- fect of heart rate on the performance of QT correction fac- tors is more variable in the pediatric age range, and pub- lished reference ranges for QTc interval values have been developed in populations that may not re ect modern soci- ety’s mix of races (132). For these reasons, the practitioner caring for pediatric patients may wish to consult with a local cardiologist with the experience and/or training to deal with the complex issues present in the pediatric population. Given the limitations in the literature, as well as complexi- ties related to categorizing risk in children and adolescents of di erent age, making broad recommendations regarding the assessment and minimization of QTc interval prolonga- tion in pediatric populations is di cult and beyond the scope of this resource document.

Non-Psychiatric Medications and QTc prolongation

While this resource document is focused on psychotropics, these represent only a subset of QTc interval prolonging medications. Over 100 non-psychotropic medications have also been shown to prolong the QTc interval and/or be asso- ciated with TdP, particularly anti-arrhythmic medications, certain antibiotics (e.g., macrolides and uoroquinolones), antivirals (HIV medications), anti-emetics (e.g., ondanse- tron), acid blockers, antihistamines (e.g., hydroxyzine and diphenhydramine) and some anti-cancer medications. While

a full discussion of QTc interval prolongation risk of all these medications is well outside the scope of this document, a few salient points are made below.

It is important to note that non-psychotropic QTc inter- val prolonging medications are frequently administered or prescribed in a variety of settings, often more so than psy- chotropics. In the intensive care population, 3-30% of pa- tients received QTc interval prolonging medications, the most frequently administered being amiodarone, along with high use of uoroquinolones (levo oxacin) and macrolides (azithromycin) (133, 134). A study in emergency depart- ments found the top nine administered or prescribed QTc interval prolonging medications as non-psychotropic, par- ticularly diphenhydramine, azithromycin, and ondansetron; ondansetron alone was prescribed in almost 10% of ED vis- its, despite being o cially FDA-approved only for post-op- erative and chemotherapy-associated nausea and vomiting (135). In outpatients, a study of a national pharmaceutical claims database found almost a quarter of prescriptions in- volving QTc interval prolonging medications, the top three being clarithromycin, erythromycin, and levo oxacin (66).

Of particular concern is the co-administration of two or more QTc interval prolonging medications, as this signi – cantly increases the risk of QTc interval prolongation (136- 138). This is particularly salient given the often-signi cant medical co-morbidity of the psychiatric population, and the resultant comingling of psychotropics and QTc interval pro- longing non-psychotropics. In intensive care, almost one in ve patients were co-administered two or more QTc interval prolonging medications; particularly frequent combinations included amiodarone and haloperidol, as well as amiodarone or haloperidol with macrolides or uoroquinolones (133). In outpatients, close to 10% of patients received 2 or more QTc interval prolonging medications concurrently, particularly antidepressants such as uoxetine and amitriptyline with macrolides or uoroquinolones (139). Clinicians should also take care to inquire about over-the-counter medications, supplements, and imported drugs not approved in the U.S. Many useful tools exist online for the clinician to track po- tential drug-drug interactions prolonging the QTc interval, such as the Medscape Multi-Drug Interaction Checker (http://reference.medscape.com/drug-interactionchecker).

Minimization of QTc prolongation risk must involve a thorough assessment of the entire medication list, as well as balancing risks/bene ts of psychotropics against those of other medications, and potential drug-drug interactions us- ing appropriate reference tools.

CLINICAL CONSIDERATIONS

When to Obtain an ECG?

A wide variety of physiologic and pharmacologic factors can in uence the QTc interval; it is therefore recommended that QTc interval measurement should be no more than one month prior to the decision point, and no substantial chang- es in medications, electrolytes, or cardiovascular status (e.g.,

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an episode of heart failure or an acute MI) should have oc- curred subsequent to the measurement. ECGs are noninva- sive, inexpensive, and readily available in most clinical set- tings, so if there is uncertainty on the patient’s status, an ECG should be considered. Clinicians should consult any guidelines surrounding the ECG monitoring for speci c medications. For example, the methadone safety guidelines published by the American Pain Society provide detailed in- formation regarding recommendations for baseline and fol- low-up ECG monitoring, when to avoid methadone use, and alternative medications to consider for patients at high risk for QTc interval prolongation or TdP (122).

In resource-poor settings ECGs may not be easily acces- sible. Practitioners should not let the absence of an ECG preclude the prescription of a psychotropic medication; rather they must carefully consider known risks vs. bene t of prescribing the medication. In settings where clinicians have access to an ECG machine in the absence of a cardiolo- gy overread, clinicians of any medical specialty should feel comfortable with measurement, calculation, and documen- tation of the QTc interval.

