What antipsychotics have a lower risk of QT interval prolongation?

Antipsychotics with Lower Risk of QT Interval Prolongation

Aripiprazole, brexpiprazole, and olanzapine are the antipsychotics with the lowest risk of QT interval prolongation and should be preferred when cardiac safety is a concern. 1, 2

Risk Stratification of Antipsychotics by QT Prolongation

Antipsychotics can be categorized based on their effect on QT interval:

Low-Risk Options (Minimal QT Prolongation)

• Aripiprazole (0 ms) - Shows no significant QT prolongation 3, 4
• Brexpiprazole (0 ms) - Does not prolong QTc interval to any clinically relevant extent 5, 2
• Olanzapine (2 ms) - Minimal QT prolongation 3, 2

Moderate-Risk Options

• Risperidone (0-5 ms) - Low to moderate QT prolongation 3, 6
• Quetiapine (6 ms) - Moderate QT prolongation 3, 7
• Haloperidol (7 ms) - Moderate QT prolongation 3
• Clozapine (8-10 ms) - Moderate QT prolongation 3

High-Risk Options (Significant QT Prolongation)

• Pimozide (13 ms) - Significant QT prolongation 3
• Ziprasidone (5-22 ms) - Substantial QT prolongation 3, 8
• Thioridazine (25-30 ms) - Highest risk of QT prolongation 3

Monitoring Recommendations

When prescribing antipsychotics, follow these evidence-based monitoring protocols:

1. Baseline ECG before initiating antipsychotic treatment 3, 1
2. Follow-up ECG after reaching stable medication levels and with dose adjustments 1
3. Regular monitoring of electrolytes, especially potassium and magnesium 3, 1
4. Immediate discontinuation if QTc exceeds 500 ms or increases by >60 ms from baseline 3, 1

Risk Factors for QT Prolongation

Be particularly cautious in patients with:

• Female gender
• Advanced age
• Pre-existing cardiac disease
• Bradycardia
• Electrolyte disturbances (especially hypokalemia, hypomagnesemia)
• Concomitant use of other QT-prolonging medications
• Congenital long QT syndrome 1

Clinical Decision Algorithm

1. Assess cardiac risk factors in patient requiring antipsychotic therapy
2. For patients with low cardiac risk:
   • Consider any clinically appropriate antipsychotic
   • Monitor ECG at baseline and follow-up
3. For patients with moderate to high cardiac risk:
   • First-line: Aripiprazole, brexpiprazole, or olanzapine
   • Avoid: Ziprasidone, thioridazine, and pimozide
   • Monitor ECG at baseline, after 7 days, and with any dose changes
4. For patients already on high-risk antipsychotics:
   • Consider switching to aripiprazole, brexpiprazole, or olanzapine if QTc >450 ms (men) or >470 ms (women)
   • Immediate medication change if QTc >500 ms or increases by >60 ms from baseline 3, 1

Common Pitfalls and Caveats

• Avoid multiple QT-prolonging medications - The risk of QT prolongation increases substantially when combining multiple QT-prolonging drugs 3, 1
• Correct electrolyte abnormalities before starting antipsychotics - Maintain potassium >4.0 mEq/L and magnesium >2.0 mg/dL 1
• Intravenous haloperidol carries higher risk - Prefer intramuscular route when parenteral administration is needed 3
• First-generation antipsychotics generally carry higher risk than second-generation antipsychotics 8
• Drug interactions - Be aware that medications affecting CYP3A4 or CYP2D6 may increase antipsychotic levels and QT prolongation risk 1

Special Considerations

• In patients with schizophrenia, a large study of 1,017 patients found that second-generation antipsychotics (olanzapine, quetiapine, risperidone) were less likely to produce QTc prolongation than first-generation antipsychotics 6
• A 2023 pharmacovigilance study confirmed that lurasidone, brexpiprazole, and aripiprazole have the lowest risk of QT prolongation in real-world settings 8
• The European Society of Cardiology recommends dosage adjustment or interruption of antipsychotic drugs when QTc reaches >500 ms or increases by >60 ms from baseline 3

By selecting antipsychotics with lower QT prolongation risk (aripiprazole, brexpiprazole, or olanzapine) and implementing appropriate monitoring, clinicians can significantly reduce the risk of cardiac arrhythmias while effectively treating psychiatric conditions.