Slowing Cognitive Decline in Major Depressive Disorder and Mild Cognitive Impairment
Authors: Rajji Tarek K. , Bowie Christopher R. , Herrmann Nathan , Pollock Bruce G. , Lanctôt Krista L. , Kumar Sanjeev , Flint Alastair J. , Mah Linda , Fischer Corinne E. , Butters Meryl A. , Bikson Marom , Kennedy James L. , Blumberger Daniel M. , Daskalakis Zafiris J. , Gallagher Damien , Rapoport Mark J. , Verhoeff Nicolaas P. L. G. Paul , Golas Angela C. , Graff-Guerrero Ariel , Vieira Erica , Voineskos Aristotle N. , Brooks Heather , Melichercik Ashley , Thorpe Kevin E. , Mulsant Benoit H. ,   PACt-MD Study Group, Mulsant Benoit H. , Rajji Tarek K. , Herrmann Nathan , Pollock Bruce G. , Blumberger Daniel , Bowie Christopher , Butters Meryl , Fischer Corinne , Flint Alastair , Golas Angela , Graff Ariel , Kennedy James L. , Kumar Sanjeev , Lanctot Krista , Lourenco Lillian , Mah Linda , Ovaysikia Shima , Rapoport Mark , Thorpe Kevin , Verhoeff Nicolaas P.L.G. , Voineskos Aristotle , Bingham Kathleen , Chiuccariello Lina , Chow Tiffany , Dham Pallavi , Diniz Breno , Miranda Dielle , Tartaglia Carmela 
Published: October 2024

ImportanceOlder adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline.ObjectiveTo 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 ParticipantsThis 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.InterventionsCR 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 MeasuresThe 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.ResultsOf 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 &amp;lt; .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4.Conclusions and RelevanceThe 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 RegistrationClinicalTrials.gov Identifier: NCT02386670