Extended-release physostigmine in Alzheimer disease: a multicenter, double-blind, 12-week study with dose enrichment. Physostigmine Study Group.
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 (F1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F1,150 = 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.
van Dyck
C H
CH
Department of Psychiatry, Yale University School of Medicine, New Haven, Conn 06520, USA. christopher.vandyck@yale.edu
Newhouse
P
P
Falk
W E
WE
Mattes
J A
JA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000523:psychology; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009483:Neuropsychological Tests; D010830:Physostigmine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D002800:Cholinesterase Inhibitors; D003692:Delayed-Action Preparations; D010919:Placebos; D010830:Physostigmine