A British trial appears to have taken some wind out of donepezil’s sails. Results from CALM-AD, aka Trial of Cholinesterase Inhibitor and Atypical Neuroleptic in the Management of Agitation in Alzheimer’s Disease, indicate that the acetylcholinesterase inhibitor is no better than placebo at treating neuropsychiatric symptoms associated with the disease. Published in the October 4 New England Journal of Medicine, the data may come as no surprise to some, since several recent studies also found no effect of donepezil on behavior (see ARF related news story).

Nevertheless, the result is disappointing. While memory and cognitive deficits typify Alzheimer’s, it is often the behavioral symptoms that place the heaviest burden on both patient and caregiver. As chief investigator Robert Howard, King’s College London, writes on behalf of the CALM-AD study group, agitation, hallucinations, and delusions often precipitate the transition to residential care; therefore any relief existing drugs can provide would be important to clinical practice.

Currently, there are no FDA-approved drugs for treating agitation in AD. Off-label use of drugs, most notably antipsychotics, is commonplace, despite indications that they, too, have limited benefit (see ARF related news story). In fact, the original intent of CALM-AD was to compare donepezil and the atypical antipsychotic risperidone, but the trial was temporarily halted in 2004 when the United Kingdom Committee for Safety of Medicine recommended that risperidone not be used for the treatment of behavioral symptoms related to dementia.

One option for treating agitation in AD patients is non-pharmacological intervention, such as psychosocial treatment. The CALM-AD trial was revamped to investigate if donepezil is suitable for treating agitation that does not respond to such intervention. This could be one reason why the drug had little effect. “Although this trial design makes good sense and reflects appropriate clinical practice, it may have led to the selection of patients most resistant to any type of treatment or those with the most severe symptoms,” writes Kristine Yaffe, University of California, San Francisco, in an accompanying editorial.

CALM-AD recruited 272 AD patients from eight clinical centers in the UK. Patients with clinically significant agitation who had not responded to a 4-week psychosocial program were randomly assigned to placebo (n = 131) or donepezil (n = 128) for 12 weeks. The primary outcome measured was change in the Cohen-Mansfield Agitation Inventory (CMAI), a scale from 29 to 203, where higher scores indicate more agitation. “We chose agitation measured by the CMAI as the primary outcome because we believe this measure captures those behaviors that are most likely to lead to requests for drug treatment,” write the authors. Response to treatment was defined as a reduction of 30 percent or more.

Howard and colleagues found that placebo and donepezil groups had no significant difference in CMAI reduction. The number of people who showed improvement was the same, 22 patients, in both the treatment and the control group. The average reduction in CMAI score was 4.99 points (+/- 18.98) for the placebo group and 6.34 (+/- 20.35) for the donepezil group. There was no difference in secondary outcomes, including the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician’s Global Impression of Change.

One might step back and ask why a cholinesterase inhibitor would improve behavior. “The reason you should think it does is because that has been predominantly Pfizer’s advertising since the late 1990s,” suggested Lon Schneider, University of Southern California, Los Angeles, in an interview with ARF. (Pfizer and Eisai jointly market donepezil. Several investigators of the CALM-AD Trial Group, including Howard, disclose receiving either speaking fees or other honoraria from the companies, as is common in drug testing these days. The CALM-AD trial itself was funded by the MRC and the Alzheimer’s Society.) Schneider believes that much of the optimism surrounding the use of cholinesterase inhibitors for behavior is based on improvements in the Neuropsychiatric Inventory Scale in earlier studies. “But those patients were mildly to moderately impaired and did not have behavioral problems,” he said, adding that he considers studies on patients with severe AD more relevant, for example Black et al., 2007; Winblad et al., 2006; Homma et al. (data not yet published). “Those studies showed that there was no effect on behavior or activities of daily living in these patients,” said Schneider, noting that the CALM-AD trial should make physicians think twice before using cholinesterase inhibitors to treat behavior in AD patients.

But at the same time, most studies of cholinesterase inhibitors report significant improvement in cognition. “You see that fantastically consistently, just as consistently as you see a lack of improvement in behavior and a lack of improvement in activities of daily living in severely affected patients,” said Schneider. “This is an interesting pharmacological dissection. Cholinesterase inhibitors do reliably improve at least attention and arousal and the cognitive components thereof, but on the other hand they don’t do anything for behavior and in severe patients do nothing for activities of daily living.”

So what can the physician do for a person with severe AD and behavioral problems? “The research field and, most important, clinicians and patients are hamstrung by the recent medication trial results,” writes Yaffe. She suggests that patients first be assessed for medical (e.g., pain, delirium) and environmental (e.g., loud noise) causes of the behavior, then receive non-pharmacological interventions as a first step. What is really needed, she suggests, are well-designed, randomized, controlled trials for psychosocial interventions in patients with dementia and neuropsychiatric symptoms.—Tom Fagan


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News Citations

  1. Donepezil—Trial Data Show Some Benefit for Patients with Severe AD
  2. Rethinking Antipsychotics for Alzheimer Patients—Again
  3. Donepezil—Relief for Patients with Severe AD?

Further Reading

Primary Papers

  1. . Donepezil for the treatment of agitation in Alzheimer's disease. N Engl J Med. 2007 Oct 4;357(14):1382-92. PubMed.
  2. . Treatment of neuropsychiatric symptoms in patients with dementia. N Engl J Med. 2007 Oct 4;357(14):1441-3. PubMed.