Assessing QT Interval Prolongation and its Associated Risks with Antipsychotics

Abstract

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500 ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.

Antipsychotic Agents

“…Prolongation of the QTc interval, and perhaps some aspects of the size and shape of electrocardiographic T-waves as well as a history of paroxysmal atrial tachycardia, hypokalemia, hypomagnesemia, hypertension, and advanced age appear to be risk factors for rare, but potentially fatal ventricular arrhythmias including torsades de pointes , and cardiac arrest [ 156 ] . The rarity of fatal cardiac reactions limits their contribution to overall mortality risk, which may well prove to be greater with prolonged metabolic abnormalities.…”

QTc interval and its variability in patients with schizophrenia and healthy subjects: implications for a thorough QT study

“…Besides coronary artery disease, drug abuse, cigarette smoking, hypercholesterolaemia, hypertension, obesity and diabetes mellitus which are more common in patients with schizophrenia (Bär et al 2007 ;Glassman & Bigger, 2001 ;Hennekens et al 2005), recent articles have highlighted the association between prolonged QT interval on the ECG and increased risk of sudden death in patients with schizophrenia (Glassman & Bigger, 2001 ;Nielsen et al 2011). QT prolongation is a non-invasive biomarker of abnormal cardiac repolarization.…”

“…Several commonly used antipsychotic medications alter cardiac repolarization and prolong the QT interval on ECG especially when used in high doses or combinations (CSISG, 2002 ;Glassman & Bigger, 2001 ;Nielsen et al 2011). The QT interval may also be prolonged by autonomic changes, widened QRS complex in the ECG or electrolyte disturbances which are seen during acute psychotic episodes (Bär et al 2007 ;CSISG, 2002).…”

Targeted next generation sequencing application in cardiac channelopathies: Analysis of a cohort of autopsy-negative sudden unexplained deaths

“…Indeed, some patients with pathogenic variant in cardiac ion channel genes may not manifest prolongation of the QT interval at baseline due to incomplete penetrance of the trait. Consequently, the particular precautions normally recommended before the introduction of psychotropic drugs with cardiovascular toxicity (including blood ionic balance and electrocardiogram) could not correctly evaluate the cardiac risk [41].…”