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Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

ABSTRACT: OBJECTIVE:Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment. METHODS:A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10?mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire). RESULTS:Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo. CONCLUSION:The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

SUBMITTER: Devanand DP

PROVIDER: S-EPMC6396676 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

Devanand Davangere P DP Pelton Gregory H GH D'Antonio Kristina K Ciarleglio Adam A Scodes Jennifer J Andrews Howard H Lunsford Julia J Beyer John L JL Petrella Jeffrey R JR Sneed Joel J Ciovacco Michaela M Doraiswamy Pudugramam Murali PM

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 20180628 10

<h4>Objective</h4>Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment.<h4>Methods</h4>A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/ ...[more]

PMID: 30037778

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Project description:ContextCognitive impairment in late-life depression is a core feature of the illness.ObjectiveTo test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment.DesignRandomized, double-blind, placebo-controlled maintenance trial.SettingUniversity clinic.ParticipantsOne hundred thirty older adults aged 65 years and older with recently remitted major depression.InterventionsRandom assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo.Main outcome measuresGlobal neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression.ResultsDonepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression.ConclusionsWhether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression.Trial registrationclinicaltrials.gov Identifier: NCT00177671.

Project description:ObjectiveTo assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI).MethodsThis was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]).ResultsSeventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog performance compared with the usual care plus education group (-1.71 point difference, 95% confidence interval [CI] -3.15 to -0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (-0.63 point difference, 95% CI -2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference, 95% CI 5.82 to 54.86, p = 0.02) and in diastolic blood pressure (-6.89 mm Hg difference, 95% CI -12.52 to -1.26, p = 0.02).ConclusionsThis study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education.Clinicaltrialsgov identifierNCT01027858.Classification of evidenceThis study provides Class II evidence that for adults with mild SIVCI, an aerobic exercise program for 6 months results in a small, significant improvement in ADAS-Cog performance.

Dataset Information

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

Publications

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

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