title: Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine.
abstract: OBJECTIVE
  Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo.
  
  
  METHODS
  Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up.
  
  
  METHODS
  Nine English old-age psychiatry services.
  
  
  METHODS
  A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+.
  
  
  METHODS
  clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer.
  
  
  METHODS
  (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily.
  
  
  METHODS
  
  
  
  RESULTS
  CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed.
  
  
  RESULTS
  Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine).
  
  
  RESULTS
  Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112).
  
  
  RESULTS
  Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group.
  
  
  CONCLUSIONS
  This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.
authors: Brighton and Sussex Medical School, BSMS Teaching Building, University of Sussex, Brighton, UK.
authors: S
authors: S
authors: Banerjee
authors: J
authors: J
authors: Hellier
authors: R
authors: R
authors: Romeo
authors: M
authors: M
authors: Dewey
authors: M
authors: M
authors: Knapp
authors: C
authors: C
authors: Ballard
authors: R
authors: R
authors: Baldwin
authors: P
authors: P
authors: Bentham
authors: C
authors: C
authors: Fox
authors: C
authors: C
authors: Holmes
authors: C
authors: C
authors: Katona
authors: C
authors: C
authors: Lawton
authors: J
authors: J
authors: Lindesay
authors: G
authors: G
authors: Livingston
authors: N
authors: N
authors: McCrae
authors: E
authors: E
authors: Moniz-Cook
authors: J
authors: J
authors: Murray
authors: S
authors: S
authors: Nurock
authors: M
authors: M
authors: Orrell
authors: J
authors: J
authors: O'Brien
authors: M
authors: M
authors: Poppe
authors: A
authors: A
authors: Thomas
authors: R
authors: R
authors: Walwyn
authors: K
authors: K
authors: Wilson
authors: A
authors: A
authors: Burns
mesh_terms: D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D003362:Cost-Benefit Analysis; D003704:Dementia / Q000150:complications / Q000523:psychology*; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000078785:Mirtazapine; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D011788:Quality of Life / Q000523:psychology; D020280:Sertraline / Q000627:therapeutic use*; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine; D020280:Sertraline