Combination Therapy for Depression with Mirtazapine and Trazodone

Guideline Support and Rationale

The American Academy of Sleep Medicine guidelines support combining sedating antidepressants, noting the general safety and efficacy of this combination, which applies to combining mirtazapine and trazodone for depression management 1
The recommended treatment sequence for depression with insomnia includes combining a sedating antidepressant, such as trazodone and mirtazapine, as a legitimate strategy 2, 3
The combination of mirtazapine and trazodone can target multiple neurotransmitter systems simultaneously, potentially improving efficacy while using lower doses of each agent 1

Mirtazapine has a faster onset of action than many SSRIs and is effective for patients with depression accompanied by insomnia, anorexia, or weight loss 4
Excessive sedation is the primary concern when combining two sedating antidepressants, and monitoring daytime drowsiness is crucial, especially in the first 1-2 weeks 1, 4
Weight gain and increased appetite occur more frequently with mirtazapine and should be discussed with patients upfront 4

Start mirtazapine at 15 mg at bedtime while continuing trazodone at its current dose, and assess therapeutic response within 1-2 weeks 4
Allow 6-8 weeks before concluding inadequate response, and don't assume failure too early 4
Don't neglect to counsel patients about expected weight gain with mirtazapine, and monitor for rare but serious cardiovascular effects with trazodone 4

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