No benefit shown for mirtazapine combination therapy in treatment-resistant depression

By Melanie Hinze
The addition of mirtazapine to a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for treatment-resistant depression has no clinically important benefit, a UK study published in the BMJ has concluded.

According to the study authors, about 50% of patients taking antidepressants at an adequate dose for an adequate duration remain depressed, representing a significant number of primary care patients. 

Scientia Professor Philip Mitchell, from the School of Psychiatry at UNSW Sydney, said combining antidepressants for those with depression who had not responded to a single agent was becoming increasingly common in both primary care and psychiatry despite a very limited and inconsistent evidence base.

‘This study is the largest randomised placebo-controlled trial to test whether adding mirtazapine to a failed antidepressant was both efficacious and well tolerated – and the findings are both important and clear cut,’ he told Medicine Today. ‘Adding mirtazapine to a failed SSRI or SNRI is not a clinically effective strategy. Moreover, the rates of adverse effects are greatly increased after adding mirtazapine.’

The two-parallel group multicentre phase III randomised placebo-controlled trial involved 480 adults from 106 UK general practices. Participants scored 14 or more on the Beck Depression Inventory Second Edition (BDI-II) and fulfilled ICD-10 criteria for depression despite using an SSRI or SNRI for at least six weeks. They were randomised to either mirtazapine or placebo, in addition to their usual SSRI or SNRI antidepressant.

At 12 weeks, BDI-II scores were lower in the mirtazapine group than the placebo group, but the difference was not statistically significant, and adverse effects were more common in the mirtazapine group. Of those who reported adverse effects, 46 participants from the mirtazapine group stopped taking the drug, compared with nine in the placebo group.

‘The lack of clear evidence of benefit … combined with the increased burden of adverse effects in the mirtazapine group, means that we cannot recommend this combination as a routine strategy in primary care for those who remain depressed after adequate treatment with SSRI or SNRI antidepressants,’ the authors concluded.
BMJ 2018; 363: k4218.