Celecoxib or Naproxen Treatment Does Not Benefit Depressive Symptoms in Persons Age 70 and Older: Findings From a Randomized Controlled Trial

Abstract

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.

A review of the relationship between proinflammatory cytokines and major depressive disorder

“…These studies suggest an adjuvant role for NSAIDs in TRD treatment. In contrast, a large scale randomized controlled trial designed to evaluate NSAID treatment (celecoxib & naproxen) in approximately 2,500 elderly adults with late-life depression found no significant effect in reducing modified Geriatric Depression Scale (GDS) scores compared to placebo (Fields et al, 2012), suggesting that antiinflammatory monotherapy may be insufficient to produce significant antidepressant effects.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…The number of studies of COX-2 inhibitors in depression is relatively small (n = 5, excluding acetylsalicylic acid), despite the fact that no less than 3 meta-analyses of these studies have appeared in the literature (threatening to outnumber the number of primary studies themselves; Faridhosseini et al, 2014;Kohler et al, 2014;Na et al, 2014). The largest of these studies was a randomized, placebo-controlled preventative trial that included over 4000 patients and showed no advantage of the COX-2 inhibitor celecoxib over placebo in preventing the development of depression in an elderly cohort of subjects (Fields et al, 2012). Of the 4 remaining trials, all were small (~n = 20 per group) and all used celecoxib versus placebo as an add-on to a conventional antidepressant in patients with major depression.…”

Targeting the Inflammatory Pathway as a Therapeutic Tool for Major Depression

“…Another RCT tested celecoxib as an add-on to fluoxetine, showing the superiority of the association [68]. Celecoxib has also shown promising results as an adjuvant in the treatment of bipolar depression and schizophrenia [69,70,71], but has negative results in improving depressive symptomatology in cognitively normal volunteers aged 70 years and older with a family history of Alzheimer-like dementia [72]. …”