US Pharm. 2024;49(5):HS8-HS12.

ABSTRACT: QT prolongation is an adverse event associated with the use of many antipsychotics. If not properly monitored and treated, QT prolongation can result in torsades de pointes (TdP), leading to sudden cardiac death. Patients who take antipsychotics may have an increased risk of developing a prolonged QT interval when presenting with multiple risk factors, such as preexisting arrhythmias or electrolyte abnormalities, or if they are on multiple agents that prolong the QT interval. Of the antipsychotics, low-potency typical antipsychotics are often associated with an increased risk of developing a prolonged QT interval and TdP. Pharmacists can recommend appropriate management and assist in monitoring patients at risk for TdP.

An ECG is used to trace the electrical activity within the heart. The electrical impulse causes the four chambers of the heart to contract and relax. Each part of the ECG represents different portions of the electrical impulse. The P wave represents depolarization of the left and right atrium or atrial contraction. The QRS (includes the Q, R, and S waves) complex indicates ventricular depolarization or the start of ventricular contraction. The T wave indicates ventricular repolarization or the beginning of ventricular relaxation.¹ The QT interval represents the summation of action potentials of ventricular myocytes—contractile cells of the ventricles. During the action potential, ions flow through specialized channels in and out of the cell.²

When the QT interval is prolonged, there is a malfunction or mutation in the genes that code for the channels. This can cause an increase in inward current or reduced outward current, increasing the action potential duration, and subsequently prolonging the QT interval. Some medications, such as antipsychotics, can cause a prolonged QT interval by causing a blockage of the inward potassium rectifier (IKr) channel. This channel is responsible for a critical current in the phase III repolarization of the action potential, which conducts a rapid delayed rectifier potassium current.² A prolonged QT interval can lead to a rare but serious cardiac arrythmia, torsades de pointes (TdP), which can lead to sudden cardiac death. TdP is a polymorphic ventricular tachycardia that is the result of prolonged ventricular repolarization. This repolarization leads to an oscillation in the membrane potential called early afterdepolarization (EAD). When the EAD reaches a critical threshold, it can lead to an ectopic beat. This beat can induce reentrant excitation and TdP.²

The QT interval is measured using a 12-lead ECG. There are multiple patient-specific factors that can impact a QT interval. Therefore, the Bazett’s formula is used to calculate the value of QTc (QT corrected for heart rate). A QTc value of >440 msec in males and >470 msec in females is considered a prolonged QT interval.² A QTc interval >500 msec puts a patient at risk for developing TdP.³

The risk for a prolonged QT interval can be evaluated by MedSafety Scan (MSS) QT prolongation risk score or the Tisdale risk score.⁴ The MSS is usually used in non-ICU patients to evaluate multiple known risk factors for QT prolongation that the patient may possess. The Tisdale risk score evaluates similar risk factors, but in ICU patients. These risk-assessment tools detect drug-drug interactions and risk severity for QT prolongation. These tools give a risk rating of moderate, high, or very high risk for TdP and provide recommendations to decrease the risk.⁴

RISK FACTORS

TABLE 1 outlines the multiple baseline characteristics that put a patient at higher risk for a prolonged QT interval and TdP. Although these factors can place a patient at higher risk for TdP, a prolonged QT interval at baseline is required to precipitate TdP.⁵

RESOURCES

Credible Meds is one of many resources available to healthcare professionals that provides risk categories for drugs that prolong QT and induce TdP. The categories include medications that have a known risk (KR) of TdP, possible risk (PR) of TdP, or conditional risk (CR) of TdP. KR refers to medications that have evidence associated with TdP even when taken as recommended, PR refers to medications that currently lack evidence for a risk of TdP when taken as recommended, and CR refers to medications that are associated with TdP only under certain conditions, such as excessive dose, electrolyte abnormalities, or drug interactions.⁶ Other resources provided by Credible Meds that pharmacists can reference to evaluate the risk of QTc prolongation include QTFactors and OncoSupport. QTFactors references a list of clinical factors or conditions that have been associated with prolonged QTc and/or TdP, and OncoSupport references common medications prescribed for oncology patients that are associated with QTc prolongation.^7,8

