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/Objectives: 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 trail aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post-randomisation compared with placebo

Design: multi-centre parallel group double-blind placebo-controlled RCT of the clinical effectiveness of sertraline and mirtazapine with 13 and 39 week follow up.

Setting: from nine English old age psychiatry services

Participants: a pragmatic trial, eligibility: probable or possible Alzheimer's Disease, depression (4+ weeks), and Cornell Scale for Depression in Dementia (CSDD) score of 8+. Exclusions: clinically too critical (eg suicide risk); contra-indication 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: 150mg sertraline or 45mg 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, 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.

Conclusion/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 Alzheimer’s disease. This implies a need to change current practice of antidepressants being the first line treatment of depression in Alzheimer’s disease.

Source of funding: this project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. [x], No. [x] (to be completed by the publisher). See the HTA programme website for further project information.

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Identifiers

ORCID for Clive Holmes: orcid.org/0000-0003-1999-6912

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