QT Interval Prolongation Risk with Antipsychotics: First and Second Generation
Both first-generation and second-generation antipsychotics can cause QT interval prolongation, with first-generation antipsychotics generally posing a higher risk than second-generation agents. 1
Comparative Risk Assessment
First-Generation Antipsychotics (Higher Risk)
- Thioridazine: Highest risk (25-30ms mean QT prolongation) with FDA black box warning 1
- Chlorpromazine: Significant risk (RR 1.37 for 100mg dose) 1, 2
- Haloperidol: Moderate risk, especially IV formulation (RR 1.29 for 2mg) 1, 2
- Pimozide: Substantial QT prolongation (13ms) 1
Second-Generation Antipsychotics (Variable Risk)
- Ziprasidone: Highest risk among second-generation agents (5-22ms) 1, 3, 4
- Amisulpride: Significant risk (HR 1.56) 3, 4
- Clozapine: Moderate risk (8-10ms) 1
- Quetiapine: Lower risk (6ms) 1, 5
- Olanzapine: Low risk (2ms) 1, 3
- Risperidone: Very low risk (0-5ms) 1
- Aripiprazole: Minimal to no risk (0ms) 1, 4
- Lurasidone: Lowest risk among all antipsychotics 4
Risk Factors for QT Prolongation
Patient-Specific Risk Factors
- Female sex
- Advanced age (>65 years)
- Heart disease or bradyarrhythmias
- Electrolyte abnormalities (particularly hypokalemia and hypomagnesemia)
- Underlying cardiac conditions 6
Medication-Related Risk Factors
- Concomitant use of other QT-prolonging medications
- Drug interactions affecting metabolism
- Higher doses or recent dose increases 6
Monitoring Recommendations
Before Starting Antipsychotic Therapy
- Obtain baseline ECG
- Check electrolytes (particularly potassium and magnesium)
- Assess for other risk factors 6
During Antipsychotic Therapy
- Monitor ECG at 2 weeks, then monthly thereafter
- Additional ECG after adding any new QT-prolonging medication
- Consider more frequent monitoring for high-risk patients or high-risk medications 6
Warning Signs
Management of QT Prolongation
- Discontinue or reduce dose of causative QT-prolonging drugs
- Correct electrolyte abnormalities aggressively
- Continue QTc monitoring until drug washes out and QTc decreases
- Consider alternative antipsychotics with lower QT prolongation risk 6
Clinical Implications
The European Society of Cardiology guidelines recommend dosage adjustment or interruption of the offending antipsychotic when the QTc interval reaches >500 ms or increases by >60 ms compared with baseline (Class I recommendation) 1.
Common Pitfalls to Avoid
- Overlooking drug interactions: Many antipsychotics are metabolized by CYP2D6, and inhibitors of this enzyme can increase plasma concentrations
- Neglecting electrolyte monitoring: Hypokalemia and hypomagnesemia significantly increase risk
- Assuming all second-generation antipsychotics are equally safe: There is considerable variation in risk within this class
- Failing to consider cumulative risk: Multiple QT-prolonging medications can have additive effects 1, 6
When selecting an antipsychotic for patients at risk of QT prolongation, consider agents with minimal effect on QT interval such as aripiprazole or lurasidone, while avoiding high-risk agents like thioridazine, ziprasidone, and chlorpromazine 4, 7.