What are the interactions between Plaquenil (hydroxychloroquine) and antidepressants?

Interactions Between Plaquenil (Hydroxychloroquine) and Antidepressants

The primary concern when combining Plaquenil with antidepressants is additive QT interval prolongation leading to potentially fatal cardiac arrhythmias (torsades de pointes), with certain antidepressants like citalopram, escitalopram, and tricyclic antidepressants being contraindicated or requiring extreme caution. 1

Critical Cardiac Risk: QT Prolongation

Hydroxychloroquine causes QT interval prolongation and when combined with QT-prolonging antidepressants creates an additive risk for torsades de pointes and sudden cardiac death. 1, 2

Contraindicated or High-Risk Antidepressants:

• Citalopram and escitalopram are contraindicated with hydroxychloroquine due to severe torsades de pointe risk 1
• Tricyclic antidepressants (particularly amitriptyline) cause both sodium channel blockade and QT prolongation, creating life-threatening cardiotoxicity when combined with hydroxychloroquine 2
• All serotonin reuptake inhibitors require caution due to QT prolongation risk 1

Baseline ECG Monitoring Required:

• Obtain baseline ECG before initiating combination therapy 2, 3
• Perform regular follow-up ECGs to monitor QT interval changes 2, 3
• Monitor electrolytes, particularly potassium levels, as hypokalemia dramatically increases arrhythmia risk 1, 2

Pharmacokinetic Interactions: CYP2D6 Pathway

Hydroxychloroquine is a weak CYP2D6 inhibitor, and strong CYP2D6 inhibitors among antidepressants can theoretically increase hydroxychloroquine levels. 1, 4

High-Risk CYP2D6 Inhibitors:

• Fluoxetine and paroxetine are strong CYP2D6 inhibitors requiring more careful monitoring for increased hydroxychloroquine levels and toxicity 4
• These combinations require intensified monitoring for hydroxychloroquine adverse effects including visual changes, cardiac symptoms, and neurotoxicity 1, 4

Safer Antidepressant Options

When antidepressant therapy is necessary with hydroxychloroquine, choose agents with minimal CYP2D6 inhibition and lower QT prolongation risk. 4

Preferred Alternatives:

• Sertraline has minimal CYP2D6 inhibition and lower cardiac risk 4
• Monitor for enhanced sedation, dizziness, or cognitive impairment during the first 24-48 hours after starting combination 4
• Start with standard dosing but maintain close monitoring for adverse effects 4

High-Risk Patient Populations

Certain patient groups require extra vigilance or may need to avoid these combinations entirely. 4, 2

Increased Risk Factors:

• Elderly patients are more sensitive to CNS depressant effects and have higher baseline QT prolongation risk 4
• Hepatic impairment reduces drug metabolism, increasing interaction severity 4
• Pre-existing cardiac conditions (as seen in 7 of 135 patients with QTc >500ms in one study) dramatically increase arrhythmia risk 3
• Concurrent electrolyte disturbances (hypokalemia from corticosteroids, diuretics) further amplify cardiac risk 1

Clinical Evidence on Safety

A 2021 study of 135 lupus patients found that while hydroxychloroquine caused mild QTc prolongation, concurrent antidepressant use did not significantly increase QTc intervals beyond hydroxychloroquine alone, though 7 patients developed QTc >500ms (most with underlying cardiac disease). 3

This suggests the interaction is real but variable, with greatest risk in patients with pre-existing cardiac vulnerability 3.

Monitoring Protocol

Implement rigorous cardiac and clinical monitoring when combination therapy is unavoidable. 4, 2

Essential Monitoring Steps:

• Baseline ECG with QTc calculation before starting combination 2, 3
• Repeat ECG at 1-2 weeks, then periodically (especially after dose changes) 2, 3
• Monitor serum potassium and magnesium levels regularly 2
• Assess for symptoms of serotonin syndrome: agitation, tremor, hyperthermia, hyperreflexia, incoordination 4
• Watch for excessive sedation, dizziness, or cognitive impairment especially in first few weeks 4
• Educate patients to report dizziness, palpitations, or syncope immediately 4

Emergency Management Considerations

If life-threatening cardiotoxicity develops from this combination, sodium bicarbonate may be required for treatment. 2

Common Pitfalls to Avoid

• Do not assume all SSRIs are equivalent - citalopram/escitalopram carry contraindication while sertraline is safer 1, 4
• Do not overlook over-the-counter medications that may further prolong QT (antihistamines, certain supplements) 5, 6
• Do not forget to check for other QT-prolonging medications the patient may be taking (ondansetron, domperidone, certain antibiotics) 1
• Do not initiate combination without baseline ECG - you need reference values to detect changes 2, 3