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For up to 6 years, cognitive remediation and transcranial direct current stimulation slowed cognitive decline associated with major depressive disorder in remission and mild cognitive impairment.
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Findings from the PACt-MD study (NCT02386670) published in JAMA Psychiatry demonstrate that a combination therapy consisting of cognitive remediation (CR) techniques and transcranial direct current stimulation (tDCS) can slow cognitive decline in older adults who are at a risk of dementia. Specifically, the research focuses on preventing cognitive decline in older adults who have major depressive disorder in remission (rMDD), mild cognitive impairment (MCI), or both, which are conditions that increase an individual’s risk of dementia.1
In the PACt-MD study, investigators enrolled and randomly assigned 375 older adults 65 or older with rMDD (with or without MCI) or MCI without rMDD to receive either CR and tDCS or the placebo. CR consisted of 2-hour sessions daily in a group supervised by trained interventionists and included CR exercises online relevant to attention, processing speed, and executive function, as well as verbal and working memory with titrated difficulty levels. At the beginning of each group session, patients also received tDCS (anode over Fz & cathode over Iz; direct current: 2 mA [current density = 0.57A/m2] for 30 min).1-3
Trial Name: Prevention of Alzheimer's Disease With CR Plus tDCS in Mild Cognitive Impairment and Depression (PACt-MD) (PACt-MD)
ClinicalTrials.gov ID: NCT02386670
Sponsor: Centre for Addiction and Mental Health
Completion Date (Estimated): December 31, 2024
Intervention sessions were administered 5 days per week for 8 weeks (induction phase), then for 5 days once every 6 months (consolidation phase). Additionally, assessments were made at baseline, 2 months, and yearly from baseline for 3 to 7 years. The study’s primary outcome was change in global composite cognitive score, and secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at the 2-month period, and progression to MCI or dementia over time.2,3
"Investing in long-term, comprehensive research like this is not only a commitment to science, but to the millions of individuals, families, and caregivers affected by dementia,” Mark Holland, the hinister of Health in Canada, said in a news release. “This research contributes to advancing dementia care in Canada and improving quality of life for people living with dementia and caregivers.”1
According to the findings, CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (month 60: 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006) over a median follow-up of 48.3 months (range: 2.1-85.9). In the preplanned primary analysis, CR and tDCS were shown not to improve cognition acutely (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 the authors did not consider it to be significant (HR, 0.66; 95% CI, 0.40 to 1.08; P = .10). Further, preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) as well as interactions with diagnosis (P = .01) and APOE ε4 (P < .001). This demonstrates a larger effect among patients with rMDD and who were not carriers of APOE ε4.3
“While there are several presumed mechanisms underlying the increased risk for dementia in older adults with depression, impaired brain plasticity, or the ability of the brain to compensate for damage, is thought to be one common pathway,” Benoit Mulsant, MD, senior scientist at Centre for Addiction and Mental Health and chair for the department of psychiatry at the Temerty Faculty of Medicine at University of Toronto, said in the news release. “In this study we targeted the prefrontal cortex for treatment because this is believed to be an area of the brain that is highly adaptable to change and critical to executive functioning.”1
Limitations of the study lack of diversity—in terms of ethnicity, race, and education—among the enrolled population and some outcome data may not be missing at random (eg as time passes and their cognition declines, participants are more likely not to complete harder cognitive tests). The authors noted that methods were used in an attempt to mitigate this issue, but the impact of these missing data on the outcomes in both the active intervention and placebo groups are uncertain.3
The authors explained that because cognitive decline is usually the result of multiple overlapping conditions, making combination therapies to treat the decline is important. These combined therapies have the potential to improve patient outcomes while also targeting different disease pathways in a synergistic way.1,3
“We are very pleased to show, after 7 years of close monitoring, that this combination of therapies is effective in slowing down cognitive decline for some of our most vulnerable populations," Tarek Rajji, MD, chair of the department of psychiatry at the University of Texas Southwestern Medical Center, said in the news release. "This study shows promise that multi-prong, non-pharmacological approaches for people with a high risk of developing dementia could help them live a more independent life for a longer time.”1
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