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Cited by 171Treatment of Major DepressionDementia and Cognitive Impairment ResearchAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

Maintenance Treatment of Depression in Old Age: A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined With Antidepressant Pharmacotherapy

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Reynolds, Charles F., Butters, Meryl A., Lopez, Oscar, Pollock, Bruce G., Dew, Mary Amanda, Mulsant, Benoit H., Lenze, Eric J., Holm, Margo +15 more·2011·Archives of General Psychiatry
DOI 10.1001/archgenpsychiatry.2010.184PMC PMC3076045
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Abstract

CONTEXT: Cognitive impairment in late-life depression is a core feature of the illness. OBJECTIVE: To 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. DESIGN: Randomized, double-blind, placebo-controlled maintenance trial. SETTING: University clinic. PARTICIPANTS: One hundred thirty older adults aged 65 years and older with recently remitted major depression. INTERVENTIONS: Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo. MAIN OUTCOME MEASURES: Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression. RESULTS: Donepezil 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. CONCLUSIONS: Whether 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 REGISTRATION: clinicaltrials.gov Identifier: NCT00177671.

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  • Some included reports reported outcomes as interaction statistics without data on within-group changes from baseline and between-group differences at study end.

    “Examples include outcomes reported as interaction statistics without data on within-group changes from baseline and between-group differences at study end24,27,51”

    From Cognitive Effects of Pharmacotherapy for Major Depressive Disorder: A Systematic Review (2014) · cites this paper as [51]

    The Results (A. Primary Analyses; page not available) report treatment-by-time interaction statistics, supporting the first part of the claim. They also report between-group effect sizes at one and two years, so the statement that no between-group differences were reported is too broad. The passages do not provide within-group changes from baseline. (LLM, conf=0.82)

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  • Donepezil added to the maintenance antidepressant therapy of LLD led to temporary positive effects on cognitive function and marginal improvement of cognitive instrumental activities of daily living.

    “Donepezil added to the maintenance antidepressant therapy of LLD that led to temporary positive effects of donepezil on cognitive function, marginal improvement of cognitive instrumental activities of daily living, and, in those with MCI, a lower rate of conversion to dementia over 2 years134.”

    From Mechanisms and treatment of late-life depression (2019) · cites this paper as [134]

  • Donepezil increased the risk of recurrence especially in cognitively impaired LLD patients.

    “Donepezil increased the risk of recurrence especially in cognitively impaired LLD patients134.”

    From Mechanisms and treatment of late-life depression (2019) · cites this paper as [134]

  • Donepezil added to the maintenance antidepressant therapy of LLD led to a lower rate of conversion to dementia over 2 years in those with MCI.

    “Donepezil added to the maintenance antidepressant therapy of LLD that led to temporary positive effects of donepezil on cognitive function, marginal improvement of cognitive instrumental activities of daily living, and, in those with MCI, a lower rate of conversion to dementia over 2 years134.”

    From Mechanisms and treatment of late-life depression (2019) · cites this paper as [134]

  • Slowing of RT/processing speed, possibly associated with increasing IIV of RT performance over time, has been observed in multiple longitudinal studies in older individuals, including patients with MDD.

    “Slowing of RT/processing speed, possibly associated with increasing IIV of RT performance over time, has been observed in multiple longitudinal studies in older individuals, including patients with MDD [35].”

    From Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study (2023) · cites this paper as [35]

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Research works printed but not linked: 2

  1. [22]First M Spitzer RL Gibbon M Williams JBW Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition (SCID-I/P). Version 2.0 ed 1995 New York State Psychiatric Institute New York
  2. [26]Holm MB Rogers JC Hemphill-Pearson B The performance assessment of self-care skills (PASS) Assessments in Occupational Therapy Mental Health 2008 101 10 SLACK Thorofare, NJ 2nd ed.

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Authors
Reynolds, C. F., Butters, M. A., Lopez, O., Pollock, B. G., Dew, M. A., Mulsant, B. H., Lenze, E. J., Holm, M., Rogers, J. C., Mazumdar, S., Houck, P. R., Begley, A., Anderson, S., Karp, J. F., Miller, M. D., Whyte, E. M., Stack, J., Gildengers, A., Szanto, K., Bensasi, S., Kaufer, D. I., Kamboh, M. I., & DeKosky, S. T.
Affiliations
  • University of Pittsburgh (US)
  • University of North Carolina at Chapel Hill (US)
ORCID
Venue
Archives of General Psychiatry
Publisher
American Medical Association (AMA)
Published
2011-01-03
Volume
68
Issue
1
Pages
51
ISSN
0003-990X (ISSN-L)
DOI
10.1001/archgenpsychiatry.2010.184
PMC
PMC3076045
OpenAlex
W2110379660
Cited by
171
References
46
Citations by year
2026: 4 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 10 · 2021: 15 · 2020: 14 · 2019: 12 · 2018: 5 · 2017: 10 · 2016: 6 · 2015: 16 · 2014: 17 · 2013: 23 · 2012: 10
FWCI
13.82
Type
journal article
Language
en
Open access
Locations
  • Archives of General Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000005, KL2TR000146)
  • Centers for Disease Control and Prevention (R49CE001495)
  • National Institute on Aging (P50AG005133, R01AG030653, P50-AG-05133, R01AG022462, R21AG033387, AG 030653)
  • National Institute of Mental Health (R01MH072947, R01MH043823, P30MH071944, R01MH037869, R01MH043832, R01MH083660)
  • National Institute of Biomedical Imaging and Bioengineering (K01EB009724)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords
geriatric depression, donepezil, cholinesterase inhibitors, cognitive impairment, instrumental activities of daily living, depression recurrence, mild cognitive impairment, conversion to dementia, antidepressant augmentation, older adults, neuropsychological performance
MeSH terms
Donepezil, Activities of Daily Living, Aged, Aged, 80 and over, Aging, Antidepressive Agents, Cholinesterase Inhibitors, Cognition, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Indans, Male, Piperidines, Treatment Outcome, Nootropic Agents, Secondary Prevention

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