title: Mirtazapine added to selective serotonin reuptake inhibitors for treatment-resistant depression in primary care (MIR trial): study protocol for a randomised controlled trial.
abstract: BACKGROUND
  People with depression are usually managed in primary care and antidepressants are often the first-line treatment, but only one third of patients respond fully to a single antidepressant. This paper describes the protocol for a randomised controlled trial (MIR) to investigate the extent to which the addition of the antidepressant mirtazapine is effective in reducing the symptoms of depression compared with placebo in patients who are still depressed after they have been treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for at least 6 weeks in primary care.
  
  
  METHODS
  MIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual. Eligible participants are those who: are aged 18 years or older; are currently taking an SSRI/SNRI antidepressant (for at least 6 weeks at an adequate dose); score ≥ 14 on the Beck Depression Inventory (BDI-II); have adhered to their medication; and meet ICD-10 criteria for depression (assessed using the Clinical Interview Schedule-Revised version). Participants who give written, informed consent, will be randomised to receive either oral mirtazapine or matched placebo, starting at 15 mg daily for 2 weeks and increasing to 30 mg daily thereafter, for up to 12 months (to be taken in addition to their usual antidepressant). Participants, their GPs, and the research team will all be blind to the allocation. The primary outcome will be depression symptoms at 12 weeks post randomisation, measured as a continuous variable using the BDI-II. Secondary outcomes (measured at 12, 24 and 52 weeks) include: response (reduction in depressive symptoms (BDI-II score) of at least 50% compared to baseline); remission of depression symptoms (BDI-II <10); change in anxiety symptoms; adverse effects; quality of life; adherence to antidepressant medication; health and social care use, time off work and cost-effectiveness. All outcomes will be analysed on an intention-to-treat basis. A qualitative study will explore patients' views and experiences of either taking two antidepressants, or an antidepressant and a placebo; and GPs' views on prescribing a second antidepressant in this patient group.
  
  
  CONCLUSIONS
  The MIR trial will provide evidence on the clinical and cost-effectiveness of mirtazapine as an adjunct to SSRI/SNRI antidepressants for patients in primary care who have not responded to monotherapy.
  
  
  BACKGROUND
  EudraCT Number: 2012-000090-23 (Registered January 2012); ISRCTN06653773 (Registered September 2012).
authors: School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK. d.tallon@bristol.ac.uk.
authors: Debbie
authors: D
authors: Tallon
authors: School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors: Nicola
authors: N
authors: Wiles
authors: University of Exeter Medical School, St Luke's Campus, Smeall Building, Magdalen Road, Exeter, EX1 2LU, UK.
authors: John
authors: J
authors: Campbell
authors: Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, UK.
authors: Carolyn
authors: C
authors: Chew-Graham
authors: University of Exeter Medical School, Room 1.04, College House, St Luke's Campus, Heavitree Road, Exeter, EX1 2LU, UK.
authors: Chris
authors: C
authors: Dickens
authors: Hull York Medical School, University of Hull, Kingston upon Hull, HU6 7RX, UK.
authors: Una
authors: U
authors: Macleod
authors: School of Clinical Sciences, 69 St Michael's Hill, Bristol, BS2 8DZ, UK.
authors: Tim J
authors: TJ
authors: Peters
authors: University College London, Maple House, 149 Tottenham Court Rd, London, W1T 7NF, UK.
authors: Glyn
authors: G
authors: Lewis
authors: Neuroscience and Psychiatry Unit, The University of Manchester, Room G809, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Ian M
authors: IM
authors: Anderson
authors: Mental Health Research Group, Department of Health Sciences and Hull York Medical School, Alcuin College C Block, University of York, YO10 5DD, Heslington, UK.
authors: Simon
authors: S
authors: Gilbody
authors: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
authors: William
authors: W
authors: Hollingworth
authors: Centre for Addiction and Mental Health, Room 6318, 80 Workman Way, Toronto, ON, Canada.
authors: Simon
authors: S
authors: Davies
authors: School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors: David
authors: D
authors: Kessler
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage*; D002985:Clinical Protocols; D003863:Depression / Q000188:drug therapy*; D004351:Drug Resistance; D006801:Humans; D008803:Mianserin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000078785:Mirtazapine; D017063:Outcome Assessment, Health Care; D011320:Primary Health Care; D036301:Qualitative Research; D018401:Sample Size; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine; D017367:Selective Serotonin Reuptake Inhibitors