ORLANDO – Predicting whether add-on donepezil will improve residual cognitive deficits in an elderly patient on adequate antidepressant therapy may be as plain as the nose on the patient’s face.
Compared with the olfaction-intact patient, those with baseline deficits in sense of smell on a simple scratch-and-sniff test had significantly more improvements in episodic memory after 12 weeks of donepezil (Aricept) in a placebo-controlled, double-blind randomized pilot study, Dr. Gregory H. Pelton reported at the annual meeting of the American Association for Geriatric Psychiatry.
"One’s ability to smell may be a predictor of Alzheimer’s disease pathology that will respond to acetylcholinesterase inhibitor therapy. That’s the logic here," explained Dr. Pelton, a psychiatrist at Columbia University, New York.
Dr. Gregory H. Pelton
Patients with late-life depression and cognitive impairment are known to be at even greater risk for progression to dementia than are patients with mild cognitive impairment. Donepezil is approved for improving cognition in patients with Alzheimer’s disease but not in those with mild cognitive impairment, where the evidence of benefit has been equivocal. Since the distinctive neurobiologic abnormalities of Alzheimer’s disease are known to be present for many years before the disease is diagnosed, Dr. Pelton and his coworkers reasoned that a low score on a test of olfactory identification might be a biomarker for donepezil responsiveness in these patients.
"The olfactory system is a very old evolutionary system. Since it projects directly to the entorhinal cortex, which then goes to the hippocampus, it’s actually directly involved in memory. Everybody has these flashes of old memories that arise with olfactory stimuli," Dr. Pelton said in an interview. The nose is an expressway to memory.
Deficits in olfactory identification as assessed by the commercially available, 40-item, multiple-choice, scratch-and-sniff University of Pennsylvania Smell Identification Test (UPSIT) have been shown to be associated with an increased rate of conversion from mild cognitive impairment to Alzheimer’s disease (Am. J. Psychiatry 2000;157:1399-405).
The pilot study included 18 patients with late-life depression and cognitive impairment with a Mini Mental State Exam score above 20 out of a possible 30. All participants received 8 weeks of open-label antidepressant therapy followed by 12 weeks of donepezil or placebo in the trial. The primary outcome was the change in episodic verbal memory between weeks 8 and 20 as reflected in the Selective Reminding Test immediate total recall score.
Five patients had a low baseline UPSIT score, meaning they correctly identified fewer than 30 of the 40 scratch-and-sniff items. Patients with a low UPSIT score who were assigned to donepezil showed a mean 10.4-point improvement on the Selective Reminding Test, while those with an UPSIT score of 30 or more showed a 2.7-point improvement in response to the acetylcholinesterase inhibitor.
Based upon these encouraging pilot study results, Dr. Pelton is now conducting a larger, confirmatory randomized trial funded by the National Institutes of Health.
"If the finding of olfactory deficits predicting acetylcholinesterase inhibitor response is replicated in larger samples, utilizing this simple, reliable, and inexpensive approach may improve the selection of patients with late-life depression and cognitive impairment, and possibly also those with mild cognitive impairment or Alzheimer’s disease, who are likely to respond to acetylcholinesterase inhibitor therapy," he noted.
The study was funded by the Alzheimer’s Association, federal research grants, and Pfizer. Dr. Pelton is a consultant to the company.