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A Multicenter, Double-blind, 12-Week Study With Dose Enrichment

Christopher H. van Dyck, MD; Paul Newhouse, MD; William E. Falk, MD; Jeffrey A. Mattes, MD; for the Physostigmine Study Group

Arch Gen Psychiatry. 2000;57:157-164.

Background  The efficacy of extended-release physostigmine salicylate, an acetylcholinesterase inhibitor, was evaluated in 850 subjects with mild-to-moderate Alzheimer disease (AD) in a multicenter trial.

Methods  Subjects initially entered a dose-enrichment phase in which they received 1 week each of physostigmine salicylate, 24 mg/d and 30 mg/d, and daily placebo. Among the subjects who completed this phase, 35.9% responded to physostigmine treatment, whereas 62.4% were considered nonresponders, and 1.6% could not be evaluated because of missing data. After a 4-week placebo-washout phase, 176 responder subjects were randomized to receive their best dose of physostigmine or placebo in a 12-week double-blind phase. Primary efficacy measures included the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC+), and the Clinical Global Impression of Change (CGIC).

Results  In the intent-to-treat analysis of the double-blind phase, physostigmine-treated subjects scored -2.02 points better than placebo-treated subjects on the ADAS-Cog (F_1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F_1,150 = 5.68 [P = .02]). No significant improvement was observed on the CGIC or the secondary outcome measures. Nausea and vomiting were experienced by 47.0% of all physostigmine-treated subjects during the double-blind phase.

Conclusions  Physostigmine demonstrated a statistically significant benefit compared with placebo on a clinical global rating of change and an objective test of cognitive function. Given the frequency of gastrointestinal side effects, the role of this agent in clinical use remains to be determined.

From the Departments of Psychiatry, Yale University School of Medicine, New Haven, Conn (Dr van Dyck), University of Vermont College of Medicine, Burlington (Dr Newhouse), and Massachusetts General Hospital, Boston (Dr Falk); and the Psychopharmacology Research Association of Princeton, Princeton, NJ (Dr Mattes).

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