In a patient with cardiac disease, a history of arrhythmias, or other QT‑prolonging drug use (especially >60 years old), which antidepressant carries the greatest risk of QT‑interval prolongation?

Which Antidepressant Has the Worst QT Prolongation?

Citalopram carries the greatest risk of QT prolongation among antidepressants, followed closely by escitalopram and tricyclic antidepressants (particularly amitriptyline), while SNRIs have the lowest risk and should be your first choice in high-risk cardiac patients. 1, 2

Risk Hierarchy from Highest to Lowest

Highest Risk: Citalopram

• Citalopram causes dose-dependent QT prolongation associated with Torsade de Pointes, ventricular tachycardia, and sudden death at doses exceeding 40 mg/day. 1, 3
• The FDA issued a 2012 boxed warning limiting citalopram to maximum 40 mg/day in adults and 20 mg/day in patients >60 years due to QT prolongation risk. 4, 3
• Real-world data confirms citalopram produces the longest QTc prolongation (+12.8 ms) compared to non-use, even when restricted to 20 mg/day in patients ≥60 years. 5
• Citalopram pharmacokinetics show 30-50% increased AUC and half-life in patients ≥60 years, compounding the risk. 3

Second Highest Risk: Escitalopram

• Escitalopram demonstrates dose-related clinically significant QT prolongation and should be avoided in patients with cardiac risk factors. 1, 6
• Maximum dose is reduced to 20 mg/day in patients over 60 years due to QT prolongation risk. 2
• The FDA and EMA have limited maximum recommended doses specifically due to dose-related QTc prolongation. 2

High Risk: Tricyclic Antidepressants (TCAs)

• TCAs significantly increase cardiac arrest risk (OR 1.69) and cause multiple cardiac effects beyond QT prolongation, including AV block, wide QRS, and sinusoidal ventricular tachycardia. 1, 2
• Amitriptyline and maprotiline specifically have documented cases of Torsade de Pointes. 1
• TCAs cause severe sodium channel blockade that amplifies arrhythmia risk beyond simple QT prolongation. 2
• Never use TCAs in patients with ischemic cardiac disease, ventricular conduction abnormalities, or baseline QTc prolongation. 2

Moderate Risk: Other SSRIs

• Fluoxetine, fluvoxamine, and sertraline show lack of clinically significant QTc increases in the majority of studies at traditional doses. 6
• Paroxetine demonstrates the lowest risk among SSRIs, with no clinically significant QTc prolongation in all studies. 6

Lowest Risk: SNRIs (Preferred Choice)

• SNRIs showed no association with cardiac arrest in Danish nationwide registry data (unlike SSRIs with OR 1.21 and TCAs with OR 1.69), making them the safest first-line choice for any patient with cardiac risk factors. 1, 2
• SNRIs cause hypertension only at high doses and have minimal cardiac conduction effects. 2

Clinical Algorithm for Your High-Risk Patient

Step 1: Identify Risk Factors

Your patient has multiple risk factors that mandate avoiding high-risk agents: 4, 2

• Cardiac disease (present)
• History of arrhythmias (present)
• Age >60 years (present)
• Concomitant QT-prolonging drugs (present)

Step 2: First-Line Choice

Prescribe an SNRI (duloxetine or venlafaxine) as first-line therapy. 1, 2

• Duloxetine 60 mg once daily causes no clinically important ECG changes. 2
• This is the only antidepressant class with registry evidence showing no increased cardiac arrest risk. 1

Step 3: If SNRI Contraindicated or Ineffective

Use paroxetine or sertraline as second-line options. 6

• Paroxetine has the lowest QT risk among all SSRIs. 6
• Sertraline shows minimal QTc prolongation at standard doses. 6

Step 4: Absolute Contraindications in Your Patient

Never prescribe: 1, 2

• Citalopram (highest SSRI risk)
• Escitalopram (second highest SSRI risk)
• Any TCA, especially amitriptyline (documented TdP cases)

Monitoring Requirements

Baseline Assessment

• Obtain baseline ECG before initiating any antidepressant in patients with cardiac risk factors. 2
• Check electrolytes, particularly potassium, as hypokalemia amplifies QTc prolongation risk. 2
• Screen for concomitant QT-prolonging medications. 2

Follow-Up Monitoring

• Repeat ECG during dose titration if using moderate-risk agents. 2
• Discontinue or reduce dose if QTc reaches >500 ms or increases by >60 ms from baseline. 2
• Consider cardiology referral if structural heart disease, baseline QT prolongation, or cardiac symptoms develop. 2

Critical Pitfalls to Avoid

• Do not assume dose restrictions make citalopram safe—even 20 mg/day in elderly patients produces significant QTc prolongation (+12.8 ms). 5
• Do not switch from citalopram to escitalopram thinking it's safer—escitalopram has similar dose-related QT risk. 1, 6
• Do not overlook CYP2C19 inhibitors (omeprazole, cimetidine)—these require citalopram dose reduction to 20 mg/day maximum due to 107% increased AUC. 3
• Do not use tertiary amine TCAs (amitriptyline, imipramine) in any patient >60 years or with cardiac disease. 2