Background:

Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant.

Objectives:

To investigate whether or not combining mirtazapine with serotonin–noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD).

Design:

The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual.

Setting:

Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele.

Participants:

Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression.

Interventions:

Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation.

Main outcome measures:

The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients’ views and experiences of managing depression and GPs’ views on prescribing a second antidepressant.

Results:

There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference –1.83 points, 95% confidence interval (CI) –3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: –0.85 points, 95% CI –3.12 to 1.43 points; 12 months: 0.17 points, 95% CI –2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants).

Conclusions:

This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant.

Limitations:

Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult.

Future work:

Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation.

Trial registration:

Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23.

Funding:

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 11/129/76. The contractual start date was in April 2013. The draft report began editorial review in May 2017 and was accepted for publication in October 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Simon Gilbody is deputy chairperson of the Health Technology Assessment programme Commissioning Board. Tim J Peters chaired the Medical Research Council–National Institute for Health Research Methodology Research Programme panel from 2007 to 2014. Ian Anderson has received personal fees from the following: Alkermes plc, Lundbeck Ltd, Otsuka Pharmaceutical Ltd, Janssen Ltd and Takeda Pharmaceutical Company Ltd.