Mirtazapine for Anxiety

An old antidepressant finds new roles in anxiety and trauma

STUDY: Caiazza C et al, Human Psychopharmacology: Clinical and Experimental 2026;41:e70037

STUDY TYPE: Systematic review and meta-analysis

FUNDING: Independent

Background

In 1996, mirtazapine was approved as Remeron for depression, and that’s where its approval ended. But its unique profile suggests utility in anxiety, such as:

• Blocks alpha-2 adrenergic receptors
• Blocks postsynaptic serotonin receptors (5-HT2 and 5-HT3)
• Antihistamine

The Study

This meta-analysis used PRISMA guidelines to gather 37 controlled trials of anxiety disorders and depression with prominent anxiety.

The trials compared mirtazapine against SSRIs, benzodiazepines, tricyclics, azapirones (like buspirone), or placebo, finding:

• Generalized anxiety disorder: mirtazapine equaled SSRIs (SMD effect size = −0.14) and benzodiazepines (SMD = −0.03) (12 small trials).
• Major depression with high anxiety: it beat SSRIs overall (SMD = −0.16), with the clearest advantage over fluoxetine (SMD = −0.30) (14 small and large trials).

For the rest of the anxiety disorders, mirtazapine has only a few small trials (around 60 subjects each) so I wouldn’t put much weight in these results:

• Posttraumatic stress disorder (PTSD): mirtazapine didn’t beat placebo as monotherapy, but it did augment sertraline — with a large effect size (SMD = −1.04) (5 small trials).
• Panic disorder: comparable to SSRIs (3 small trials)
• Social anxiety disorder: it failed to outperform placebo (4 small trials).

Through all trials, mirtazapine’s overall tolerability was comparable to placebo and SSRIs.

The results are in line with an a secondary analysis of the large MIR trial (Mirtazapine Added to SSRIs or SNRIs for Treatment-Resistant Depression in Primary Care), which found that mirtazapine augmentation in depression works in patients with high anxiety, but otherwise failed to augment in general depression.

Practice Implications

1. Mirtazapine is a top choice for depression with high anxiety.
2. Its lack of sexual side effects and ability to deepen sleep are useful, though 12-20% gain signifiacant weight (more than 7% of body weight) on it, and the weight gain is higher for children (it is not FDA approved in children).
3. It may treat generalized anxiety as monotherapy (, and PTSD as augmentation, but these trials are smaller.