Refractory depression – does adding mirtazapine help?

10th December 2018, Dr Chee L Khoo

Treatment resistant depression is not that uncommon in general practice. We have quite a few patients that don’t respond to maximal dose of our usual SSRI or SNRIs. Naturally, we need to check adherence to medications and alcohol intake. A review of the history is important as there may be hidden skeletons unresolved (including sexual abuse). After that, it’s matter of perhaps, changing to a different SSRi/SNRI or a different class altogether. As you know, the efficacy of different SSRI/SNRIs are pretty much similar. What do you after that?

There is a pharmacological rationale for adding a second antidepressant with a different and complimentary mode of action to SSRIs or SNRIs. Mirtazapine, a noradrenaline (α2 adrenoreceptor) and serotonin (5 hydroxtryptamine receptors 2 and 3) antagonist, has the potential for an additive and perhaps synergistic action with SSRIs and SNRIs and could enhance clinical response compared with monotherapy with SSRIs or SNRIs.

In a small study involving 26 patients on anti-depressant monotherapy, addition of 15-30mg of mirtazapine yielded positive response rate of 64% for active drug and 20% for placebo. Remission rates were 45.4% and 13.3% for active drug and placebo groups respectively (1). In a double blind study comparing paroxetine monotherapy, mirtazapine monotherapy with combination therapy of both paroxetine and mirtazapine, combination therapy was well tolerated and produced greater improvement than monotherapy (2).

In yet another study comparing fluoxetine monotherapy with mirtazapine combined with various SSRI/SNRIs, remission rates were 25% for fluoxetine, 52% for mirtazapine plus fluoxetine, 58% for mirtazapine plus venlafaxine, and 46% for mirtazapine plus bupropion (3). On the other hand, in a single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites Escitalopram monotherapy were compared with sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day). At 7 months, response rates and remission rates were not significantly different.

A recent study has muddied the waters somewhat, though. Between August 2013 and October 2015, patients who has been antidepressants for >6 weeks  in 106 general practices in four UK sites were contacted. Those who fulfilled the ICD-10 criteria of depression and who are still on their SSRI/SNRIs were randomised to either 30mg mirtazapine or placebo for 50 weeks. Patients were excluded from the study if they had bipolar disorder, psychosis, major alcohol or substance misuse, a diagnosis of dementia, and an inability to complete the questionnaires. Women who were pregnant, breast feeding, or planning pregnancy were also excluded.

701 were eligible and consented to the trial. The primary outcome was comparison of depression scores between the groups. The secondary outcome was at least 50% improvement in depression scores from baseline in the patient. The two groups had similar baseline characteristics but some evidence showed that participants in the mirtazapine group had more severe depression. Participants randomised to mirtazapine were more likely to have a history of depression, and a higher proportion had had suicidal thoughts in the past.

In the primary analysis at 12 weeks, the adjusted means of the intervention group improved more than the placebo group improved from a baseline scores but there were not clinically important.  Similar observations of small differences between the treatment groups in favour of the mirtazapine group were observed for the secondary outcomes at 12 weeks. Outcomes at later time points showed smaller between group differences with no evidence of benefit over the longer term. 

This study did not find convincing evidence of a clinically important benefit for mirtazapine over placebo when given in addition to an SSRI or SNRI antidepressant for patients who had remained depressed after at least six weeks of antidepressant treatment, recruited from primary care.

Access the abstract here.


  1. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry 2002;51:183-8. doi:10.1016/S0006-3223(01)01262-8
  2. Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine and paroxetine in major depression: a comparison of monotherapy versus their combination from treatment initiation. Eur Neuropsychopharmacol
  3. 2009;19:457-65. doi:10.1016/j.euroneuro.2009.01.015
  4. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry 2010;167:281-8. doi:10.1176/appi.ajp.2009.09020186
  5. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry 2011;168:689-701. doi:10.1176/appi.ajp.2011.10111645
  6. David S Kessler,1 Stephanie J MacNeill,2 Deborah Tallon 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 | doi: 10.1136/bmj.k4218