Comment Antidepressant treatment in Alzheimer’s dia
The negative results from the UK Health Technology Asssment (HTA) Study of the U of Antidepressants for D epression in D ementia (SAD D)1 trial reported by Sube Banerjee and colleagues in The Lancet are important for veral reasons, not least becau of the compelling size of the study. 326 participants with Alzheimer’s dia and depression were randomly allocated to receive rtraline, mirtazapine, or placebo, making this landmark study the largest trial of antidepressant drugs in dementia ever and almost equalling the combined total from previously published work.2
Second, depression in dementia is very common, affecting around 20% of the 36 million people with dementia worldwide.3 Third, previous results of trials of antidepressants for depression in people with Alzheimer’s dia have been unconvincing.2 The promi offered by the first D epression in Alzheimer D ia Study (D IAD S) study,4 which reported benefi t with rtraline, a lective rotonin reuptake inhibitor, was dashed by the negative fi ndings at 12 or 24 weeks from the larger DIADS-2 trial.5
Fourth, the abnce of effi cacy of antidepressants in the dementia population rais questions about
whether there are diff erent pathogenic mechanisms at play in depression in Alzheimer’s dia. Antidepressants have moderate but robust benefits for people with depression in general (effect size 0·497 for drugs compared with placebo)6 as well as in elderly people with depression.7 Although vascular depression might have a poorer respon rate, participants in the SAD D trial predominantly had Alzheimer’s dia as suggested by a mean Hachinski index of 2·2.
The trial mimicked clinical practice. Participants were aged about 80 years, had moderately vere Alzheimer’s dia with average mini-mental state examination scores of around 18, were mainly living in the community (about 85%), had clinically signifi cant depression with more than half of participants having Cornell scale for depression in dementia (CSDD) scores of 12 or more, had been depresd for a substantial amount of time (68% for more than 6 months), and had been referred to old-age psychiatric rvices.
D rug dos were escalated to three tablets per day of rtraline 50 mg, mirtazapine 15 mg, or placebo. There were few exclusions. Withdrawal rates ranged from 24% to 35%. Mean dos achieved were 95 mg per
day for rtraline and 30 mg per day for mirtazapine,
which is typical for clinical practice in this population.
There was no diff erence between groups in terms of the
primary outcome (change in CSD D score) at 13 weeks
or 39 weeks, or in nearly all other outcome measures洪的成语
for participants or carers. Adver eff ects occurred more
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often in active drug groups than they did in the placebo
group, and possibly more often in the rtraline than the
mirtazapine group.中华美食街
Caveats are that the results might not be applicable to
primary care ttings, to individuals who depression
was very vere (ie, tho who were critically ill or
suicidal), to other types of dementia, or, necessarily, to
other antidepressant drugs. The trial did not include
a responder analysis, and subgroups of participants
not yet identified might be responsive to drugs.
The possibility that raid CSD D scores result from
non-depressive dementia symptoms might mitigate
proof of responsiveness to antidepressants. However,
the nsitivity analysis that did not show a diff erence in
the primary outcome for participants with CSDD scores
of 12 or more partially militates against this possibility.
What are clinicians confronted by the fi ndings to
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do? Banerjee and colleagues emphasi a stepped care
approach of watchful waiting, followed-up by low-
intensity psychosocial interventions and, if unsuccessful,
by more complex and inten interventions.8 The
authors recommend 13 weeks’ watchful waiting in view
Published Online
July 18, 2011
DOI:10.1016/S0140-
6736(11)61031-3
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Comment
New hope for immune intervention therapy in type 1 diabetes
In the wake of disappointing results from the fi rst pha 3 immune intervention trials in type 1 diabetes mellitus, a report by Tihamer Orban and colleagues in The Lancet1 could provide a much desired glimmer of hope that the cour of dia progression can be altered by immunotherapy after all. Treatment of patients with recent-ont type 1 diabetes for 2 years with abatacept (CTLA4 immunoglobulin fusion protein), believed to interfere with priming and activation of T cells, eff ectively delayed loss of β-cell function for 9 months. This protective eff ect was prerved for the complete p
eriod of 2 years’ therapy. This trial is yet another important deliverable from the international Diabetes TrialNet Consortium,2 which has an impressive efficiency in designing and executing clinical immune intervention trials in type 1 diabetes with swift recruitment of eligible patients.
Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an esntial negative regulator of T-cell immune respons (fi gure). T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. Converly, blockade of CTLA4 by ipilimumab augments T-cell activation and proliferation and improved overall survival in a pha 3 study in patients with metastatic melanoma.3 Becau T-cell autoimmunity is pivotal
of the 43% reduction in CSD D scores in the placebo group in that time. If waiting is too distressing for patients or their families, the next step of psychosocial interventions could occur sooner.
Evidence of improvement in rates and verity of depression exists for veral community bad-interventions involving carers of people with Alzheimer’s dia: carer-given problem solving therapy or pleasurable events schedules;9 exercis and carer-given behaviour management therapy;10 interpersonal therapy;11 or occupational therapist training in compen-satory and environmental strategies combined with cognitive behavioural therapy provided to carers.12
The HTA-SADD trial1 does not advocate abandonment of antidepressants in people with Alzheimer’s dia and depression. Anecdotally, clinicians report successful treatment of patients with antidepressants. Therapeutic trials for individual patients are warranted, although not as fi rst-line treatment unless depression is vere. Antidepressants might have benefi ts to other psychiatric symptoms condary to dementia, as indicated by reports that hallucinations, delusions, and agitation benefit from citalopram.13 Finally, there are anecdotal accounts of u of electroconvulsive therapy in vere depression.
The HTA-SAD D trial1 has underscored the need for clinicians to think about creative alternatives to drug treatment for management of depression in people with dementia, and to u evidence-bad techniques and partnerships with family carers.Henry Brodaty
Brain and Ageing Rearch Program and Primary Dementia Collaborative Rearch Centre, School of Psychiatry, Faculty of Medicine, University of New South Wales, NSW 2052, Australia h.brodaty@unsw.edu.au
I declare that I have no confl icts of interest.
1 Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for
depression in dementia (HTA-SADD): a randomid, multicentre,
double-blind, placebo-controlled trial. Lancet 2011; published online
打电话的英文
July 18. DOI:10.1016/S0140-6736(11)60830-1.
2 Nelson JC, Devanand DP. A systematic review and meta-analysis of
placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc 2011; 59: 577–85.
3 Prince M, Jackson J. World Alzheimer’s report 2009. London: Alzheimer’s
Dia International, 2009.
4 Weintraub D, Ronberg PB, Drye LT, et al. Sertraline for the treatment of
depression in Alzheimer dia: week-24 outcomes. Am J Geriatr Psychiatry 2010; 18: 332–40.
5 Ronberg PB, Drye LT, Martin BK, et al. Sertraline for the treatment of
depression in Alzheimer dia. Am J Geriatr Psychiatry 2010; 18: 136–45.6个月宝宝
6 Joff e R, Sokolov S, Streiner D. Antidepressant treatment of depression:
a metaanalysis. Can Child Adolesc Psychiatr Rev 1996; 41: 613–16.
7 Nelson JC, Delucchi K, Schneider LS. Effi cacy of cond generation
antidepressants in late-life depression: a meta-analysis of the evidence.
Focus 2010; 8: 605–13.
8 National Institute for Health and Clinical Excellence. Depression—the
雪茫茫treatment and management of depression in adults. London, UK:
晚饭的英语Department of Health, 2009.
9 Teri L, Logsdon RG, Uomoto J, McCurry SM. Behavioral treatment
of depression in dementia patients: a controlled clinical trial.
J Gerontol B Psychol Sci Soc Sci 1997; 52B: 159–66.
10 Teri L, Gibbons LE, McCurry SM, et al. Exerci plus behavioral management
in patients with alzheimer dia. JAMA 2003; 290: 2015–22.
11 Miller MD, Reynolds CF. Expanding the ufulness of interpersonal
psychotherapy (IPT) for depresd elders with co-morbid cognitive
impairment. Int J Geriatr Psychiatry 2007; 22: 101–05.
12 Graff MJL, Vernooij-Dasn MJM, Thijsn M, Dekker J, Hoefnagels WHL,
Olderikkert MGM. Eff ects of community occupational therapy on quality of life, mood, and health status in dementia patients and their caregivers: a
randomized controlled trial. J Gerontol A Biol Sci Med Sci 2007; 62: 1002–09.
13 Pollock BG, Mulsant BH, Ron J, et al. A double-blind comparison of
citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007;
15: 942–52.
Published Online
June 28, 2011 DOI:10.1016/S0140-
6736(11)60977-X See Articles page 412
