Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease

N. C. Bodick, W. W. Offen, A. I. Levey, N. R. Cutler, S. G. Gauthier, A. Satlin, H. E. Shannon, G. D. Tollefson, K. Rasmussen, F. P. Bymaster, D. J. Hurley, W. Z. Potter and S. M. Paul
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Ind, USA.

OBJECTIVE: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). DESIGN: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout. SETTING: Outpatients at 17 centers in the United States and Canada. PARTICIPANTS: A total of 343 men and women at least 60 years of age with mild to moderate AD. INTERVENTIONS: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. OUTCOME MEASURES: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). RESULTS: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P < or = .02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. CONCLUSIONS: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

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References
APPI Online CME 2007;2007:2-2.
FULL TEXT  

AMPA potentiator treatment of cognitive deficits in Alzheimer disease
Chappell et al.
Neurology 2007;68:1008-1012.
ABSTRACT | FULL TEXT  

Sympathetic sprouting drives hippocampal cholinergic reinnervation that prevents loss of a muscarinic receptor-dependent long-term depression at CA3-CA1 synapses.
Scheiderer et al.
J. Neurosci. 2006;26:3745-3756.
ABSTRACT | FULL TEXT  

Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M5 Receptor
Grant and El-Fakahany
J. Pharmacol. Exp. Ther. 2005;315:313-319.
ABSTRACT | FULL TEXT  

Pharmacologic Interactions between the Muscarinic Cholinergic and Dopaminergic Systems in the Modulation of Prepulse Inhibition in Rats
Jones et al.
J. Pharmacol. Exp. Ther. 2005;312:1055-1063.
ABSTRACT | FULL TEXT  

Cholinergic systems in progressive supranuclear palsy
Warren et al.
Brain 2005;128:239-249.
ABSTRACT | FULL TEXT  

N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity
Sur et al.
Proc. Natl. Acad. Sci. USA 2003;100:13674-13679.
ABSTRACT | FULL TEXT  

Recent Advances in the Neurobiology of Schizophrenia
Miyamoto et al.
Mol. Interv. 2003;3:27-39.
ABSTRACT | FULL TEXT  

Rab11a and Myosin Vb Regulate Recycling of the M4 Muscarinic Acetylcholine Receptor
Volpicelli et al.
J. Neurosci. 2002;22:9776-9784.
ABSTRACT | FULL TEXT  

Muscarinic Agonist-Mediated Increases in Serum Corticosterone Levels Are Abolished in M2 Muscarinic Acetylcholine Receptor Knockout Mice
Hemrick-Luecke et al.
J. Pharmacol. Exp. Ther. 2002;303:99-103.
ABSTRACT | FULL TEXT  

Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Suh and Checler
Pharmacol. Rev. 2002;54:469-525.
ABSTRACT | FULL TEXT  

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M1 Muscarinic Acetylcholine Receptor
Jakubik et al.
J. Pharmacol. Exp. Ther. 2002;301:1033-1041.
ABSTRACT | FULL TEXT  

Discovery of an Ectopic Activation Site on the M1 Muscarinic Receptor
Spalding et al.
Mol. Pharmacol. 2002;61:1297-1302.
ABSTRACT | FULL TEXT  

The Muscarinic Receptor Agonist Xanomeline Has an Antipsychotic-Like Profile in the Rat
Stanhope et al.
J. Pharmacol. Exp. Ther. 2001;299:782-792.
ABSTRACT | FULL TEXT  

Synthesis and Pharmacological Evaluation of Dimeric Muscarinic Acetylcholine Receptor Agonists
Christopoulos et al.
J. Pharmacol. Exp. Ther. 2001;298:1260-1268.
ABSTRACT | FULL TEXT  

Efficacy of Metrifonate in Improving the Psychiatric and Behavioral Disturbances of Patients with Alzheimer's Disease
Cummings et al.
J Geriatr Psychiatry Neurol 2001;14:101-108.
ABSTRACT  

Practice parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology
Doody et al.
Neurology 2001;56:1154-1166.
ABSTRACT | FULL TEXT  

Low-Affinity M2 Receptor Binding State Mediates Mouse Atrial Bradycardia: Comparative Effects of Carbamylcholine and the M1 Receptor Agonists Sabcomeline and Xanomeline
Stengel and Cohen
J. Pharmacol. Exp. Ther. 2001;296:818-824.
ABSTRACT | FULL TEXT  

Cholinergic deficits contribute to behavioral disturbance in patients with dementia
Minger et al.
Neurology 2000;55:1460-1467.
ABSTRACT | FULL TEXT  

