QT prolongation and torsades de pointes with psychotropic agents.

The unexpected and catastrophic cardiovascular effects of psychotropic drugs are well described albeit uncommon. The list of drugs which have been associated with prolonging QT interval and hence potentially causing Torsades de pointes is exhaustive. The insight into the plausible mechanisms are largely unclear. However, the practical implications of anticipating and recognizing QT prolongation cannot be overemphasized.

INTRODUCTION

Many drugs are notoriously known to prolong the QT interval, especially those used in cardiology and psychiatry practice. QT prolongation can remain asymptomatic or lead to torsades de pointes (TdP), a rare tachyarrhythmia which can be life-threatening or nearly fatal due to ventricular fibrillation and sudden cardiac death. In 2005, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) published guidelines to evaluate QT interval prolongation and pro-arrhythmic potential of nonantiarrhythmic drugs (ICH-E14).[1] With few exceptions, all new drugs entering the market have to undergo a “thorough QT study” (TQT) defined by the ICH-E14.[12] However, a majority of the presently used drugs were marketed before TQT studies were made mandatory. In addition, even a well-performed TQT study cannot rule out the pro-arrhythmic potential of the drug when used in different clinical situations, as in comorbid heart disease, substance abuse, and self medication with over-the-counter drugs and drug-drug interactions due to polypharmacy.

THE QT INTERVAL

The QT duration is a measure of the cardiac electrical cycle. It includes both ventricular depolarization and repolarization.[3] Repolarization is shortened in tachycardia and hence, a correction of the observed QT to the heart rate is to be applied. Normally, over a 24 h period, intra individual variability of the corrected QT (QTc) is anywhere from 76 to 102 ms.[3]

CALCULATION OF QT INTERVAL AND CORRECTED QT

The QT interval is the duration between the beginning of the q wave to the end of the t wave in the surface electrocardiogram (ECG), taken usually in limb lead II as an average of measurements from at least 3 to 5 complexes.[4] In case it is not possible, other alternate limb and chest leads have also been recommended. For better measurement of the QT interval, some authorities have used a total of 6 leads, including 3 limb leads and 3 chest leads, and the median of the 6 individual leads as the QT value.[5]

CALCULATION OF THE CORRECTED QT

As repolarization is faster when the heart beats more rapidly, the QT interval should also be corrected for the heart rate. For calculating the QTc interval, most commonly Bazett's square root formula (QTc = QT/RR0.5) is used and is recommended for relatively low heart rates (60–80 bpm). The Fridericia cube root formula (QTc = QT/RR0.33) is suitable for higher heart rates.[3] Isbister's QT–heart rate nomogram (QT nomogram) may also be used for this purpose.[4]

The upper limit of the normal reference QTc intervals for males is 450 ms and that for females is 460 ms. There is considerable intra-individual variability of the QTc up to 76–102 ms over the course of 24 h. QTc intervals longer than 500 ms are a major risk factor for the development of TdP.[6]

MECHANISM OF CORRECTED QT PROLONGATION

Drugs prolonging QT interval bind to the cardiac potassium channels (IKr, also known as human ether-a-go-go related gene channels), usually the rapid component of the delayed rectifier potassium channel leading to a blockade of potassium efflux from cardiac myocytes. Hence, ICH-E14 guideline reiterates the importance of in-vitro IKr inhibition assay.[1] Some authorities have recommended using the multiple ion channel effects approach in evaluating the pro-arrhythmic risk of new drugs as false-positive results are fewer.[7]

Classic antipsychotic drugs and tricyclic antidepressants may induce dose-dependent QT prolongation which may not necessarily result in TdP.[8] Certain cardiac drugs such as sotalol, flecainide, propafenone (class IC and class III antiarrhythmic drugs) may induce TdP in accordance with the extent of prolongation of the QT interval, which may not be the case with other repolarization-prolonging drugs.[8]

RISK FACTORS FOR QT PROLONGATION AND TORSADES DE POINTES

Many factors may influence QT interval and may in turn predispose to TdP[91011] (see infra).

