Can mirtazapine and citalopram (Selective Serotonin Reuptake Inhibitor - SSRI) be given together?

Can Mirtazapine and Citalopram Be Given Together?

Yes, mirtazapine and citalopram can be given together with appropriate caution and monitoring for serotonin syndrome, though the combination requires careful dose titration and vigilant surveillance, particularly in the first 24-48 hours after initiation or dose changes. 1

Key Safety Considerations

Serotonin Syndrome Risk

The primary concern when combining these medications is serotonin syndrome, which occurs when serotonergic medications are combined and can develop within 24-48 hours. 1 The FDA drug label for mirtazapine explicitly states that concomitant use with SSRIs (including citalopram) increases the risk of serotonin syndrome and requires monitoring for signs and symptoms, particularly during treatment initiation and dosage increases. 2

Watch for these symptoms:

• Mental status changes: confusion, agitation, anxiety 1
• Neuromuscular hyperactivity: tremors, clonus, hyperreflexia, muscle rigidity 1
• Autonomic hyperactivity: hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis, shivering, vomiting, diarrhea 1
• Advanced symptoms: fever, seizures, arrhythmias, unconsciousness (potentially fatal) 1

QT Prolongation Concerns

Citalopram carries specific cardiac risks that become more relevant when combined with other medications. Citalopram may cause QT prolongation associated with Torsades de Pointes, ventricular tachycardia, and sudden death at daily doses exceeding 40 mg/day, and should be avoided in patients with long QT syndrome. 1 The FDA and EMA have limited the recommended maximum doses of citalopram, with further reductions for patients older than 60 years. 1

Mirtazapine's drug label warns that concomitant use with drugs that prolong the QTc interval increases the risk of QTc prolongation and/or ventricular arrhythmias. 2 Use caution when combining these agents, particularly in elderly patients or those with cardiac risk factors. 1

Clinical Evidence for Combination Therapy

Efficacy Data

The combination has been studied with mixed results:

• A large randomized controlled trial (MIR trial, n=480) found that adding mirtazapine to SSRIs or SNRIs in treatment-resistant depression showed only a modest, non-clinically significant benefit (BDI-II difference -1.83 points at 12 weeks, 95% CI -3.92 to 0.27; p=0.087), which was smaller than the minimum clinically important difference. 3

• However, a pilot study in OCD patients demonstrated that mirtazapine augmentation of citalopram achieved response acceleration, with the combination group achieving ≥35% reduction in symptoms from week 4, compared to week 8 for citalopram alone. 4

• Case reports document successful use of mirtazapine combinations in difficult-to-treat depression, though serotonin syndrome has been reported when mirtazapine was combined with fluvoxamine (another SSRI). 5, 6

Practical Prescribing Algorithm

If you decide to combine these medications:

1. Start low: Begin the second serotonergic drug (typically mirtazapine added to existing citalopram) at a low dose 1

   • Mirtazapine: start at 15 mg daily for 2 weeks before increasing to 30 mg 3
   • Keep citalopram ≤40 mg daily (≤20 mg if age >60 years) 1

2. Titrate slowly: Increase doses gradually with close monitoring 1

3. Monitor intensively: Watch for serotonin syndrome symptoms especially in the first 24-48 hours after starting or any dosage changes 1, 2

4. Assess cardiac risk: Consider baseline ECG if patient has cardiac risk factors, given citalopram's QT prolongation risk 1

5. Discontinue immediately if any signs of serotonin syndrome develop, with hospital-based supportive care and continuous cardiac monitoring 1

Common Pitfalls to Avoid

• Don't ignore withdrawal concerns: More participants withdrew from mirtazapine citing mild adverse events (46 vs. 9 in placebo group) in the MIR trial 3
• Don't overlook drug interactions: Citalopram may interact with other drugs that prolong QT interval 1
• Don't forget metabolic effects: Mirtazapine commonly causes increased appetite and weight gain more than other antidepressants 7
• Don't use with MAOIs: This combination is absolutely contraindicated due to severe serotonin syndrome risk 1, 2

Clinical Context

The American Heart Association notes that mirtazapine has been shown to be safe in cardiovascular disease patients, though its efficacy in treating depression in this population hasn't been fully assessed. 1 SSRIs like citalopram are well-studied in coronary heart disease and heart failure and appear safe, though sertraline may have a lower risk of QTc prolongation than citalopram. 1

The combination is feasible but requires clinical judgment: While guidelines acknowledge that caution should be exercised when combining two or more non-MAOI serotonergic drugs, they do not prohibit this practice when done with appropriate monitoring. 1 The key is vigilant surveillance and patient education about warning signs.