Can mirtazapine be combined with other Selective Serotonin Reuptake Inhibitors (SSRIs)?

Combining Mirtazapine with SSRIs: Risk of Serotonin Syndrome

Mirtazapine can be combined with SSRIs, but this combination significantly increases the risk of serotonin syndrome and requires careful monitoring, with the FDA explicitly warning about this interaction. 1

FDA-Mandated Warnings and Monitoring Requirements

The FDA drug label for mirtazapine clearly states that concomitant use of serotonergic drugs, including SSRIs, increases the risk of serotonin syndrome. 1 The label provides specific guidance:

• Monitor all patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. 1
• If serotonin syndrome occurs, immediately discontinue mirtazapine and/or concomitant serotonergic drugs. 1
• The combination is not contraindicated (unlike MAOIs), but requires heightened vigilance. 1

Clinical Evidence on Combination Therapy

The largest and most recent randomized controlled trial (MIR trial, 2018) involving 480 patients found no clinically important benefit when adding mirtazapine to SSRIs or SNRIs for treatment-resistant depression. 2, 3

Key findings from this trial:

• At 12 weeks, the difference in Beck Depression Inventory scores was only -1.83 points (95% CI -3.92 to 0.27), which was smaller than the minimum clinically important difference. 2, 3
• More participants in the mirtazapine combination group withdrew from trial medication, citing adverse effects (46 versus 9 participants). 2
• The combination did not prove cost-effective for NHS resources. 2

Serotonin Syndrome Recognition and Management

Serotonin syndrome presents with a characteristic triad: mental status changes, neuromuscular hyperactivity, and autonomic instability. 1

Specific signs to monitor include:

• Mental status changes: agitation, hallucinations, delirium, confusion, or coma 1
• Neuromuscular symptoms: tremor, rigidity, myoclonus, hyperreflexia, incoordination, or seizures 1
• Autonomic instability: tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia, nausea, vomiting, or diarrhea 1

Case Reports of Serious Complications

Published case reports document severe serotonin syndrome from mirtazapine combinations, including cases complicated by rhabdomyolysis, acute renal failure, and acute pulmonary edema. 4

• A 2001 case report documented serotonin syndrome from combining fluvoxamine (an SSRI) with mirtazapine, presenting with tremors, restlessness, twitching, flushing, diaphoresis, and nausea. 5
• These cases resolved after withdrawal of the offending agents and treatment with benzodiazepines and cyproheptadine. 4

Clinical Decision Algorithm

If considering this combination:

1. Assess necessity: Given the lack of proven benefit in the largest trial, reconsider whether combination therapy is truly needed versus switching to a different monotherapy agent. 2, 3

2. If proceeding with combination:

   • Start with close monitoring during the first 24-48 hours after initiation or dose changes 6
   • Educate patients and caregivers about serotonin syndrome symptoms and instruct them to report immediately 1
   • Use the lowest effective doses of both agents 1

3. If serotonin syndrome develops:

   • Immediately discontinue all serotonergic agents 1
   • Provide supportive care with benzodiazepines, IV fluids, and external cooling 6
   • Consider cyproheptadine (a serotonin antagonist) for severe cases 6, 4
   • Approximately 25% of severe cases require ICU admission and mechanical ventilation 6

Important Caveats

• The combination is pharmacologically rational but clinically unproven: While mirtazapine enhances noradrenergic and serotonergic neurotransmission through different mechanisms than SSRIs, the largest trial failed to demonstrate meaningful clinical benefit. 2, 7, 3

• Mirtazapine alone has a comparatively low incidence of side effects, but combination therapy increases risk. 4, 7

• Alternative strategies for treatment-resistant depression may be more appropriate, including switching to a different antidepressant class, augmentation with atypical antipsychotics, or transcranial magnetic stimulation. 2