PSYCHIATRIC MEDICATIONS

Antipsychotics can be used to treat a variety of conditions, such as psychosis, mania, or schizophrenia.⁹ Antipsychotics are thought to prolong the QT interval and put a patient at risk of TdP by inhibiting the IKr, causing an efflux of potassium ions. IKr blockage results in a delay in phase III rapid repolarization of the action potential, leading to QT prolongation and subsequent TdP.¹⁰

Typical Antipsychotics

Typical antipsychotics, or first-generation antipsychotics, are potent dopamine 2 receptor antagonists. Common low-potency dopamine receptor antagonists include chlorpromazine and thioridazine, and common high-potency dopamine receptor antagonists include perphenazine, pimozide, and haloperidol.¹¹ All first-generation antipsychotics have an increased risk of causing significant extrapyramidal side effects due to the dopamine blockage. This includes dystonic reactions, tardive dyskinesia, akathisia, parkinsonism, and neuroleptic malignant syndrome.¹¹

Among the antipsychotics, the low-potency typical antipsychotics, including chlorpromazine and thioridazine, have the highest risk of increased QTc prolongation.¹² A prospective, open-label, randomized evaluation by Harrigan and colleagues studied the effects of six antipsychotics on the QTc interval at or around the time of peak plasma/serum concentrations in the absence and presence of metabolic inhibition.¹³ Patients received the low-potency typical antipsychotic thioridazine 300 mg/day (n = 30); the high-potency typical antipsychotic haloperidol 15 mg/day (n = 27); or the atypical antipsychotics ziprasidone 160 mg/day (n = 31), quetiapine 750 mg/day (n = 27), olanzapine 20 mg/day (n = 24), or risperidone 6 mg/day to 8 mg/day increased to 16 mg/day (n = 25/20). The study included adult patients aged 18 to 59 years who required chronic treatment of a psychotic disorder and had not had an exacerbation of psychosis for at least 3 months. The antipsychotics were initiated and titrated up to the target dose based on the recommended titration schedule per the manufacturer. Once the target dose was achieved, it was continued for five times the known half-life, plus 3 additional days to ensure steady state at the target dose, before initiating a metabolic inhibitor. Investigators initiated a cytochrome P450 metabolic inhibitor based on previous studies of drug interactions with the antipsychotic agents. Coadministration continued for several days, and the mean QTc interval change was calculated before and after coadministering the metabolic inhibitor. Prior to initiating the metabolic inhibitor, the mean QTc interval change was the greatest in the thioridazine group (30.1 msec) and least with olanzapine (1.7 msec). The mean change in QTc interval of ziprasidone reported 15.9 msec, haloperidol reported 7.1 msec, and quetiapine reported 5.7 msec. Risperidone had a mean change in QTc prolongation of 3.9 msec at the 6-mg/day dosage and 3.6 msec at the 8-mg/day dosage. However, the mean QTc changes from baseline were similar in the presence of metabolic inhibition compared with those observed during monotherapy. In conclusion, the low-potency typical antipsychotic thioridazine displayed the largest increase in QTc interval, and the presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent.¹³ Overall, typical antipsychotics, especially the low-potency typical antipsychotics, have an increased risk of prolonging the QT interval compared with atypical antipsychotics, with or without metabolic inhibitors.

TABLE 2 outlines the risk of TdP, administration, and FDA-approved dosing of the low- and high-potency typical antipsychotics.

Atypical Antipsychotics

Atypical antipsychotics, or second-generation antipsychotics (SGAs), have less affinity for D₂ dopamine receptors and have a higher degree of affinity for serotoninergic 5-hydroxytryptamine_2A receptors. As a result, the SGAs hold a decreased risk of extrapyramidal side effects but are associated with significant weight gain and the development of metabolic syndrome.¹⁰ All SGAs carry an FDA boxed warning of an increased risk of stroke in older adult patients with dementia, and it is recommended to avoid the use of SGAs concomitantly with other medications that prolong the QTc interval.¹⁰

TABLE 3 outlines the risk of TdP and administration of atypical antipsychotics.

Drug Interactions

In addition to antipsychotics, there are various medications that also increase the risk of developing a prolonged QT interval.⁶ Therefore, patients who take antipsychotics are at further risk of developing QTc prolongation and TdP when concomitantly taking an additional medication that also increases the risk of QTc prolongation.¹⁴ Common medications that increase the risk of QTc prolongation, especially when taken in addition to antipsychotics, are outlined in TABLE 4.

