• David Kessler, Alison Burns, Debbie Tallon, Glyn Lewis, Stephanie MacNeill, Jeff Round, William Hollingworth, Carolyn Chew-Graham, Ian Anderson, John Campbell, Chris Dickens, Una Macleod, Simon Gilbody, Simon Davies, Tim J Peters, and Nicola Wiles.
• Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, UK.
• Health Technol Assess. 2018 Nov 1; 22 (63): 1-136.

BackgroundDepression 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.ObjectivesTo 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).DesignThe MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual.SettingParticipants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele.ParticipantsEligible 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.InterventionsParticipants 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 MeasuresThe 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.ResultsThere 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).ConclusionsThis 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.LimitationsVoluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult.Future WorkTreatment-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 RegistrationCurrent Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23.FundingThis 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.

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