Abstract
BackgroundThe objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer's disease (AD).Methodology/Principal FindingsThis double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinician's Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8±7.6), than in the placebo group (9.3±10.0). This difference (1.5 points; CI −4.5–7.5) was not statistically significant, and neither were any of the secondary outcome measures.Conclusions/SignificanceThe results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD.Trial RegistrationClinicalTrials.gov NCT00432081
Highlights
IntroductionIndications that inflammation plays an important role in the pathogenesis of Alzheimer’s disease (AD) emerged in 1982, when complement factors were found in senile plaques. [1] Many studies followed that supported the inflammatory hypothesis, and evidence accumulated that anti-inflammatory drugs, in particular nonsteroidal anti-inflammatory drugs (NSAIDs) would either prevent, postpone or treat AD. [2] 25 years later, there is still no clinical evidence that nonsteroidal antiinflammatory drug (NSAID) have an effect in AD patients, nor is there incontrovertible evidence of the contrary.In a small randomized controlled trial, the traditional NSAID indomethacin appeared to protect AD patients from cognitive decline. [3] Another small randomized controlled trial studying the effect of diclofenac/misoprostol in AD, found a nonsignificant trend of more advanced deterioration in the placebo group than in the diclofenac/misoprostol group. [4] A large randomized controlled trial with naproxen (440 mg/d) could not confirm the earlier observed trends. [5] Both pilot studies were hampered by high withdrawal rates in the treatment groups due to side effects
[1] Many studies followed that supported the inflammatory hypothesis, and evidence accumulated that anti-inflammatory drugs, in particular nonsteroidal anti-inflammatory drugs (NSAIDs) would either prevent, postpone or treat Alzheimer’s disease (AD)
It was suggested that the beneficial actions of NSAIDs are linked to their ability to inhibit cyclooxygenase-2 (COX-2), while their side effects result from inhibition of COX-1
Summary
Indications that inflammation plays an important role in the pathogenesis of Alzheimer’s disease (AD) emerged in 1982, when complement factors were found in senile plaques. [1] Many studies followed that supported the inflammatory hypothesis, and evidence accumulated that anti-inflammatory drugs, in particular nonsteroidal anti-inflammatory drugs (NSAIDs) would either prevent, postpone or treat AD. [2] 25 years later, there is still no clinical evidence that NSAIDs have an effect in AD patients, nor is there incontrovertible evidence of the contrary.In a small randomized controlled trial, the traditional NSAID indomethacin appeared to protect AD patients from cognitive decline. [3] Another small randomized controlled trial studying the effect of diclofenac/misoprostol in AD, found a nonsignificant trend of more advanced deterioration in the placebo group than in the diclofenac/misoprostol group. [4] A large randomized controlled trial with naproxen (440 mg/d) could not confirm the earlier observed trends. [5] Both pilot studies were hampered by high withdrawal rates in the treatment groups due to side effects. In a small randomized controlled trial, the traditional NSAID indomethacin appeared to protect AD patients from cognitive decline. [3] Another small randomized controlled trial studying the effect of diclofenac/misoprostol in AD, found a nonsignificant trend of more advanced deterioration in the placebo group than in the diclofenac/misoprostol group. The objective of this study was to determine whether treatment with the nonselective nonsteroidal antiinflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer’s disease (AD). This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. The deterioration on the ADAS-cog was less in the indomethacin group (7.867.6), than in the placebo group (9.3610.0) This difference (1.5 points; CI 24.5–7.5) was not statistically significant, and neither were any of the secondary outcome measures.
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