RISK DEVELOPMENT FOR TDP

It is important to be aware that having only one risk factor to increase the QTc interval is a relatively poor predictor of the development of TdP, and multiple factors should be considered, including modifiable and nonmodifiable risk factors, concomitant medications, electrolyte disturbances, and preexisting arrythmias.¹⁴ In addition, patients with poor renal function who are taking antipsychotics may be at further risk of increased QTc prolongation, as they are at an increased risk of drug accumulation and increased risk of adverse effects, including increased QT interval.¹⁵ Other factors can help variation in QTc calculations, such as using multiple leads or technology readings. Therefore, manual calculation is preferred. Pharmacists should also evaluate the risks versus benefits of discontinuing a medication before switching to another agent.¹⁴

MANAGEMENT

Patients who are initiated on an antipsychotic agent should receive a baseline ECG to predict the QTc interval. A normal QTc is defined as <470 msec for women and <440 msec for men. Patients who have a normal QTc may continue the antipsychotic and repeat the ECG annually. Healthcare providers may consider decreasing the dose or switching to an alternative agent if the QTc is >470 msec for women and >440 msec in men, but <500 msec. If the ECG is abnormal after altering the medication, a referral to a cardiologist should be initiated. For patients who have baseline QTc >500 msec at baseline, an antipsychotic should not be initiated. If the QTc interval increases to >500 msec after the antipsychotic is initiated, it is recommended to discontinue the suspected causative drug and give prompt referral to a cardiologist.¹⁶ However, it is important to rule out all other risk factors for prolonging the QT prior to discontinuing the medication and perform a risk-benefit analysis.¹⁴ For example, possible contributors may include electrolyte imbalances such as hypokalemia, hypocalcemia, and hypomagnesemia that should be monitored and corrected.¹⁴

FIGURE 1 displays a stepwise approach when evaluating the QTc interval in patients taking antipsychotics.¹⁶

THE ROLE OF THE PHARMACIST

Pharmacists can assist in monitoring a patient’s risk of developing QTc prolongation and TdP. When a patient is started on a new antipsychotic medication in the inpatient setting, pharmacists should first evaluate any interactions with current medications and potential risks that the patient may possess to precipitate a prolonged QT interval. Tools, such as the MSS QT prolongation risk score or the Tisdale risk score, can help a pharmacist assess a patient’s susceptibility to QT prolongation. MSS uses the Credible Meds database to identify drug-drug interactions and identify patients at the greatest risk for QT prolongation.⁴ Pharmacists should complete an MSS QT risk score at the initiation of a new medication or whenever a dose adjustment is made. These resources can help a pharmacist obtain a more comprehensive assessment of the patient. Pharmacists should recommend that providers obtain a baseline ECG and serum potassium before initiating antipsychotics in patients with a known risk or with multiple risk factors for QT prolongation. Additional ECG monitoring should be considered with the addition of a risk factor or any dose increase/drug change. Pharmacists are responsible for providing recommendations for lowering a patient’s risk. Depending on the severity of the risk, pharmacists can recommend dose changes, changing the route of administration, or discontinuation of offending agents.

Though many patients are asymptomatic when experiencing a prolonged QT interval, there are some signs and symptoms that pharmacists can educate patients to look for. These include presyncope, palpitations, syncope, and cardiac arrest.¹⁷ In addition, pharmacists should counsel patients on any drug-drug interactions that may be present.

CONCLUSION

In conclusion, typical and atypical antipsychotics have been linked to QT prolongation, which poses the risk of progressing to TdP. Of the antipsychotics, the low-potency typical antipsychotics, including chlorpromazine and thioridazine, have an increased risk of QTc prolongation. However, multiple factors should be considered when evaluating a patient’s risk of developing TdP, such as modifiable and nonmodifiable risk factors, concomitant medications, and preexisting arrythmias or electrolyte abnormalities. Pharmacists can aid in monitoring patients at risk for TdP and make clinical interventions to either discontinue a medication, decrease the dose, or switch to an alternative agent in patients with an abnormal QTc or in patients at risk for developing an abnormal QTc.

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