PMID- 30468145 OWN - NLM STAT- MEDLINE DCOM- 20190409 LR - 20221207 IS - 2046-4924 (Electronic) IS - 1366-5278 (Print) IS - 1366-5278 (Linking) VI - 22 IP - 63 DP - 2018 Nov TI - Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT. PG - 1-136 LID - 10.3310/hta22630 [doi] AB - 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. FAU - Kessler, David AU - Kessler D AD - Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, UK. FAU - Burns, Alison AU - Burns A AD - Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, UK. FAU - Tallon, Debbie AU - Tallon D AD - Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, UK. FAU - Lewis, Glyn AU - Lewis G AD - Mental Health Services Unit, University College London, London, UK. FAU - MacNeill, Stephanie AU - MacNeill S AD - Bristol Randomised Trials Collaboration, School of Social and Community Medicine, University of Bristol, Bristol, UK. FAU - Round, Jeff AU - Round J AD - Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol, UK. FAU - Hollingworth, William AU - Hollingworth W AD - Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol, UK. FAU - Chew-Graham, Carolyn AU - Chew-Graham C AD - Research Institute for Primary Care and Health Sciences, Keele University, Keele, UK. FAU - Anderson, Ian AU - Anderson I AD - Neuroscience and Psychiatry Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. FAU - Campbell, John AU - Campbell J AD - University of Exeter Medical School, Exeter, UK. FAU - Dickens, Chris AU - Dickens C AD - University of Exeter Medical School, Exeter, UK. FAU - Macleod, Una AU - Macleod U AD - Hull York Medical School, University of Hull, Hull, UK. FAU - Gilbody, Simon AU - Gilbody S AD - Mental Health Research Group, University of York, York, UK. FAU - Davies, Simon AU - Davies S AD - Centre for Addiction and Mental Health, Toronto, ON, Canada. FAU - Peters, Tim J AU - Peters TJ AD - School of Clinical Sciences, University of Bristol, Bristol, UK. FAU - Wiles, Nicola AU - Wiles N AD - Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, UK. LA - eng SI - ISRCTN/ISRCTN06653773 SI - EudraCT/2012-000090-23 GR - 11/129/76/DH_/Department of Health/United Kingdom PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Health Technol Assess JT - Health technology assessment (Winchester, England) JID - 9706284 RN - 0 (Antidepressive Agents) RN - 0 (Serotonin Uptake Inhibitors) RN - 0 (Serotonin and Noradrenaline Reuptake Inhibitors) RN - A051Q2099Q (Mirtazapine) SB - IM MH - Adult MH - Aged MH - Antidepressive Agents/administration & dosage/adverse effects/economics/*therapeutic use MH - Cost-Benefit Analysis MH - Depressive Disorder, Treatment-Resistant/*drug therapy MH - Drug Therapy, Combination MH - Female MH - Health Expenditures/statistics & numerical data MH - Health Resources/economics/statistics & numerical data MH - Humans MH - Male MH - Medication Adherence/statistics & numerical data MH - Mental Health MH - Middle Aged MH - Mirtazapine/administration & dosage/adverse effects/economics/*therapeutic use MH - Quality of Life MH - Quality-Adjusted Life Years MH - Selective Serotonin Reuptake Inhibitors/administration & dosage/adverse effects/economics/*therapeutic use MH - Serotonin and Noradrenaline Reuptake Inhibitors/administration & dosage/adverse effects/economics/*therapeutic use MH - Severity of Illness Index MH - Social Work/economics/statistics & numerical data MH - Time Factors PMC - PMC6287172 COIS- 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. EDAT- 2018/11/24 06:00 MHDA- 2019/04/10 06:00 PMCR- 2018/12/10 CRDT- 2018/11/24 06:00 PHST- 2018/11/24 06:00 [entrez] PHST- 2018/11/24 06:00 [pubmed] PHST- 2019/04/10 06:00 [medline] PHST- 2018/12/10 00:00 [pmc-release] AID - 10.3310/hta22630 [doi] PST - ppublish SO - Health Technol Assess. 2018 Nov;22(63):1-136. doi: 10.3310/hta22630.