Mirtazapine Augmentation for Treatment‑Resistant Depression – Evidence Summary

Efficacy of Augmentation

The 2023 American College of Physicians (ACP) guideline, based on the highest‑quality evidence, states that augmentation strategies—including adding mirtazapine to an existing SSRI or SNRI—have comparable efficacy to switching to a different antidepressant when the initial treatment fails. 1
Two moderate‑quality randomized trials enrolling a total of 1,231 adults with major depressive disorder found no statistically or clinically significant differences in depression improvement or safety between (a) switching from an SSRI to mirtazapine monotherapy and (b) augmenting the same SSRI with mirtazapine. 1

The ACP guideline advises initiating mirtazapine at 15 mg taken orally at bedtime for two weeks, then increasing to 30 mg nightly if tolerated, while maintaining the current dose of the SSRI or SNRI. 1

According to the 2023 ACP guideline, augmentation with bupropion SR or buspirone provides efficacy similar to mirtazapine augmentation; however, bupropion is associated with fewer discontinuations due to adverse events than buspirone (approximately 12 % vs 21 %). 1
A single trial judged to have a high risk of bias suggests that aripiprazole augmentation may achieve higher remission rates than bupropion augmentation (about 55 % vs 34 % remission), indicating a potential superiority that requires confirmation. 1

The guideline recommends viewing mirtazapine augmentation as one of several equally effective strategies (including switching antidepressants or augmenting with bupropion or buspirone); the choice should be guided by individual symptom profiles—for example, mirtazapine may be favored when insomnia or poor appetite are prominent, but avoided if weight gain is a concern. 1
If a patient does not achieve a satisfactory clinical response after 4–6 weeks of adequate‑dose mirtazapine augmentation, the guideline suggests transitioning to a different antidepressant class or exploring alternative augmentation approaches rather than continuing indefinitely. 1