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

Antidepressants with Lowest QT Prolongation Risk

SNRIs (serotonin-norepinephrine reuptake inhibitors) have the lowest risk of QT prolongation among all antidepressants, showing no significant association with cardiac arrest in large registry studies. 1

Primary Recommendation by Risk Category

Lowest Risk: SNRIs

• SNRIs are the safest first-line choice for patients with any cardiac risk factors, as they demonstrated no association with cardiac arrest in Danish nationwide registry data (unlike SSRIs with OR 1.21 and TCAs with OR 1.69). 2, 1
• SNRIs should be preferentially selected for patients over 60 years, those with baseline QT prolongation, or those taking other QT-prolonging medications. 1

Among SSRIs: Paroxetine Has Lowest Risk

• Paroxetine appears to have the lowest QT prolongation risk among SSRIs, showing no clinically significant QTc prolongation in all studies examined. 3
• Fluoxetine, fluvoxamine, and sertraline demonstrate similar low risk profiles, with lack of clinically significant QTc increases at traditional doses in the majority of studies. 3

Highest Risk SSRIs to Avoid

• Citalopram and escitalopram carry the highest risk among SSRIs and should be avoided in patients with cardiac risk factors. 2, 1, 4
• Citalopram causes QT prolongation associated with Torsade de Pointes, ventricular tachycardia, and sudden death at daily doses exceeding 40 mg/d. 2
• Pharmacovigilance data show significant reporting odds ratios only for citalopram (ROR 3.35) and escitalopram (ROR 2.50), indicating QT prolongation is not an SSRI class effect. 4
• Escitalopram has caused QTc prolongation even at low doses (5 mg/day for 2 days) in case reports. 5

Tricyclic Antidepressants: High Risk

• TCAs significantly increase cardiac arrest risk (OR 1.69) and should be avoided when QT prolongation is a concern. 2
• Amitriptyline and maprotiline specifically have documented cases of Torsade de Pointes. 2
• TCAs can cause multiple cardiac effects including AV block, wide QRS, and sinusoidal ventricular tachycardia beyond just QT prolongation. 2

Critical Clinical Considerations

Polytherapy Substantially Increases Risk

• Combining antipsychotics with antidepressants causes significantly greater QT prolongation (mean 24 ms increase) compared to monotherapy (mean -1 ms). 6
• 38% of patients on combination therapy exceeded the 450 ms threshold versus only 7% on monotherapy. 6
• When combining psychotropic medications, baseline and follow-up ECG monitoring becomes essential. 1

Monitoring Recommendations

• Obtain baseline ECG for all patients with cardiac risk factors before initiating antidepressants. 1
• Follow-up ECG is recommended for patients on high-risk antidepressants (citalopram, escitalopram, TCAs) or those with multiple risk factors. 1
• Age over 60 years should be considered a risk factor requiring ECG monitoring. 1

Practical Algorithm

For patients WITHOUT cardiac risk factors:

• SNRIs remain safest option, but paroxetine, fluoxetine, fluvoxamine, or sertraline are acceptable alternatives. 1, 3

For patients WITH cardiac risk factors (age >60, baseline QT prolongation, structural heart disease, electrolyte abnormalities, concomitant QT-prolonging drugs):

• First choice: SNRI 1
• Second choice: Paroxetine 3
• Avoid: Citalopram, escitalopram, all TCAs 2, 1, 4

For patients on polytherapy with antipsychotics:

• Strongly prefer SNRIs and obtain ECG monitoring regardless of baseline risk. 6