Many patients with mild cognitive impairment are also clinically depressed, yet the course of treatment is unclear. Could donepezil help? A June 28 paper in the American Journal of Geriatric Psychiatry suggests not. In a Phase 4 trial, 14 months of donepezil treatment failed to slow cognitive decline in depressed patients with MCI. “This is a huge population,” said Murali Doraiswamy, Duke University School of Medicine, Durham, North Carolina, who co-authored the study led by Davangere Devanand at Columbia University Medical Center, New York.

  • In a Phase 4 trial, donepezil no help for MCI with depression.
  • The drug did not slow cognitive decline, but had side effects.
  • Results may call into question the widespread use of donepezil in these patients.

About a third of MCI patients have some degree of depression, which can cause cognitive impairment of its own and raise the risk of progression to AD, Doraiswamy said. “It is very important to find an effective treatment for this high-risk group.”

Ronald Petersen, Mayo Clinic, Rochester Minnesota, found the study to be well done. “It was a nice clinical trial done with all the right considerations and controls,” he told Alzforum. He agreed with the authors that the sample size was relatively small, but nevertheless saw this as good evidence that depressed people who are also cognitively impaired may not benefit from donepezil.

One of three acetylcholinesterase inhibitors approved by the FDA to boost cholinergic activity in the brains of AD patients, donepezil has not been shown to benefit people with MCI (Petersen, 2004; Salloway et al., 2004; Doody et al., 2009). Nevertheless, doctors prescribe it, off-label, in around 40 percent of these patients, Doraiswamy told Alzforum. The AAN recommends that people with MCI be advised of the lack of evidence that donepezil will help them (Petersen et al., 2018). 

Patients with both MCI and depression are understudied because people with cognitive impairment tend to be excluded from studies of depression, and vice versa. However, some studies have hinted that donepezil could help people with both syndromes. A re-analysis of a multicenter trial suggested that among 208 participants with mild depressive symptoms, donepezil slowed the rate of progression to AD compared to placebo or vitamin E (Lu et al., 2009). A one-year pilot study by Devanand and colleagues suggested donepezil could improve episodic verbal memory in people with both MCI and depression (Pelton et al., 2008). 

To further explore the question, Devanand and colleagues enrolled 79 people, average age 70, who had major depression and MCI. Each had a baseline MRI scan, then received antidepressants for 16 weeks, whereupon they were randomly assigned to receive either add-on donepezil or placebo for another 62 weeks. During the first 16 weeks, 18 patients dropped out. In 64 percent of the remaining patients, depressive symptoms improved with antidepressant therapy.

At the end of the study, there was no difference between the donepezil and placebo groups on the co-primary outcomes of change from baseline scores on the ADAS-Cog 13 and on the Selective Reminding Test (SRT) total immediate recall. This was true regardless of whether a patient responded to antidepressants. Likewise, neither ApoE4 genotype nor baseline hippocampal volume predicted response.

There was no difference in secondary outcomes, either. Change in functional activity scores and the SRT delayed recall were similar for drug and placebo groups. Since only four people—two in each group—progressed to dementia, the researchers did not assess that as an outcome.

These negative results fit with other studies that suggest donepezil is ineffective in patients with MCI. Even so, Doraiswamy wonders if the drug could have worked in that subset of MCI patients with Alzheimer’s disease as an underlying etiology. Since the trial measured no AD biomarkers, the only way to find out would be another prospective trial including only amyloid-positive patients, he said.

Petersen echoed this caveat, pointing out while the patients were primarily seeking treatment for depression, those from a memory disorders clinic might have a different outcome, assuming they would be likelier to carry ApoE4 and have amyloid. “The source of people coming into the clinic might have an impact,” he told Alzforum.

The study has implications for current practice. “It calls into question the off-label use of donepezil in these patients,” Devanand told Alzforum. Doctors should avoid exposing people to donepezil if they are unlikely to benefit, he said. In this study, side effects such as diarrhea, headaches, dizziness, insomnia, fatigue, and nightmares were about twice as common in the treated group as in those on placebo.—Gwyneth Dickey Zakaib


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Therapeutics Citations

  1. Donepezil

Paper Citations

  1. . Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004 Sep;256(3):183-94. PubMed.
  2. . Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology. 2004 Aug 24;63(4):651-7. PubMed.
  3. . Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology. 2009 May 5;72(18):1555-61. PubMed.
  4. . Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Jan 16;90(3):126-135. Epub 2017 Dec 27 PubMed.
  5. . Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 2009 Jun 16;72(24):2115-21. PubMed.
  6. . Randomized double-blind placebo-controlled donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive impairment: a pilot study. Int J Geriatr Psychiatry. 2008 Jul;23(7):670-6. PubMed.

External Citations

  1. Phase 4 trial

Further Reading


  1. . Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry. 2018 Aug;26(8):819-827. Epub 2018 May 9 PubMed.
  2. . Depressive symptoms increase the risk of progression to dementia in subjects with mild cognitive impairment: systematic review and meta-analysis. Int J Geriatr Psychiatry. 2015 Dec 17; PubMed.
  3. . Diversity of neurodegenerative pathophysiology in nondemented patients with major depressive disorder: Evidence of cerebral amyloidosis and hippocampal atrophy. Brain Behav. 2018 Jul;8(7):e01016. Epub 2018 Jun 21 PubMed.
  4. . Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment. Int J Geriatr Psychiatry. 2018 Oct;33(10):1305-1311. Epub 2018 Jun 28 PubMed.

Primary Papers

  1. . Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial. Am J Geriatr Psychiatry. 2018 Oct;26(10):1050-1060. Epub 2018 Jun 28 PubMed.