Slowing Cognitive Decline in Major Depressive Disorder and Mild Cognitive Impairment A Randomized Clinical Trial
JAMA Psychiatry . 2024 Oct 30:e243241. doi: 10.1001/jamapsychiatry.2024.3241.
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
Affiliations
1 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
2 Department of Psychiatry and Toronto Dementia Research Alliance, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
3 University of Texas Southwestern Medical Center, Dallas.
4 Department of Psychology, Queen's University, Kingston, Ontario, Canada.
5 Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
6 University Health Network, Toronto, Ontario, Canada.
7 Baycrest Health Sciences, Toronto, Ontario, Canada.
8 Keenan Research for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.
9 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
10 Department of Biomedical Engineering, The City College of New York, New York.
11 Department of Psychiatry, University of California, San Diego, La Jolla.
12 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
JAMA Psychiatry. Published online October 30, 2024. doi:10.1001/jamapsychiatry.2024.3241
Key Points
Question Does cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) slow cognitive decline in older adults with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI)?
Findings In this randomized clinical trial including 375 participants with rMDD or MCI, those randomized to receive active CR plus active tDCS experienced a slower cognitive decline over a median follow-up of 4 years than those randomized to receive sham-plus-sham treatments. The effects were more prominent in the rMDD (with or without MCI) than in the MCI without rMDD group.
Meaning The treatment of CR plus tDCS is effective in slowing cognitive decline in older adults with rMDD.
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
