Which selective serotonin reuptake inhibitors (SSRIs) have the lowest risk of QT interval prolongation?

SSRIs with Lowest QT Prolongation Risk

Paroxetine has the lowest risk of QT prolongation among SSRIs, followed by sertraline, fluoxetine, and fluvoxamine, while citalopram and escitalopram carry the highest risk and should be avoided in patients with cardiac risk factors. 1, 2

Risk Stratification by Individual SSRI

Lowest Risk

• Paroxetine demonstrates no clinically significant QTc prolongation in all studies and shows the lowest risk profile among all SSRIs 2
• Paroxetine is specifically recommended by the European Heart Journal as the preferred SSRI for high-risk cardiac patients 1

Low-to-Moderate Risk

• Sertraline, fluoxetine, and fluvoxamine show similar, low risk for QT prolongation at traditional therapeutic doses 2
• These agents lack clinically significant QTc increases in the majority of studies, though isolated case reports exist 2
• The European Heart Journal guidelines recommend these three agents (along with paroxetine) as preferred alternatives in patients with moderate to high cardiac risk 1

Highest Risk

• Citalopram causes the most pronounced QT prolongation among SSRIs, with a mean increase of +12.8 ms compared to non-use 3
• Citalopram shows significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine in meta-analysis 4
• Escitalopram carries the second-highest risk, with dose-dependent QT prolongation documented even at low doses (5 mg/day for 2 days) 5
• Both citalopram and escitalopram are the only SSRIs showing a clear pharmacovigilance signal for QT prolongation (ROR 3.35 and 2.50, respectively) 6

Quantitative Risk Data

Meta-analysis findings demonstrate:

• SSRIs as a class cause a mean QTc increase of +6.10 ms compared to placebo 4
• Citalopram produces significantly more QTc prolongation than other SSRIs in head-to-head comparisons 4
• This QT prolongation persists even when citalopram is restricted to ≤20 mg daily in patients >60 years old 3

Clinical Management Algorithm

Step 1: Assess Baseline Cardiac Risk

High-risk patients include those with: 1

• Age >60 years
• Structural heart disease
• Baseline QTc prolongation
• Electrolyte abnormalities (hypokalemia, hypomagnesemia)
• Concomitant QT-prolonging medications
• Congenital long QT syndrome

Step 2: Select SSRI Based on Risk Profile

• High cardiac risk patients: Use paroxetine as first-line 1
• Moderate cardiac risk: Consider sertraline, fluoxetine, or fluvoxamine 1
• Low cardiac risk: Any SSRI may be used, though paroxetine remains safest 2

Step 3: Monitoring Requirements

• Obtain baseline ECG before initiating any SSRI in at-risk patients 1
• Repeat ECG during dose titration and when combining with other QT-prolonging drugs 1
• Check baseline electrolytes (potassium, magnesium) and correct abnormalities before starting treatment 1
• Discontinue or adjust dosage if QTc reaches >500 ms or increases >60 ms from baseline 7

Critical Contraindications

The FDA mandates that citalopram must not be used in patients with: 1

• Congenital long QT syndrome
• Bradycardia
• Hypokalemia
• Hypomagnesemia

The American Academy of Child and Adolescent Psychiatry specifically warns that citalopram can cause QT prolongation associated with Torsade de Pointes, ventricular tachycardia, and sudden death at daily doses exceeding 40 mg 7

Common Pitfalls to Avoid

• Do not combine citalopram or escitalopram with other QT-prolonging medications (including ondansetron, domperidone, antipsychotics, or certain antimicrobials), as this creates additive QT prolongation 7, 1
• Do not assume dose restrictions eliminate risk: Even low-dose citalopram (≤20 mg in elderly patients) continues to show QTc prolongation 3
• Do not overlook drug-drug interactions: Escitalopram, venlafaxine, and sertraline are specifically noted as problematic when combined with other QT-prolonging agents in cancer patients 7
• Do not ignore electrolyte disturbances: Nausea, vomiting, and diarrhea from any cause can precipitate hypokalemia/hypomagnesemia and unmask QT prolongation 7

Comparison with Other Antidepressants

Tricyclic antidepressants (TCAs) cause significantly greater QTc prolongation than SSRIs (+7.05 ms more than SSRIs), making SSRIs the safer choice when antidepressants are needed in cardiac patients 4. SNRIs as a class showed no association with cardiac arrest in registry studies, unlike SSRIs and TCAs 7.