Multiple Central Nervous System Targets for Eliciting Beneficial Effects on Memory and Cognition
Buccafusco and Terry
J. Pharmacol. Exp. Ther. 2000;295:438-446.
ABSTRACT | FULL TEXT  

Muscarinic Cholinergic Modulation of Prepulse Inhibition of the Acoustic Startle Reflex
Jones and Shannon
J. Pharmacol. Exp. Ther. 2000;294:1017-1023.
ABSTRACT | FULL TEXT  

Effects of chewing betel nut (Areca catechu) on the symptoms of people with schizophrenia in Palau, Micronesia
SULLIVAN et al.
Br. J. Psychiatry 2000;177:174-178.
ABSTRACT | FULL TEXT  

Molecular biology of Alzheimer's disease
Holmes and Wilkinson
Adv. Psychiatr. Treat. 2000;6:193-200.
FULL TEXT  

The Preclinical Pharmacological Profile of WAY-132983, a Potent M1 Preferring Agonist
Bartolomeo et al.
J. Pharmacol. Exp. Ther. 2000;292:584-596.
ABSTRACT | FULL TEXT  

Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer's disease
Thal et al.
Neurology 2000;54:421-421.
ABSTRACT | FULL TEXT  

Treatment of Alzheimer's Disease
Mayeux and Sano
NEJM 1999;341:1670-1679.
FULL TEXT  

The cholinergic hypothesis of Alzheimer's disease: a review of progress
BABIC; et al.
J. Neurol. Neurosurg. Psychiatry 1999;67:558-558.
FULL TEXT  

Alzheimer's Disease and Its Management in the Year 2010
Cummings and Jeste
Psychiatr. Serv. 1999;50:1173-1177.
ABSTRACT | FULL TEXT  

Brain Choline Acetyltransferase and Mental Function in Alzheimer Disease
Baskin et al.
Arch Neurol 1999;56:1121-1123.
ABSTRACT | FULL TEXT  

Muscarinic Receptor Agonists, Like Dopamine Receptor Antagonist Antipsychotics, Inhibit Conditioned Avoidance Response in Rats
Shannon et al.
J. Pharmacol. Exp. Ther. 1999;290:901-907.
ABSTRACT | FULL TEXT  

Treating Visual Hallucinations With Donepezil
BURKE et al.
Am. J. Psychiatry 1999;156:1117a-1118.
FULL TEXT  

Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor
Christopoulos et al.
J. Pharmacol. Exp. Ther. 1999;289:1220-1228.
ABSTRACT | FULL TEXT  

Pharmacologic Efficacy in Neuropsychiatry: A Review of Placebo-Controlled Treatment Trials
Rummans et al.
J. Neuropsychiatry Clin. Neurosi. 1999;11:176-189.
ABSTRACT | FULL TEXT  

Diagnosis, Management, and Treatment of Alzheimer Disease: A Guide for the Internist
Richards and Hendrie
Arch Intern Med 1999;159:789-798.
ABSTRACT | FULL TEXT  

A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer's disease
Thal et al.
Neurology 1999;52:1146-1146.
ABSTRACT | FULL TEXT  

The cholinergic hypothesis of Alzheimer's disease: a review of progress
Francis et al.
J. Neurol. Neurosurg. Psychiatry 1999;66:137-147.
ABSTRACT | FULL TEXT  

The Neurobiology and Pharmacotherapy of Alzheimer's Disease
Felician and Sandson
J. Neuropsychiatry Clin. Neurosi. 1999;11:19-31.
ABSTRACT | FULL TEXT  

Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells
Marino et al.
Proc. Natl. Acad. Sci. USA 1998;95:11465-11470.
ABSTRACT | FULL TEXT  

Coadministration of Galanin Antagonist M40 with a Muscarinic M1 Agonist Improves Delayed Nonmatching to Position Choice Accuracy in Rats with Cholinergic Lesions
McDonald et al.
J. Neurosci. 1998;18:5078-5085.
ABSTRACT | FULL TEXT  

On the Unique Binding and Activating Properties of Xanomeline at the M1 Muscarinic Acetylcholine Receptor
Christopoulos et al.
Mol. Pharmacol. 1998;53:1120-1130.
ABSTRACT | FULL TEXT  

The Cholinergic Hypothesis of Neuropsychiatric Symptoms in Alzheimer's Disease
Cummings and Back
AJGP 1998;6:64S-78.
ABSTRACT | FULL TEXT