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Randomized Controlled Trial
. 2025 Jan 1;82(1):12-21.
doi: 10.1001/jamapsychiatry.2024.3241.

Slowing Cognitive Decline in Major Depressive Disorder and Mild Cognitive Impairment: A Randomized Clinical Trial

Tarek K Rajji  1   2   3 , Christopher R Bowie  1   4 , Nathan Herrmann  2   5 , Bruce G Pollock  1   2 , Krista L Lanctôt  2   5 , Sanjeev Kumar  1   2 , Alastair J Flint  2   6 , Linda Mah  2   7 , Corinne E Fischer  2   8 , Meryl A Butters  9 , Marom Bikson  10 , James L Kennedy  1   2 , Daniel M Blumberger  1   2 , Zafiris J Daskalakis  11 , Damien Gallagher  2   5 , Mark J Rapoport  2   5 , Nicolaas P L G Paul Verhoeff  2   7 , Angela C Golas  1   2 , Ariel Graff-Guerrero  1   2 , Erica Vieira  1   2 , Aristotle N Voineskos  1   2 , Heather Brooks  1 , Ashley Melichercik  1 , Kevin E Thorpe  12 , Benoit H Mulsant  1   2   9 ; PACt-MD Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Slowing Cognitive Decline in Major Depressive Disorder and Mild Cognitive Impairment: A Randomized Clinical Trial

Tarek K Rajji et al. JAMA Psychiatry. .

Abstract

Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline.

Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both.

Design, setting, and participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years.

Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR.

Main outcomes and measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time.

Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4.

Conclusions and relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease.

Trial registration: ClinicalTrials.gov Identifier: NCT02386670.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rajji reported research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Centre for Addiction and Mental Health (CAMH) Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research (CIHR), Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute and in-kind equipment support for an investigator-initiated study from Magstim; in-kind research accounts from Scientific Brain Training Pro; and a patent for 17/396,030 pending with CAMH. Dr Bowie reported receiving consulting fees from Boehringer Ingelheim, Pfizer, and Lundbeck; funding from Lundbeck, Takeda, and Pfizer; and in-kind research support from Scientific Brain Training; and royalties from Oxford University Press. Dr Pollock reported research support from the Peter & Shelagh Godsoe Endowed Chair in Late-Life Mental Health, CAMH Foundation and Discovery Fund, National Institute of Aging, Brain Canada, CIHR, Alzheimer’s Drug Discovery Foundation, Ontario Brain Institute, Centre for Aging and Brain Health Innovation, Bright Focus Foundation, Alzheimer’s Society of Canada, W. Garfield Weston Foundation, Weston Brain Institute, and Canadian Consortium on Neurodegeneration in Aging (CCNA), and Genome Canada; honoraria from the American Geriatrics Society for book authorship; and a US provisional patent (6/490,680, 17/396,030) and Canadian provisional patent (3,054,093) for a cell-based assay and kits for assessing serum anticholinergic activity. Dr Lanctôt reported support by the Bernick Chair in Geriatric Psychopharmacology; grants from the CIHR, Alzheimer’s Association, National Institutes of Health (NIH), Alzheimer’s Drug Discovery Foundation, and Weston Brain Institute; and personal fees for serving on the advisory boards of BioXcel Therapeutics, Boehringer Ingelheim, Bright Minds, Bristol Myers Squibb, Cerevel Therapeutics, Eisai, Exciva, Ironshore Pharmaceuticals, Kondor Pharma, Lundbeck, Novo Nordisk, Otsuka, Praxis Therapeutics, and Sumitomo; and medication donation from PBG Biopharma outside the submitted work. Dr Kumar reported grants from the CIHR, Weston Brain Institute, BrightFocus Foundation, National Institute on Aging (R01AG052510-01), Brain and Behavior Foundation, Brain Canada, CCNA, CAMH, and Centre for Aging and Brain Health Innovation; receiving an Academic Scholars Award from the Department of Psychiatry, University of Toronto; nonfinancial support from Soterix Medical outside the submitted work; and participation in guideline development panels outside the submitted work. Dr Flint reported grant support from the NIH, Patient-Centered Outcomes Research Institute (PCORI), CIHR, Brain Canada, Ontario Brain Institute, Alzheimer’s Association, and AGE-WELL. Dr Mah reported nonfinancial support from Brainsway and grants from the Ministry of Health Long-term Funding AFP Innovation Funds, Alzheimer’s Society of Canada, Centre for Aging and Brain Health Innovation, Ontario Ministry of Health and Long-Term Care, and Brainsway outside the submitted work. Dr Fischer reported grants from Vielight, Novo Nordisk, NIH, Canadian Consortium on Neurodegeneration in Aging (CCNA), Hilary and Galen Weston Foundation, Brain Canada, PCORI, Hoffman LaRoche, and Mito2i outside the submitted work. Dr Bikson reported having equity in Soterix Medical; being an inventor on patents that City University of New York has on brain stimulation; and serving on the scientific advisory boards for and/or receiving grants from Boston Scientific, X, Mecta, Halo Neuroscience, and GlaxoSmithKline outside the submitted work. Dr Kennedy reported being a scientific advisory board member for Myriad Neuroscience outside the submitted work. Dr Blumberger reported research support from the CIHR, NIH, Brain Canada, and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute; research support and in-kind equipment support for an investigator-initiated study from Brainsway; serving as the site principal investigator for 3 sponsor-initiated studies for Brainsway; in-kind equipment support from Magventure for 2 investigator-initiated studies; medication supplies for an investigator-initiated trial from Indivior; nonfinancial support from Magstim; and personal fees from Sooma outside the submitted work. Dr Daskalakis reported research and equipment in-kind support for an investigator-initiated study through Brainsway and Magventure; support from the CIHR, National Institutes of Mental Health (NIMH), Brain Canada, and the Temerty Family and Grant Family and through the CAMH Foundation and the Campbell Institute. Dr Voineskos reported grants from National Institute of Mental Health, CIHR, Canada Foundation for Innovation, CAMH Foundation, University of Toronto, Brain Canada, and Wellcome Trust during the conduct of the study. Dr Mulsant reported holding and receiving support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; being a member of the CAMH Board of Trustees; research support from Brain Canada, CIHR, CAMH Foundation, PCORI, and NIH; and nonfinancial support from Capital Solution Design (software used in this study) and HappyNeuron (software used in this study). No other disclosures were reported.

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