Adding mirtazapine (Remeron) to a serotonergic antidepressant is a popular augmentation strategy. When added to venlafaxine, the combo was thought to possess a particularly potent synergy that Stephen Stahl called “California Rocket Fuel.” However, the strategy has failed in a handful of new studies, some of them much larger than the original data. Is it time to stop using it?

How does mirtazapine work?
Mirtazapine is in a class of its own pharmacologically. Like venlafaxine and other SNRIs, it increases norepinephrine and serotonin transmission, but it does so through a different mechanism. Instead of blocking the reuptake of these neurotransmitters as SNRIs do, it enhances their release by binding to alpha-2 adrenergic receptors. Theoretically, mirtazapine has a synergistic effect with serotonergic medications, enhancing their benefits and—through post-synaptic serotonin blockade—reducing common side effects like nausea and sexual dysfunction.

Mirtazapine’s main drawbacks—weight gain and sedation—derive from its antihistaminergic effects at H1. About 30%-75% of patients gain significant weight on mirtazapine (Uguz F et al, Gen Hosp Psychiatry 2015;37(1):46-48). 

A promising beginning
Beginning in the 1990’s, a series of open label trials suggested that mirtazapine (30-45 mg/night) is an effective augmentation agent in treatment-resistant depression.

Placebo-controlled confirmation started to roll in with a small study in 2002. The results were impressive, with remission rates of 45% with mirtazapine vs. 14% on placebo, but the study was small (n=26) (Carpenter LL et al, Biol Psychiatry 2002;15;51(2):183-188).

The venlafaxine/mirtazapine “rocket fuel” combination was used in the STAR-D trial, where it was compared to tranylcypromine monotherapy after failure of 3 antidepressants. STAR-D was designed to test whether any of the popular augmentation strategies from the 1990’s worked better than the others. The bottom line is that none of them did, including the rocket fuel, but because it lacked a placebo arm the study can’t tell us if any of those strategies actually worked at all (McGrath PJ et al, Am J Psychiatry 2006;163(9):1531-1541). The other study to test this combination had promising results but very poor design. It was a retrospective chart review of 39 patients that found higher remission rates with venlafaxine/mirtazapine than venlafaxine alone (Aydemir O et al, Bulletin of Clinical Psychopharm 2009;19:347-352).

So, up until 2018 mirtazapine augmentation held a lot of promise, and a bit of hype, but little in the way of confirmation.

New conflicting data
In the past year, a series of well-designed studies have brought those early results to question. In the first large, placebo-controlled trial of mirtazapine augmentation, the medication failed to separate from placebo in 480 patients who had failed a six-week antidepressant trial in a primary care setting. Remission rates were 24% on placebo vs. 29% with mirtazapine (Kessler DS et al, BMJ 2018;363:k4218). Negative results like this are often blamed on an unusually large placebo response, but that was not the case here. Most studies of treatment resistant depression see about 25% of their subjects remit with placebo.

The next study was also randomized, but open-label and not placebo-controlled. It followed 112 patients whose depression had failed to respond to venlafaxine. They were randomized to augmentation with mirtazapine or a switch to imipramine. Although augmentation usually outperforms switching in most depression trials, here the remission rates nearly doubled when switching to imipramine (72% vs. 39%) (Navarro V et al, J Clin Psychopharmacol. 2019;39(1):63-66).

New, yet to be published data presented at the May 2019 APA annual meeting is continuing this trend. This study randomized 204 patients who did not respond to paroxetine monotherapy to three treatment arms: paroxetine/mirtazapine, paroxetine/placebo, and mirtazapine/placebo. Mirtazapine augmentation failed to separate from the two placebo arms after 8 weeks (Xiao L et al, APA Poster 2019).

Mirtazapine for specific co-morbidities
Although mirtazapine augmentation has yet to demonstrate efficacy, it may have a useful role in certain types of depressed patients. Its sedative qualities can help insomnia, and it also improves deep stage N3 sleep and reduces nighttime awakenings (Karsten J et al, J Psychopharmacol 2017;31(3):327-337). In small, placebo-controlled trials, mirtazapine augmentation has improved obsessive-compulsive disorder, depressive symptoms of PTSD, and negative symptoms of schizophrenia (Pallanti S et al, J Clin Psychiatry 2004;65(10):1394-1399)

TCPR Verdict: “California Rocket Fuel” turns out to be no better than regular, unleaded gasoline. As is often the case, the positive studies are small and flawed, while the negative ones are large and well-designed. Nevertheless, mirtazapine augmentation may still be useful for depressed patients with insomnia and weight loss.