The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease

Alzheimer Dis Assoc Disord. 1997;11 Suppl 4:S16-22.


The therapeutic effects of selective cholinergic replacement using oral xanomeline, an m1/m4 receptor agonist, were assessed in a multicenter study of 343 patients with Alzheimer disease (AD). Patients were randomized to parallel treatment arms (placebo, 25, 50, and 75 mg t.i.d. xanomeline) and followed through 6 months of double-blind therapy and 1 month of single-blind placebo washout. Completer analysis, using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), revealed a significant treatment effect (75 mg t.i.d. vs. placebo; p = 0.045). Similar assessment of global status, using the Clinician's Interview-Based Impression of Change, was also significant (75 mg t.i.d. vs. placebo; p = 0.022). Treatment Emergent Signs and Symptoms analysis of the Alzheimer's Disease Symptomatology Scale, revealed highly significant (p < or = 0.002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, the Nurses' Observational Scale for Geriatric Patients also showed a significant dose-response relationship (p = 0.018). The improvement in ADAS-Cog provides the first clinical evidence of involvement of the m1 muscarinic receptor in cognition. Furthermore, the favorable effects of xanomeline on disturbing behaviors suggest a novel approach for treatment of the noncognitive symptoms of AD. Although adverse effects (mainly gastrointestinal) associated with the oral formulation appear to limit its use, a large-scale study investigating the safety and efficacy of transdermal xanomeline is under way.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / psychology
  • Behavioral Symptoms / diagnosis
  • Behavioral Symptoms / drug therapy
  • Behavioral Symptoms / psychology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Muscarinic Agonists / adverse effects
  • Muscarinic Agonists / therapeutic use*
  • Neurobehavioral Manifestations / drug effects*
  • Neuropsychological Tests / statistics & numerical data
  • Psychometrics
  • Psychotropic Drugs / adverse effects
  • Psychotropic Drugs / therapeutic use*
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Thiadiazoles / adverse effects
  • Thiadiazoles / therapeutic use*
  • Treatment Outcome


  • Muscarinic Agonists
  • Psychotropic Drugs
  • Pyridines
  • Thiadiazoles
  • xanomeline