American Academy of Neurology

BrainDonepezil Therapy in Alzheimer’s Disease

Speaker: Jeffrey Cummings, MD, Professor of Neurology, Department of Neurology, University of California, Los Angeles, School of Medicine, Los Angeles, California.

Therapy with donepezil (Pfizer) has been found to significantly improve behavioral symptoms in patients with mild-to-moderate Alzheimer’s disease (AD). A 20-week study was designed primarily to compare the efficacy and safety of the antidepressant sertraline (Zoloft®, Pfizer) with placebo in patients already receiving donepezil therapy. The patients were not depressed but were exhibiting substantial behavioral symptoms, with Neuropsychiatric Inventory (NPI) total scores above 5 at screening and NPI severity scores in at least two domains.

The patients received open-label donepezil 5 mg daily for four weeks, followed by four weeks daily in an open-label fashion. At the eighth week, patients receiving donepezil were randomly assigned to receive placebo or sertraline 25 to 200 mg/day, in addition to the open-label donepezil 10 mg/day.

The primary efficacy variables were:

  • 10-item and 12-item NPI scores.
  • Clinician’s Global Impression Scale for Improvement (CGI-I) and Severity (CGI-S) subscales.

The secondary efficacy measures included:

  • behavioral symptoms, as assessed by the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BE-HAVE-AD) and the Cohen-Mansfield Agitation Inventory-Community (CMAI-C).
  • cognition, as assessed by the Alzheimer’s Disease Assessment Scale-Cognition subscale (ADAS-Cog) and the Mini-Mental State Examination (MMSE).

The randomized placebo cohort included 121 patients who received donepezil monotherapy only during the 20-week study period. After 20 weeks of monotherapy, statistically significant improvements from baseline were observed in the NPI-12 scores, (of -8.2 and a relative change of 27.6%) and in NPI-10 scores (of -7.2 and a relative change of 28.7%). Statistically significant differences in both the CGI-S and CGI-I measures were observed from baseline to the end of the 20 weeks. discount drugs canda

The BEHAVE-AD scores, as well as two items on the CMAI-C, also improved significantly. Cognition, as measured by the MMSE and ADAS-Cog, was maintained at or above baseline values at the end of the study.

Overall, donepezil was well tolerated. Adverse drug events (ADEs) led to discontinuation in 10.8% of patients receiving donepezil monotherapy. The most common side effects involved the digestive and nervous systems.

Memantine Monotherapy in Mild-to-Moderate Alzheimer’s Disease

Speaker: Steven G. Potkin, MD, Professor of Psychiatry and Human Behavior, and Director of the Brain Imaging Center, University of California at Irvine, Irvine, California.

Memantine (Namenda™, Forest) monotherapy has been shown to be effective and safe for the treatment of mild-to-moderate AD and superior in efficacy to placebo on measures of cognition, global status, and behavior.
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A total of 403 patients were enrolled into a randomized, double-blind, parallel-arm, placebo-controlled phase III clinical trial at 42 U.S. centers. These patients, all of whom had mild-to-moderate AD, were randomly assigned to receive memantine 10 mg twice daily or placebo for six months. The two primary outcome measures were the ADAS-Cog and the Clinician’s Interview-Based Impression of Change-Plus version (CIBIC-Plus). Secondary outcomes included:

  • daily functioning, as assessed by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), with 23 items.
  • behavior, as assessed by the 12-item NPI.
  • safety, as measured by the incidence of ADEs and changes in laboratory parameters, electrocardiograms, and vital signs.

Overall, 394 patients were included in the intent-to-treat (ITT) population. As assessed by the ADAS-Cog, patients receiving memantine monotherapy maintained their cognitive abilities above baseline values for the entire 24 weeks of the study. In contrast, patients receiving placebo exhibited a progressive decline during the study, and the difference between the two treatment groups was statistically significant.

Patients who took memantine had significantly better global status than did those taking placebo, as measured by the CIBIC-Plus.

A pilot study of positron emission tomography (PET) to evaluate memantine’s action on brain metabolism in a subset of 10 patients from the phase III trial demonstrated a statistically significant increase in glucose metabolism in several regions of the brain associated with language and attention in these patients. In contrast, the placebo patients showed metabolic declines in these same regions.

With regard to safety, the incidence of treatment-related ADEs was similar in the memantine and placebo patients. Somnolence was reported in more than 25% of patients taking memantine than in those taking placebo. By the same criteria, more than 25% of patients in the placebo group reported upper respiratory infection and depression.

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