Do Selective Serotonin Reuptake Inhibitors (SSRIs) affect the QTc interval?

Do SSRIs Affect the QTc Interval?

Yes, SSRIs do affect the QTc interval, but the degree of prolongation varies significantly among individual agents, with citalopram and escitalopram causing the most clinically significant prolongation, while paroxetine appears to have the lowest risk. 1, 2, 3

Differential Risk Among SSRIs

High-Risk SSRIs

Citalopram causes dose-dependent QTc prolongation and is associated with the highest risk among SSRIs 2:

• At 20 mg daily: mean QTc prolongation of 8.5 ms (upper CI: 10.8 ms) 2
• At 40 mg daily: predicted QTc prolongation of 12.6 ms (upper CI: 14.3 ms) 2
• At 60 mg daily: mean QTc prolongation of 18.5 ms (upper CI: 21.0 ms) 2
• Real-world data shows +12.8 ms prolongation (90% CI: 7.5-18.2 ms) even at recommended doses 4

Escitalopram also demonstrates dose-dependent QTc prolongation 5:

• At 10 mg daily: mean QTc prolongation of 4.5 ms (upper CI: 6.4 ms) 5
• At 20 mg daily: predicted QTc prolongation of 6.6 ms (upper CI: 7.9 ms) 5
• At 30 mg daily (supratherapeutic): mean QTc prolongation of 10.7 ms (upper CI: 12.7 ms) 5
• Case reports document QTc prolongation with doses as low as 5 mg/day for only 2 days 6

Lower-Risk SSRIs

Paroxetine appears to have the lowest risk of QTc prolongation among all SSRIs, with no clinically significant QTc prolongation demonstrated in monotherapy studies 3, 7

Fluoxetine, fluvoxamine, and sertraline show minimal clinically significant QTc increases at traditional doses in the majority of studies 3, 8

Clinical Implications and Contraindications

Absolute Contraindications for Citalopram/Escitalopram

The FDA mandates that citalopram should NOT be used in patients with 2:

• Congenital long QT syndrome
• Bradycardia
• Hypokalemia or hypomagnesemia
• Recent acute myocardial infarction
• Uncompensated heart failure
• Concurrent use of other QT-prolonging drugs (Class IA antiarrhythmics like quinidine/procainamide, Class III antiarrhythmics like amiodarone/sotalol, antipsychotics, certain antibiotics) 2

Dose Restrictions

Maximum citalopram dose must be limited to 20 mg/day in 2:

• Patients >60 years of age
• CYP2C19 poor metabolizers
• Patients taking CYP2C19 inhibitors (e.g., cimetidine)
• Patients with hepatic impairment

Citalopram should not exceed 40 mg/day in any patient 2

Monitoring Requirements

When to Monitor

The 2015 ESC Guidelines recommend 1:

• Baseline ECG before initiating treatment with QT-prolonging antidepressants
• Follow-up ECG during dose titration
• Baseline and periodic electrolyte monitoring (potassium and magnesium) in patients at risk for electrolyte disturbances 1

Action Thresholds

Dosage adjustment or discontinuation is mandatory when 1:

• QTc reaches >500 ms
• QTc increases by >60 ms from baseline

Discontinue immediately if 2:

• Persistent QTc measurements >500 ms
• Symptoms suggesting cardiac arrhythmias occur (dizziness, palpitations, syncope)

Risk Stratification Algorithm

Step 1: Assess Baseline Cardiac Risk

Evaluate for 1, 2:

• Age >60 years
• Structural heart disease (CAD, heart failure, recent MI)
• Baseline QTc prolongation
• Electrolyte abnormalities (hypokalemia, hypomagnesemia)
• Concomitant QT-prolonging medications
• CYP2C19 poor metabolizer status
• Hepatic impairment

Step 2: Select Appropriate SSRI

• Low cardiac risk patients: Any SSRI may be considered, though paroxetine has the lowest QTc risk 3
• Moderate cardiac risk patients: Avoid citalopram and escitalopram; prefer paroxetine, sertraline, or fluoxetine 3, 7
• High cardiac risk patients: Strongly prefer paroxetine; if other SSRIs needed, use lowest effective dose with ECG monitoring 1, 3

Step 3: Implement Monitoring Based on Risk

• High-risk patients requiring citalopram/escitalopram: Baseline ECG, electrolytes, and periodic ECG monitoring 1, 2
• Patients on multiple QT-prolonging drugs: Continuous cardiac monitoring should be considered 1

Comparison with Other Antidepressants

Tricyclic antidepressants (TCAs) are associated with greater QTc prolongation and higher risk of torsades de pointes than SSRIs, particularly when combined with severe sodium channel blockade 1, 8

The European Heart Journal guidelines note that SSRIs as a class have lower cardiovascular ADR rates (0.08%) compared to TCAs (0.15%) and MAOIs (0.27%) 8

Common Pitfalls to Avoid

Do not combine citalopram or escitalopram with other QT-prolonging medications, particularly Class III antiarrhythmics like sotalol, as this creates additive QT prolongation with significantly increased arrhythmia risk 9, 2

Do not assume dose restrictions eliminate risk: Even at the recommended maximum dose of 20 mg in elderly patients, citalopram still causes clinically significant QTc prolongation 4

Do not overlook electrolyte monitoring: Hypokalemia and hypomagnesemia potentiate QT prolongation and must be corrected before initiating therapy and monitored periodically 1, 2

Do not ignore patient-reported symptoms: Dizziness, palpitations, or syncope during SSRI treatment warrant immediate ECG evaluation, as these may indicate cardiac arrhythmias 2