Is it safe to add Remeron (mirtazapine) to an adult patient's medication regimen for moderate to severe depression who is already taking Trazodone (trazodone hydrochloride)?

Adding Mirtazapine to Trazodone for Depression

Yes, it is safe and clinically appropriate to add mirtazapine (Remeron) to trazodone for treatment of depression, as this combination is explicitly recognized in clinical guidelines as a reasonable treatment strategy. 1

Guideline Support for This Combination

The American Academy of Sleep Medicine guidelines specifically address combining sedating antidepressants and note that "a wealth of clinical experience with the co-administration of these drugs suggests the general safety and efficacy of this combination." 1 While this guideline discusses insomnia treatment, the principle applies directly to your scenario since both medications are sedating antidepressants commonly used in depression management.

The recommended treatment sequence for depression with insomnia explicitly includes "Combined BzRA or ramelteon and sedating antidepressant" as a legitimate strategy, with both trazodone and mirtazapine listed as examples of sedating antidepressants. 1

Rationale for This Combination

Complementary Mechanisms

• Mirtazapine blocks α2-adrenergic receptors and enhances both noradrenergic and serotonergic neurotransmission through 5-HT1 receptor stimulation while blocking 5-HT2 and 5-HT3 receptors. 2
• Trazodone acts as a serotonin receptor antagonist and reuptake inhibitor with additional adrenolytic properties. 3
• These different mechanisms can target multiple neurotransmitter systems simultaneously, potentially improving efficacy while using lower doses of each agent. 1

Clinical Advantages

• Mirtazapine has a faster onset of action than many SSRIs and is particularly effective for patients with depression accompanied by insomnia, anorexia, or weight loss. 4
• Trazodone is effective for improving sleep in depressed patients without causing tolerance or REM rebound on discontinuation. 5
• The combination may address both core depressive symptoms and associated sleep disturbances more comprehensively than monotherapy. 4, 3

Important Monitoring Considerations

Side Effects to Watch

• Excessive sedation is the primary concern when combining two sedating antidepressants—monitor daytime drowsiness carefully, especially in the first 1-2 weeks. 1, 4
• Weight gain and increased appetite occur more frequently with mirtazapine (10% vs 1% placebo) and should be discussed with patients upfront. 4, 2
• Dry mouth, constipation, and dizziness may be additive given both medications have some adrenergic effects. 4, 2

Dosing Strategy

• Start mirtazapine at 15 mg at bedtime (or 7.5 mg in elderly/frail patients) while continuing trazodone at its current dose. 4
• Assess therapeutic response within 1-2 weeks, but allow 6-8 weeks before concluding inadequate response. 4
• Trazodone is best dosed at 150 mg predominantly at bedtime, with increases to 200-300 mg as needed for full antidepressant efficacy. 5
• The sedating effects of both medications make bedtime dosing optimal to minimize daytime drowsiness. 4, 5

Common Pitfalls to Avoid

• Don't assume failure too early—antidepressants require 6-8 weeks for adequate therapeutic assessment, not 3-4 weeks. 4
• Don't neglect to counsel patients about expected weight gain with mirtazapine, as this occurs more frequently than with other antidepressants and can affect adherence. 4
• Don't combine with alcohol or other CNS depressants without explicit patient education about additive psychomotor impairment. 1, 2
• Monitor for rare but serious cardiovascular effects with trazodone, though these are uncommon. 3

When to Reassess

• Follow up within 1-2 weeks after adding mirtazapine to assess tolerability and early response. 4
• If inadequate response by 6-8 weeks, consider switching strategies rather than continuing ineffective treatment. 4
• Continue successful treatment for 4-9 months after achieving remission in first-episode depression, or longer for recurrent depression. 4