Which antipsychotic is least likely to cause QT (QT interval) prolongation?

Aripiprazole and Brexpiprazole Are the Antipsychotics Least Likely to Cause QT Prolongation

Aripiprazole and brexpiprazole should be the preferred antipsychotics when QT prolongation is a concern, as they demonstrate 0 ms mean QTc prolongation and are specifically recommended by the American Academy of Pediatrics and European Heart Journal for this indication. 1

First-Line Agents with Minimal QTc Risk

• Aripiprazole has a 0 ms mean QTc prolongation and is classified as having minimal to no effect on the QTc interval 1
• Meta-analyses demonstrate that aripiprazole actually decreases the mean ΔQTc interval compared to placebo and active controls, with lower QTc prolongation risk than comparators 2
• Brexpiprazole similarly shows no clinically significant QTc prolongation and is recommended alongside aripiprazole as a first-line option 1
• Low-quality evidence from multiple RCTs confirms that aripiprazole does not increase QT interval in clinical practice 3
• Real-world pharmacovigilance data from VigiBase (1967-2019) found that lurasidone was associated with the lowest risk of QT prolongation reporting among all antipsychotics studied 4

Second-Line Options with Minimal Risk

If aripiprazole or brexpiprazole are not suitable:

• Olanzapine causes only 2 ms mean QTc prolongation and is classified as very low risk 1
• Multiple RCTs demonstrate olanzapine does not significantly increase QT interval 3
• Real-world data from 1,017 patients with schizophrenia showed second-generation antipsychotics including olanzapine, quetiapine, and risperidone did not prolong QTc interval 5

Moderate Risk Agents to Use Cautiously

• Risperidone: 0-5 ms mean QTc prolongation 1, though some evidence suggests association with QT prolongation and torsades de pointes risk, particularly in overdose 3
• Quetiapine: 6 ms mean QTc prolongation 1, with evidence of QT prolongation and greater odds of torsades de pointes especially in overdose situations 3

High-Risk Agents to Avoid

When QTc prolongation is a concern, avoid:

• Ziprasidone: 5-22 ms mean QTc prolongation 1, with real-world pharmacovigilance data showing it as the second-highest risk antipsychotic for QT prolongation reporting 4
• Haloperidol: 7 ms mean QTc prolongation, with significantly higher risk via IV route (46% increased risk of ventricular arrhythmia/sudden cardiac death, OR 1.46) 1
• Thioridazine: 25-30 ms mean QTc prolongation with FDA black box warning 1
• Sertindole: highest risk of QT prolongation reporting in real-world pharmacovigilance data 4

Clinical Algorithm for Selection

Step 1: Assess baseline risk factors 1

• Female gender and age >65 years
• Baseline QTc >500 ms
• Electrolyte abnormalities (hypokalemia, hypomagnesemia)
• Concomitant QTc-prolonging medications
• Pre-existing cardiovascular disease
• History of sudden cardiac death

Step 2: Choose antipsychotic based on risk stratification 1

• Low to moderate risk patients: Aripiprazole or brexpiprazole first-line; olanzapine second-line
• High-risk patients: Aripiprazole or brexpiprazole only; avoid all other agents if possible

Step 3: Implement monitoring protocol 1

• Obtain baseline ECG before initiating therapy
• Perform follow-up ECG after dose titration
• Monitor electrolytes, particularly potassium levels
• Consider medication adjustment if QTc exceeds 500 ms or increases >60 ms from baseline

Critical Pitfalls to Avoid

• Route of administration matters critically: IV haloperidol carries substantially higher risk than oral or IM administration 1
• Drug-drug interactions amplify risk: Multiple QTc-prolonging medications exponentially increase torsades de pointes risk 1
• Sex differences are clinically significant: Women have higher baseline risk of QTc prolongation and torsades de pointes with all antipsychotics 1
• First-generation antipsychotics carry 21% greater risk (ROR 1.21) compared to second-generation agents in real-world settings 4