What antipsychotic medications do not significantly cause QT (QT interval) prolongation?

Antipsychotics with Minimal to No QT Prolongation

Aripiprazole and brexpiprazole are the preferred antipsychotics when QT prolongation is a concern, as they cause 0 ms mean QTc prolongation and have no clinically significant effect on the QT interval. 1

First-Line Recommendations

Aripiprazole is the gold standard for patients requiring antipsychotic therapy with QTc concerns:

• Causes 0 ms mean QTc prolongation per American Academy of Pediatrics and European Heart Journal guidelines 1
• FDA-approved brexpiprazole label confirms it "does not prolong the QTc interval to any clinically relevant extent" at therapeutic doses 2
• Multiple randomized controlled trials demonstrate lack of QTc prolongation with aripiprazole 3, 4
• Real-world pharmacovigilance data from VigiBase confirms aripiprazole among the lowest risk antipsychotics for QT prolongation reporting 5

Brexpiprazole is equally safe as a first-line option:

• No clinically significant QTc prolongation at doses 3-4 times the maximum recommended human dose 2
• Low quality evidence from systematic reviews and RCTs confirms no QT interval increase 6
• Recommended alongside aripiprazole by American Academy of Pediatrics and European Heart Journal 1

Second-Line Options

Olanzapine represents the next safest choice when first-line agents are unsuitable:

• Causes only 2 ms mean QTc prolongation 1
• Multiple meta-analyses and 20 RCTs demonstrate minimal QT effect 6
• Significantly safer than quetiapine (6 ms prolongation) or risperidone (0-5 ms) 1

Antipsychotics to Avoid

The following agents carry unacceptable QT prolongation risk and should be avoided when cardiac safety is a priority:

Highest Risk (Contraindicated):

• Thioridazine: 25-30 ms prolongation with FDA black box warning 1
• Sertindole: Highest real-world reporting risk for QT prolongation 5
• Pimozide: 13 ms mean prolongation 1

High Risk (Avoid if Possible):

• Ziprasidone: 5-22 ms prolongation, second highest real-world reporting risk 1, 5
• Amisulpride: High real-world QT prolongation reporting 5
• Clozapine: 8-10 ms mean prolongation 1

Moderate Risk (Use with Caution):

• Haloperidol: 7 ms prolongation (oral/IM), significantly higher risk with IV administration 1
• Quetiapine: 6 ms mean prolongation, associated with torsades de pointes in overdose 1, 6
• Risperidone: 0-5 ms prolongation, but associated with QT prolongation and torsades risk 1, 6

Risk Stratification Algorithm

High-risk patients requiring aripiprazole or brexpiprazole exclusively:

• Female gender 1
• Age >65 years 1
• Baseline QTc >500 ms 1
• History of sudden cardiac death 1
• Concomitant QT-prolonging medications 1
• Electrolyte abnormalities (hypokalemia, hypomagnesemia) 1
• Pre-existing cardiovascular disease 1

Monitoring Protocol

Baseline assessment:

• Obtain ECG before initiating any antipsychotic 1
• Check potassium and magnesium levels 1

Follow-up monitoring:

• Repeat ECG after dose titration 1
• Discontinue or switch to aripiprazole if QTc exceeds 500 ms or increases >60 ms from baseline 1
• Monitor electrolytes throughout treatment 1

Critical Pitfalls

Route of administration matters significantly: IV haloperidol carries substantially higher QT prolongation and torsades risk than oral or IM formulations 1. Always prefer oral or IM routes when haloperidol is necessary.

Drug interactions amplify risk: Multiple QT-prolonging medications exponentially increase torsades risk 1. Review all concomitant medications before prescribing.

Sex differences are clinically significant: Women have inherently higher risk of QT prolongation and torsades de pointes with all antipsychotics 1. Lower threshold for choosing aripiprazole or brexpiprazole in female patients.

Electrolyte monitoring is non-negotiable: Hypokalemia and hypomagnesemia dramatically increase arrhythmia risk even with lower-risk antipsychotics 1. Correct abnormalities before initiating therapy and monitor regularly.