SUMMARY Background Depression is common in Alzheimer’s disease [AD], and antidepressants are commonly used for its treatment, yet evidence for antidepressant efficacy in this population is lacking. We conducted a multi-center, randomized, placebo-controlled trial titled “Depression in Alzheimer’s Disease-2” (DIADS-2) to assess the efficacy and tolerability of sertraline for depression in AD. Methods One hundred thiry-one participants from 5 U.S. medical centers with mild-to-moderate AD (Mini-Mental State Examination [MMSE] scores 10–26) and depression of AD were randomized to double-blinded treatment with sertraline (N=67) or placebo (N=64), with a target dosage of 100 mg daily. Efficacy was assessed using logistic regressions and mixed effects models in an intention to treat (ITT) analysis with imputation of missing data. Principal outcome measures were modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), change in Cornell Scale for Depression in Dementia (CSDD) scores, and remission defined by both mADCS-CGIC score ≤2 and CSDD score ≤ 6. Findings mADCS-CGIC ratings (OR = 1.01 (95% CI: 0.52, 1.97, p=0.98), CSDD scores (median difference at 12 weeks 1.2,[95% CI -1.65, 4.05], p=0.41), and remission at 12 weeks of followup (OR = 2.06, [95% CI - 0.84, 5.04], p=0.11) did not differ between sertraline (N=67) and placebo (N=64). Sertraline-treated patients experienced more adverse events, most notably gastrointestinal and respiratory, than placebo-treated patients. Interpretation Sertraline did not demonstrate efficacy for the treatment depression symptoms in patients with Alzheimer's disease. In addition, its use was associated with an increased incidence of adverse events. Thus, selective serotonin reuptake inhibitors may be of limited value for treating depression in AD patients

Objective In a recent crossover trial, methylphenidate treatment decreased apathy in Alzheimer's disease. We further assessed this finding in the Alzheimer's Disease Methylphenidate Trial (ADMET). Method Six-week, randomized, double-blind, placebo-controlled multicenter trial enrolling Alzheimer's disease participants (NINCDS-ADRDA criteria) with apathy assigned to methylphenidate 20 mg daily or placebo, conducted from June 2010 to December 2011. Primary outcomes were change in Apathy Evaluation Scale (AES) score and modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGI-C). Secondary outcomes included change in Neuropsychiatric Inventory (NPI) apathy score, Mini-Mental State Examination (MMSE) score, and safety. Results 60 participants were randomly assigned (29 methylphenidate, 31 placebo). At baseline, mean (SD) age = 76 (8) years, MMSE score = 20 (5), AES score = 51 (12), NPI total score = 16 (8), and 62% of the participants (n = 37) were female. After 6 weeks' treatment, mean (SD) change in AES score was −1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (P = .23). Odds ratio for improvement in ADCS-CGI-C was 3.7 (95% CI, 1.3 to 10.8) (P = .02), with 21% of methylphenidate versus 3% of placebo rated as moderately or markedly improved. NPI apathy score improvement was 1.8 points (95% CI, 0.3 to 3.4) greater on methylphenidate than on placebo (P = .02). MMSE trended toward improvement on methylphenidate (P = .06). There were trends toward greater anxiety and weight loss > 2% in the methylphenidate-treated group. Conclusions Methylphenidate treatment of apathy in Alzheimer's disease was associated with significant improvement in 2 of 3 efficacy outcomes and a trend toward improved global cognition with minimal adverse events, supporting the safety and efficacy of methylphenidate treatment for apathy in Alzheimer's disease.

Background Depression and antidepressant use are common in Alzheimer’s disease (AD), but the effect of antidepressant treatment for depression on longer-term outcomes is unknown. We report the week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD. Methods 131 participants (sertraline=67, placebo=64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer’s Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, non-mood neuropsychiatric symptoms, global cognition, function, and quality of life. Results 117 (89.3%) participants completed all study assessments and 74 (56.5%; sertraline=38, placebo=36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline=44.8%, placebo=35.9%; odds ratio [95% CI]=1.23 [0.64, 2.35]), change in CSDD score (median difference=0.6 [95% CI −2.26, 3.46], χ2 [df=2]=1.03), remission rates (sertraline=32.8%, placebo=21.8%; odds ratio [95% CI]=1.61 [0.70, 3.68]), or secondary outcomes. Common SSRI-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events (SAEs) were more frequent in sertraline-randomized patients than in placebo subjects. Conclusions Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.

Background Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. Objective To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. Methods The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers aged 70 and over with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200mg BID, naproxen sodium 220mg BID, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score >5 at baseline were classified as depressed. Results Of 2,528 participants enrolled 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using Generalized Estimating Equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. Conclusions Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late life depression, these results do not support the hypothesis that inhibition of the cyclooxygenase pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults.