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Study finds no evidence to support the use of antidepressants as a first-line treatment for people with depression in Alzheimer's disease who are referred to old-age psychiatry services, as many cases will resolve with usual care.

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S Banerjee,1,* J Hellier,2 R Romeo,3 M Dewey,3 M Knapp,3 C Ballard,4 R Baldwin,5 P Bentham,6 C Fox,7 C Holmes,8 C Katona,9 C Lawton,10 J Lindesay,11 G Livingston,9 N McCrae,3 E Moniz-Cook,12 J Murray,3 S Nurock,13 M Orrell,9 J O'Brien,14 M Poppe,3 A Thomas,14 R Walwyn,2 K Wilson,15 A Burns,5 

1 Brighton and Sussex Medical School, BSMS Teaching Building, University of Sussex, Brighton, UK
2 King's College London, Mental Health and Neuroscience Clinical Trials Unit, London, UK
3 King's College London, Institute of Psychiatry, Health Services and Population Research Department, London, UK
4 King's College London, Wolfson Centre for Age-Related Disease, London, UK
5 Department of Community Based Medicine, University of Manchester, Manchester, UK
6 Department of Psychiatry, University of Birmingham, Birmingham, UK
7 School of Medicine, University of East Anglia, Norwich, UK
8 Department of Psychiatry, University of Southampton, Southampton, UK
9 Department of Mental Health Sciences, University College London, London, UK
10 Department of Psychiatry, University of Cambridge, Cambridge, UK
11 Department of Psychiatry, University of Leicester, Leicester, UK
12 Institute of Rehabilitation, Hull York Medical School, Hull, UK
13 Alzheimer's Society, Research Network Volunteer, London, UK
14 Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
15 Department of Psychiatry, Liverpool University, Liverpool, UK
* Corresponding author ; Email: s.banerjee@kcl.ac.uk

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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.

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.

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.

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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