Age over 65 years

Female sex (longer QTc interval than men and twice the risk of drug-induced TdP)

Increased myocardial mass (e.g., in arterial hypertension)

Congenital QT prolongation syndrome

Bradycardia

Electrolyte disturbances (hypokalemia, hypomagnesemia)

Preexisting heart disease

High plasma concentrations of the drug

Inhibition of drug metabolism by concomitantly administered drugs

Reduced drug clearance due to renal or hepatic insufficiency, or due to rapid infusion of the drug

Polymorphisms of genes coding ion channels or enzymes involved in drug metabolism.

Considerable variation between antipsychotic drugs can be expected, possibly due to the differences in affinity of the drugs to different receptors. The risk of TdP is dose-dependent, though its occurrence cannot be predicted within the therapeutic range. Though a drug, by itself may not cause QT prolongation and TdP when used individually, concomitant use of other QT prolonging drugs and/or other risk factors as referred to above, can significantly increase the risk of TdP. Both oral and parenteral psychotropic agents have been associated with the risk of QT prolongation, the risk being higher with high dose IV medications as available evidence suggests.[11]

STATUS OF CURRENTLY USED PSYCHOTROPIC AGENT CLASSES AND THEIR RISK OF INDUCING CORRECTED QT PROLONGATION AND TORSADES DE POINTES

Antipsychotics

Among the antipsychotics, though the newer atypical antipsychotics were considered to be more cardio safe than the typical ones, studies have negated this belief and reported similarly increased risks of sudden cardiac deaths. Patients on aripiprazole,[12] olanzapine,[13] and perphenazine,[13] are reported to be at low risk while those on amisulpride,[13] clozapine,[13] flupenthixol,[13] levomepromazine,[13] sulpiride,[13] quetiapine,[13] paliperidone,[14] and risperidone,[14] are at moderate risk. Those on chlorpromazine,[13] haloperidol,[13] pimozide,[15] sertindole,[16] and ziprasidone[17] are at high risk of QTc prolongation, the risk being highest with thioridazine.[13]

Antidepressants

Among tricyclics and mono amine oxidase inhibitors, mirtazapine[18] has least risk while amitriptyline,[19] clomipramine, doxepin,[20] imipramine, moclobemide, nortriptyline[21] fluoxetine, venlafaxine, and paroxetine[22] are reported to be at a moderate risk of QTc prolongation.

Citalopram,[19] duloxetine,[23] and escitalopram,[19] carry a moderate risk while most of the selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors such as - bupropion,[19] desvenlafaxine, levomilnacipran, mianserin, sertraline, vilazodone[24] and reboxetine[25] are reported to be safe with a low risk of QTc prolongation at therapeutic doses.

Mood stabilizers

Among the mood stabilizers, lithium[22] has a moderate risk of QTc prolongation while the antiepileptics used for this purpose such as carbamazepine, oxcarbazepine, topiramate, valproate,[26] pregabalin, gabapentin,[27] and lamotrigine[28] are reported to be safe with a low risk of QTc prolongation.

Anxiolytic drugs and sedatives

Most of the benzodiazepines are reported to be safe with a low risk of inducing QTc prolongation.[13]

Anticholinergics

Among the anticholinergic drugs, biperiden, orphenadrine, and trihexiphenidyl are relatively safe with a low risk.[13]

OPIOID AGONISTS

Among opioid substitutes, methadone has been reported to have a moderate risk, while buprenorphine is relatively safe with a low risk of QTc prolongation in patients.[29]

QT prolongation has been reported with the usage of nearly all psychotropic drugs. However, TdP is rare. The clinician should have a fair knowledge of the risk posed by the drugs prescribed by him/her in medical practice; in this context, that of QTc prolongation and the risk of TdP.

CONCLUSION

No drug is totally safe. Every patient is unique and so is his/her response to any drug. Individualization of treatment is the greatest challenge for the attending clinician whose role is pivotal in selecting the right drug for the right patient. It can be recommended to perform an ECG to record the QT interval at baseline, after introduction of the psychotropic agent, and to be repeated in an event that may be suspected to alter the QT interval. Polypharmacy and over-the-counter self-medication being rampant, can compound the problem. A simple approach is being vigilant on the patient's new symptom or change in QTc on ECG review should alert the clinician to withdraw the offending drugs to prevent a catastrophe.

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Conflicts of interest

There are no conflicts of interest.