Can mirtazapine be given together with Celexa (citalopram) in an adult patient?

Can Mirtazapine and Celexa (Citalopram) Be Given Together?

Yes, mirtazapine and citalopram can be safely combined in adult patients with major depressive disorder, and this combination is supported by clinical evidence as an effective augmentation strategy for treatment-resistant depression. 1

Evidence Supporting Combination Therapy

Two high-quality trials (n=1,231 participants) demonstrated that augmenting an SSRI like citalopram with mirtazapine is equally effective and safe as switching to mirtazapine monotherapy, with no differences in efficacy or adverse event rates. 1 This provides strong evidence that the combination is well-tolerated and clinically appropriate.

Mechanism and Clinical Rationale

• Mirtazapine works through a dual noradrenergic and specific serotonergic mechanism (NaSSA), antagonizing alpha-2 autoreceptors and heteroreceptors while blocking 5-HT2 and 5-HT3 receptors. 2, 3
• When combined with citalopram (an SSRI), the two agents provide complementary mechanisms: citalopram enhances serotonin availability through reuptake inhibition, while mirtazapine enhances both norepinephrine release and 5-HT1A-mediated serotonergic transmission. 3, 4
• This dual action may produce faster onset of antidepressant effects compared to monotherapy. 2, 3

Clinical Advantages of This Combination

Mirtazapine can counteract common SSRI side effects while adding therapeutic benefit:

• Sexual dysfunction: Mirtazapine has no sexual side effects, unlike SSRIs, and may help mitigate SSRI-induced sexual dysfunction. 3, 5
• Insomnia and anxiety: Mirtazapine is particularly effective for patients with depression accompanied by anxiety symptoms and sleep disturbance, which are common with SSRIs. 2, 3
• Appetite and weight: While mirtazapine increases appetite and weight (its most common side effect), this can be beneficial for patients experiencing SSRI-related appetite suppression. 2, 3

When to Use This Combination

Consider combining mirtazapine with citalopram in these scenarios:

• After 6-8 weeks of citalopram monotherapy without adequate response (augmentation strategy). 1
• In patients with depression plus prominent anxiety or insomnia that persists despite SSRI treatment. 2, 3
• When SSRI-related sexual dysfunction is limiting treatment adherence. 3, 5
• As initial combination therapy in severe depression, though evidence for this approach is more limited. 4

Dosing Recommendations

Standard therapeutic dosing:

• Citalopram: 20-40 mg daily (maximum 40 mg due to QT prolongation risk at higher doses). 1
• Mirtazapine: 15-45 mg daily, typically starting at 15 mg and titrating to 30 mg. 1

When augmenting citalopram with mirtazapine, maintain the current citalopram dose and add mirtazapine at 15 mg nightly, increasing to 30 mg after one week if tolerated. 1, 3

Safety Monitoring and Drug Interactions

Low Risk of Pharmacokinetic Interactions

Mirtazapine has minimal potential for cytochrome P450-mediated drug interactions, making it safe to combine with citalopram. 2, 3 In vitro studies demonstrate that mirtazapine is unlikely to affect metabolism of drugs metabolized by CYP2D6, and it is metabolized primarily by CYP1A2, CYP2D6, and CYP3A4 without significantly inhibiting these enzymes. 3

Critical Monitoring Parameters

Monitor for these parameters when initiating combination therapy:

• Suicidal ideation: Assess within 1-2 weeks of starting treatment, especially in patients under 24 years, as the risk of suicide attempts is highest during the first 1-2 months. 1
• Sedation: Mirtazapine commonly causes sedation (19% in combination studies), which typically improves with continued use. 6 Advise taking mirtazapine at bedtime to leverage this effect for sleep improvement. 1
• Weight gain: Monitor weight regularly, as 19% of patients experience weight gain with mirtazapine. 6
• QT interval: Citalopram can prolong QT interval, particularly at doses above 40 mg; baseline ECG may be warranted in patients with cardiac risk factors. 1

Contraindications and Precautions

Absolute contraindications for this combination:

• Current or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs), due to risk of serotonin syndrome. 1
• Known hypersensitivity to either medication. 1

Dose adjustments required:

• Hepatic impairment: Reduce citalopram dose in severe hepatic disease; mirtazapine clearance is also reduced, requiring dose adjustment. 1, 3
• Renal impairment: Consider dose reduction for citalopram in severe renal impairment. 1
• Elderly patients: Start with approximately 50% of standard adult doses for both medications. 1

Expected Timeline and Response Assessment

Allow 6-8 weeks at therapeutic doses before determining treatment adequacy. 1 However, some patients may experience earlier improvement in sleep, anxiety, and energy within 2-4 weeks due to mirtazapine's rapid onset of action. 2, 4

If no adequate response occurs by 6-8 weeks, consider:

• Increasing mirtazapine dose to 45 mg daily (if currently at 30 mg). 1
• Switching to an alternative augmentation strategy. 1
• Re-evaluating the diagnosis and presence of comorbid conditions. 1

Common Pitfalls to Avoid

Do not discontinue treatment prematurely before 6-8 weeks unless significant adverse effects occur. 1 Early sedation or mild weight gain often improve with continued treatment and should not prompt immediate discontinuation. 6

Do not exceed citalopram 40 mg daily due to dose-dependent QT prolongation risk. 1 If higher antidepressant dosing is needed, increase mirtazapine instead.

Do not combine with other serotonergic agents (tramadol, triptans, St. John's wort) without careful monitoring for serotonin syndrome. While the risk is lower with mirtazapine than with other antidepressants, vigilance is still required. 3

Clinical Evidence Quality

The recommendation to combine mirtazapine with SSRIs like citalopram is supported by:

• High-quality evidence: Two trials with 1,231 participants showing equivalent efficacy and safety of augmentation versus switching strategies. 1
• Moderate-quality evidence: Multiple studies demonstrating mirtazapine's complementary mechanism and ability to counteract SSRI side effects. 2, 3, 4
• Clinical experience: Observational data showing 50-56% response rates in treatment-resistant depression with combination therapy. 6

This combination represents a well-established, evidence-based approach for patients who have not responded adequately to SSRI monotherapy or who experience limiting side effects from SSRIs alone. 1, 5