Which atypical antipsychotics are known to prolong the QT(c) (corrected QT) interval?

Atypical Antipsychotics and QTc Prolongation Risk

Among atypical antipsychotics, ziprasidone, quetiapine, and risperidone are most associated with QTc prolongation, while aripiprazole, brexpiprazole, and olanzapine have minimal effects on QTc interval. 1

Risk Classification of Atypical Antipsychotics

Higher Risk for QTc Prolongation

• Ziprasidone: Strongest evidence for QTc prolongation among atypical antipsychotics 1
• Quetiapine: Associated with QTc prolongation and greater risk of torsades de pointes, especially in overdose 1, 2
• Risperidone: Linked to QTc prolongation and torsades de pointes 1
• Clozapine: Associated with QTc prolongation 3
• Paliperidone: Causes modest increase in QTc interval 4

Lower Risk for QTc Prolongation

• Aripiprazole: Multiple studies show minimal effect on QTc interval 1
• Brexpiprazole: Low quality evidence suggests no significant QTc prolongation 1
• Olanzapine: Multiple studies indicate minimal QTc prolongation 1, 5

Mechanism and Clinical Significance

QTc prolongation occurs through blockade of the human ether-a-go-go-related gene (hERG) potassium channels, which delays cardiac repolarization. This can lead to torsades de pointes (TdP), a potentially fatal ventricular arrhythmia 6.

The European Society of Cardiology (ESC) guidelines recommend:

• Dosage adjustment or interruption when QTc reaches >500 ms or increases by >60 ms from baseline (Class I recommendation) 6
• Monitoring plasma potassium levels to avoid hypokalemia 6
• Avoiding concurrent use of multiple QT-prolonging medications 6

Risk Factors for QTc Prolongation

Several factors increase the risk of QTc prolongation with atypical antipsychotics:

• Patient-specific factors:

  • Female sex
  • Age >65 years
  • Heart disease or bradyarrhythmias
  • Electrolyte abnormalities (hypokalemia, hypomagnesemia)
  • Hepatic or renal impairment 7, 8

• Medication-related factors:

  • High doses of antipsychotics
  • Intravenous administration (higher risk than oral)
  • Concomitant use of other QT-prolonging medications 6

Monitoring Recommendations

For patients receiving atypical antipsychotics with QTc prolongation risk:

1. Obtain baseline ECG before initiating treatment 6
2. Follow-up ECG during dose titration 6
3. Regular monitoring of electrolytes, particularly potassium 6
4. More frequent ECG monitoring for patients with additional risk factors 8

Clinical Decision Making

When selecting an atypical antipsychotic, consider this algorithm:

1. Assess baseline risk: Evaluate patient for existing risk factors for QTc prolongation
2. Choose appropriate agent:
   • For patients with multiple risk factors: Select aripiprazole, brexpiprazole, or olanzapine 1
   • For patients with history of cardiac disease: Avoid ziprasidone, quetiapine, and risperidone 1, 7
3. Monitor appropriately:
   • Higher risk medications require more frequent ECG monitoring
   • Document QTc at baseline and follow-up, especially with dose changes 6

Management of QTc Prolongation

If QTc prolongation occurs:

1. Discontinue the offending agent if QTc >500 ms or increases >60 ms from baseline 6
2. Correct electrolyte abnormalities, particularly potassium and magnesium 6
3. Consider switching to an atypical antipsychotic with lower QTc risk 1
4. For patients who must continue antipsychotic therapy despite QTc concerns, aripiprazole, brexpiprazole, or olanzapine are the safest options 1

Common Pitfalls to Avoid

• Relying solely on automated ECG measurements of QTc interval
• Failing to correct QT interval for heart rate
• Not considering drug interactions that may potentiate QTc prolongation
• Continuing multiple QT-prolonging medications simultaneously 8
• Ignoring electrolyte abnormalities that can exacerbate QTc prolongation 6

In critical care settings, antipsychotics should be avoided in patients at significant risk for torsades de pointes, including those with baseline QT prolongation or receiving other QT-prolonging medications 6.