Additional Monitoring

It is important to monitor electrolytes in patients that may have risk of electrolyte dysfunction, speci cally hypokale- mia or hypomagnesemia. Electrolyte monitoring is particu- larly indicated in patients with severe diarrhea or vomiting, alcohol use disorder, susceptible to rapid uid shifts as in dialysis, and in individuals receiving certain medications such as loop and thiazide diuretics, amphotericin B, and proton-pump inhibitors. Empiric supplementation with a bio-available magnesium preparation may be considered in patients at risk of chronic electrolyte de ciency. Renal and/ or liver function, depending on the medication utilized and the patient’s status, should be monitored to determine if re- nal or hepatic impairment may increase the risk for dose-de- pendent QTc interval prolongation. As always, monitoring for the addition or removal of speci c medications that may a ect drug concentrations of any o ending medication(s) should also occur.

Intensive Care Unit (ICU)

Patients in the ICU setting are at increased risk of TdP given the very nature of having severe medical/surgical illness. In one survey, 18.2% of patients admitted to a coronary care unit had a QTc interval > 500 ms (134). Patients are more likely to have multiple risk factors for QTc interval prolon- gation, including concurrent use of medications associated with QTc interval prolongation, parenteral administration of such medications, electrolyte disturbance, hepatic/renal dysfunction, older age, and underlying cardiac illness.

It is essential for all members of the ICU team, psychia- try, cardiology and other specialty services to work collabo- ratively and broadly to approach risk strati cation and risk mitigation in ICU patients. Clinical conversations about risk strati cation in the ICU may super cially focus on the ques-

tion: “does the patient have a QTc interval > 500 ms?” often stopping short of an all-inclusive evaluation of all pertinent risks, bene ts and risk-mitigation strategies. There is no ab- solute QTc interval at which a psychotropic should not be used. The decision of where to draw the line requires a com- prehensive risk-bene t assessment.

An important risk/bene t consideration is the risk of not appropriately controlling agitation which may result in harm to patient via self-removal of external devices includ- ing vascular access, monitoring devices, temporary pacing wires, endotracheal tubes, etc. It is critical that antipsychot- ics are not inappropriately under-dosed for agitation out of concern for QTc interval prolongation. The intensive care unit should be considered the “safest” place in the hospital where patients are closely monitored and sta are equipped to rapidly manage arrhythmias. In very high-risk cases (e.g., patient with history of past TdP, on high-risk antiarrhythmic medication, and severe agitation requiring parenteral halo- peridol) the team may consult cardiology for temporary over-drive pacing to prevent bradycardia. Re-intubation may be considered in patients with uncontrollable agitation.

When to Consult Cardiology

Routine cardiology consultation is not indicated when pre- scribing QTc interval prolonging medications to a patient without cardiac risk factors; however, many higher-risk clinical scenarios are best approached with cardiology in- put. In patients with known heart disease and one or more risk factors for drug-induced TdP, the clinician may consid- er consulting with the existing cardiologist when starting a medication with liability. In higher risk scenarios including co-administration of high-risk medications (e.g., amiodarone and parenteral haloperidol), marked QTc interval prolonga- tion (>500ms), or a sudden increase of QTc interval (>60 ms from baseline), referral to cardiology is appropriate. Patients on a known o ending drug who experience cardiac symp- toms such as syncope, dizziness, and palpitations should im- mediately be referred to cardiology. Again, a team-based care approach with open communication between special- ties is paramount.

Approach to the Patient with a Pacemaker or Implantable Cardioverter De brillator
Practitioners commonly assume that the presence of a pace- maker (PPM), implantable cardioverter de brillator (ICD), or cardiac resynchronization therapy (CRT) device is pro- tective against TdP, regardless of QTc interval prolongation. Speci cally, clinicians may suppose that such devices will prevent TdP by pacing, or that a single appropriate shock could terminate a ventricular arrhythmia without complica- tion.

