What is the relationship between Clozapine (Clozaril) and QT interval prolongation?

From the Guidelines

Clozapine can prolong the QT interval, but this effect is generally modest, with a mean QT prolongation of 8-10 ms, and clinicians should obtain baseline ECGs before starting clozapine and monitor the QT interval periodically during treatment. The risk of QT prolongation with clozapine is lower compared to other antipsychotics, such as thioridazine, which has a mean QT prolongation of 25-30 ms 1. However, clinicians should still be aware of the potential risk of QT prolongation, especially in patients with risk factors, including electrolyte abnormalities, congenital long QT syndrome, heart failure, bradycardia, and concurrent use of other QT-prolonging medications.

The management of patients with QT prolongation due to clozapine should follow the guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, which recommend careful monitoring of the QTc during therapy and avoiding the use of QT-prolonging medications unless there is no suitable alternative 1. Additionally, maintaining normal potassium and magnesium balance is an important component of management, as hypokalemia and hypomagnesemia can increase the risk of QT prolongation and torsades de pointes 1.

In terms of specific monitoring and management strategies, clinicians should consider the following:

• Obtain baseline ECGs before starting clozapine
• Monitor the QT interval periodically during treatment
• Correct electrolyte abnormalities promptly
• Avoid concurrent use of other QT-prolonging medications
• Consider dose reduction, discontinuation, or switching to an alternative antipsychotic with less QT effect if significant QT prolongation occurs
• Be aware of the potential risk of torsades de pointes and other dangerous arrhythmias, especially in patients with risk factors.

Overall, while clozapine can prolong the QT interval, the risk is generally modest, and careful monitoring and management can help minimize the risk of adverse cardiac events. The most recent and highest quality study on this topic is from 2018, which provides guidance on the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death 1.

From the FDA Drug Label

QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing clozapine, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.

Discontinue clozapine if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias (e. g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue clozapine.

Clozapine and QT Interval: Clozapine can cause QT interval prolongation, which may lead to life-threatening ventricular arrhythmias, cardiac arrest, and sudden death. The risk of QT prolongation is increased in patients with a history of QT prolongation, long QT syndrome, or other cardiac conditions.

• Risk Factors: Conditions that increase the risk of QT prolongation include history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.
• Monitoring and Treatment: Discontinue clozapine if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias, obtain a cardiac evaluation and discontinue clozapine 2.

From the Research

Clozapine and QT Interval

• The relationship between clozapine and QT interval prolongation has been studied in several research papers 3, 4, 5, 6, 7.
• A study published in 2011 found no significant differences in the prevalence of prolonged QTc or mean QTc before and after 18 weeks of clozapine treatment 3.
• Another study published in 2017 suggested that adequate correction for heart rate may show that clozapine does not prolong the QT interval 4.
• A meta-analysis published in 2018 found that low-quality evidence suggests that some atypical antipsychotic drugs, such as aripiprazole, brexpiprazole, and olanzapine, do not increase QT interval, while others, such as ziprasidone and risperidone, may be associated with QT prolongation 5.
• A study published in 2022 found that clozapine blood concentration predicts corrected QT-interval prolongation in patients with psychoses, and that a clozapine TDM value above the therapeutic range was associated with a high risk of QTc interval prolongation 6.
• A cross-sectional study published in 2025 found that clozapine was associated with a longer QTc interval compared to other antipsychotics, while aripiprazole was associated with a shorter QTc interval 7.

Predictors of QT Interval Prolongation

• Age, heart rate at 18th week, and QTc prior to clozapine treatment have been found to have significant effects on QTc at follow-up 3.
• Prolonged QTc during previous treatment and heart rate >95 beats/min at 18 weeks have been found to be predictors of QTc prolongation 3.
• Clozapine TDM value has been found to be a predictive factor for QTc interval prolongation 6.

Clinical Implications

• Monitoring of the QTc interval is recommended for patients taking clozapine, particularly those with risk factors for QTc interval prolongation 4, 7.
• Clinicians may recommend aripiprazole, brexpiprazole, or olanzapine in licensed doses to avoid QT prolongation and reduce the risk of ventricular tachycardia 5.
• The prescription of antipsychotics should always be accompanied by close monitoring of the QTc interval to prevent the risk of severe cardiac arrhythmia, particularly concerning clozapine 7.