THE SELECTIVE MUSCARINIC AGONIST XANOMELINE IMPROVES BOTH THE COGNITIVE DEFICITS AND BEHAVIORAL SYMPTOMS OF ALZHEIMER-DISEASE

The therapeutic effects of selective cholinergic replacement using ora l xanomeline, an m1/m4 receptor agonist, were assessed in a multicente r study of 343 patients with Alzheimer disease (AD). Patients were ran domized 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. placeb o; p = 0.045). Similar assessment of global status, using the Clinicia n'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 hig hly significant (p less than or equal to 0.002) dose-dependent reducti ons in vocal outbursts, suspiciousness, delusions, agitation, and hall ucinations. On end-point analysis, the Nurses' Observational Scale for Geriatric Patients also showed a significant dose-response relationsh ip (p = 0.018). The improvement in ADAS-Cog provides the first clinica l evidence of involvement of the mi muscarinic receptor in cognition. Furthermore, the favorable effects of xanomeline on disturbing behavio rs 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 un der way.