When to Use Mirtazapine Augmentation


After a string of disappointing results, mirtazapine gets another look in a recent study.




One of the biggest stories in psychopharmacology in recent years was not a very promising one. Mirtazapine, which has been used since the 1990s to augment antidepressant treatment, failed to work in the first well-designed studies to test that strategy.1 Now a new analysis offers more specific direction on when mirtazapine augmentation might still be useful in major depressive disorder (MDD).2

A Promising Theory Falls Flat

Interest in mirtazapine augmentation began with a theory. Like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine affects serotonergic and noradrenergic transmission, but it does so through a different mechanism, suggesting a potential synergy with combination therapy. Mirtazapine also has the potential to reduce SSRI side effects, including nausea, insomnia, and sexual dysfunction.

The strategy took off from there, aided by the catchy nickname California rocket fuel that Stephen Stahl, MD, PhD, coined for the venlafaxine-mirtazapine combination. But the empiric support for the strategy was always thin, mostly resting on a singular placebo-controlled trial that was significantly hindered by its 26-subject size.3,4

After more than 20 years of clinical use, mirtazapine augmentation was finally tested in 2 high quality trials (large, double-blind, randomized, placebo-controlled), 1 from the United Kingdom (UK) and 1 from China.1,5 Both tested mirtazapine augmentation after unsuccessful treatment with an SSRI or SNRI, and in both mirtazapine worked no better than placebo. These were followed by a third study in which 112 patients who had not recovered on venlafaxine were randomized to either switch to imipramine or augment with mirtazapine. Unfortunately for mirtazapine, the imipramine switch was nearly twice as effective as mirtazapine augmentation.6

A Second Look

Those 3 negative trials caused mirtazapine to slide down a few rungs on the augmentation algorithm. But a small signal in the UK trial inspired the investigators to give the data a second look. The study, dubbed the MIR trial, was the largest of the 3 negative trials, and involved 480 primary care patients whose depression did not respond to 6 weeks of an SSRI or SNRI. Although mirtazapine failed to make a difference on the primary outcome of depression, it did improve anxiety on secondary measures.1

The investigators reanalyzed the data to see if patients with high levels of anxiety had a more favorable response to mirtazapine augmentation. After stratifying the sample by baseline anxiety level (mild, moderate, or severe on the GAD-7), they found that patients with severe anxiety made significant gains with mirtazapine, while those with no anxiety at baseline did not improve at all with the medication. Those gains included both depressive and anxious symptoms. Patients with moderate anxiety had gains between the 2 extremes.

To test whether anxiety was just a marker for illness severity, they stratified the sample by overall severity of depression. That analysis turned up negative, suggesting that it was the anxious symptoms themselves, and not the overall severity, that was driving the change.

The findings were significant, but are they clinically meaningful? They appear to be, at least in the severe anxiety group where the Generalized Anxiety Disorder-7 scale dropped 2.8 points (out of a max of 21) points and the Beck Depression Inventory II fell 2.8 (max of 63).

The Bottom Line

Mirtazapine is not the most effective augmentation strategy in depression, but it is worth considering in depressed patients with high anxiety.

Dr Aiken is the Mood Disorders Section Editor for Psychiatric TimesTM, the Editor in Chief of The Carlat Psychiatry Report, and the Director of the Mood Treatment Center. He has written several books on mood disorders, most recently The Depression and Bipolar Workbook. He can be heard in the weekly Carlat Psychiatry Podcast with his co-host Kellie Newsome, PMH-NP.


1. Rifkin-Zybutz R, MacNeill S, Davies SJ, et al. Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial. J Psychopharmacol. 2020;34(12):1342-1349.

2. Kessler DS, MacNeill SJ, Tallon D, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). BMJ. 2018;363:k4218.

3. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51(2):183-188.

4. Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288.

5. Xiao L, Zhu X, Gillespie A, et al. Effectiveness of mirtazapine as add-on to paroxetine v. paroxetine or mirtazapine monotherapy in patients with major depressive disorder with early non-response to paroxetine: a two-phase, multicentre, randomized, double-blind clinical trial. Psychol Med. 2021;51(7):1166-1174.

6. Navarro V, Boulahfa I, Obach A, et al. Switching to imipramine versus add-on mirtazapine in venlafaxine-resistant major depression: a 10-week randomized open study. J Clin Psychopharmacol. 2019;39(1):63-66.

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