It should be rst considered that patients with a cardio- vascular implantable electronic device (CIED) are already at increased risk for TdP by the mere nature of having pre-ex- isting cardiac disease. It is important to remember that all CIEDs have intrinsic pacing function, however to prevent

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accelerated PPM battery depletion and unnecessary ventric- ular strain, most pacemakers are not set to pace until the heart rate drops below 40-50 beats/minute. A review of all published case reports of TdP in patients with PPMs over a 24 year period found a pacing rate of 55+/-11 beats/min when TdP occurred (140). Hence, typical pacing parameters will not prevent TdP. Tachycardia pacing (>70 beats/min) is an accepted approach that may e ectively prevent TdP and may be strategically used, in collaboration with cardiology col- leagues, in the setting of acute medical/surgical illness re- quiring higher-risk psychotropic medication (e.g., parenteral haloperidol for delirium in the cardiac intensive care unit).

ICDs and CRTs both have the capability to recognize TdP and deliver appropriate shock therapy. Though the goal of de brillation is to terminate the ventricular arrhythmia, in most settings a single shock is not enough to stabilize the patient. Recalling that TdP typically occurs in a milieu of multiple risk factors, often including hypokalemia, hypo- magnesemia, and medications that prolong ventricular re- polarization, TdP may continue, despite repeated de brilla- tion, until the underlying milieu is corrected. Patients may experience a phenomenon known as “ICD storm” in which the ICD/CRT delivers repeated shocks in an attempt to abort the arrhythmia. ICD storm can result in additional co- morbidity, including posttraumatic stress disorder (PTSD), increased anxiety and reduced quality of life (141, 142). When prescribing medications known to increase risk of TdP to patients with a CIED, the clinician should not as- sume that the patient is “protected,” rather the presence of a cardiac device should trigger increased vigilance (143).

CONCLUSIONS

• The most widely used correction formula (Bazett), pro- grammed into most ECG machines, is not a consistently reliable method of correction. It overestimates QTc in- terval at high heart rates and underestimates it in brady- cardia. Manual measurement with heart-rate correction using Fridericia or an alternative population-based no- mogram is more consistently reliable across a range of clinical scenarios.

• Currently available sources that classify drugs according to ‘level of risk’ are based on evidence of very variable quality and validity.

• Medications are only one of the several possible risk fac- tors for QTc interval prolongation, each of which can in- crease the risk of TdP independently. Combinations of these risk factors can create cumulative risk. The co-ad- ministration of two or more QTc interval prolonging medications is of particular concern.

• There is not unanimity in the guidelines and warnings among the Food and Drug Administration (FDA) in the USA and analogous bodies in other countries.

• In patients with signi cant cardiac risk factors, psycho- tropic drugs with a known risk to prolong QTc interval or

those with a regulatory warning in this regard should be avoided when relatively safer alternatives are available.

• Though there is no absolute QTc interval at which a psy- chotropic drug should not be used, the risk-bene t ratio in patients with pretreatment QTc intervals >500ms must be assessed comprehensively with careful attention to risk mitigation strategies. The treatment team must consider risk of failure to control high risk psychopathol- ogy or of psychiatric decompensation.

• Routine cardiology consultation is not indicated when prescribing QTc interval prolonging medications to a pa- tient without cardiac risk factors. When signi cant car- diac disease is present and/or when other risk factors for QTc interval prolongation are present, cardiology input should be considered.
AUTHOR AND ARTICLE INFORMATION
Approved by the Joint Reference Committee, June 2018.
“The ndings, opinions, and conclusions of this report do not necessarily represent the views of the o cers, trustees, or all members of the Amer- ican Psychiatric Association. The views expressed are those of the au- thors of the individual chapters.” —APA Operations Manual.
1 Mental Health Service Line, Veterans A airs Southern Oregon Rehabili- tation Center and Clinics, White City, OR; 2 Department of Psychiatry, Massachusetts General Hospital, Boston, MA; 3 Harvard Medical School, Boston, MA; 4 Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI; 5 Mount Pearl, Newfoundland, Can- ada; 6 Department of Psychiatry, Virginia Commonwealth University, Richmond, VA; 7 Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL; 8 Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI; 9 Kran- nert Institute of Cardiology, Indiana University School of Medicine, India- napolis, IN.
Corresponding Author: Margo C. Funk, M.D., M.A., 940 Belmont Street, Brockton, MA, 02301. Phone: (774) 826-2456. Email: margo.funk@va.gov
Disclosures and Acknowledgements: Dr. Celano has received honoraria from Sunovion Pharmaceuticals for speaking on topics unrelated to this manuscript. Drs. Funk, Beach, Bostwick, Celano, Hasnain, Pandurangi, Khandai, Taylor, Levenson, Riba, and Kovacs report no competing inter- ests.
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ds16 ajp.psychiatryonline.org Data supplement for doi: 10.1176/appi.ajp.2019.1760501 Am J Psychiatry 177:3, March 2020

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