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.
Author(s): Banerjee S(1), Hellier J, Romeo R, Dewey M, Knapp M, Ballard C, Baldwin R,
Bentham P, Fox C, Holmes C, Katona C, Lawton C, Lindesay J, Livingston G, McCrae
N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O'Brien J, Poppe M, Thomas A,
Walwyn R, Wilson K, Burns A.
Affiliation(s): Author information:
(1)Brighton and Sussex Medical School, BSMS Teaching Building, University of Sussex,
Brighton, UK.
Publication date & source: 2013, Health Technol Assess. , 17(7):1-166
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.
DESIGN: 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.
SETTING: Nine English old-age psychiatry services.
PARTICIPANTS: 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+.
EXCLUSIONS: clinically too critical (e.g. suicide risk); contraindication to
medication; taking antidepressants; in another trial; and having no carer.
INTERVENTIONS: (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal
care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily.
MAIN OUTCOME MEASURES:
OUTCOME: 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).
OUTCOME: 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).
HARMS: 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.
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