Current issues of ACP Journal Club are published in Annals of Internal Medicine


Metrifonate was effective in mild-to-moderate Alzheimer disease

ACP J Club. 1999 Nov-Dec;131:72. doi:10.7326/ACPJC-1999-131-3-072

Source Citation

Raskind MA, Cyrus PA, Ruzicka BB, Gulanski BI, for the Metrifonate Study Group. The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's disease patients. J Clin Psychiatry. 1999 May;60:318-25.



In patients with mild-to-moderate Alzheimer disease (AD), is metrifonate effective and safe for improving cognitive, psychiatric, behavioral, and functional outcomes?


Randomized (allocation concealed), double-blind, placebo-controlled trial with 26-week follow-up.


U.S. and Canadian clinical centers.


264 patients (mean age 75 y, 64% women) who met the criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association for probable AD, had Mini-Mental State Examination (MMSE) scores from 10 to 26 and modified ischemia scale scores < 4, weighed from 43 to 98 kg, and were in contact with their caregiver ≥ 4 times/wk. Exclusion criteria were dementia or cognitive impairment not related to probable AD, history of any disorder associated with dementia, clinically significant medical problems, previous use of metrifonate, or use of other drugs within 30 days. 83% of patients completed the study.


Patients were allocated to metrifonate, 50 mg (n = 177), or placebo (n = 87) in a tablet given once daily for 26 weeks.

Main outcome measures

Cognition, psychiatric and behavioral problems, activities of daily living (ADLs), global state, symptom severity, and adverse events.

Main results

Metrifonate improved cognition, psychiatric and behavioral problems, ADLs, and global state more than did placebo (Table). Symptom severity scores and severe adverse events were similar in both groups.


In patients with mild-to-moderate Alzheimer disease, metrifonate was safe and effective for improving cognitive, behavioral, psychiatric, and functional outcomes.

Source of funding: Bayer Corporation.

For correspondence: Dr. M.A. Raskind, VA Puget Sound Health Care System (116), 1660 South Columbian Way, Seattle, WA 98108, USA. FAX 206-764-2573.

Table. Metrifonate vs placebo for mild-to-moderate Alzheimer disease*

Outcomes at 26 wk Scale Difference in mean score change P value
Cognition MMSE 1.85 <0.001
ADAS-Cog Not reported 0.012
Psychiatric and behavioral problems NPI 3.42 0.024
ADLs DAD 4.07 0.036
Mean score difference
Global state CIBIC-Plus 0.20 0.039

*All score differences favor metrifonate. ADLs = activities of daily living; ADAS-Cog = Alzheimer's Disease Assessment Scale-Cognitive subscale; CIBIC-Plus = Clinician Interview-Based Impression of Change with Caregiver Input; DAD = Disability Assessment for Dementia; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory.


This well-executed and relatively unbiased clinical trial by Raskind and colleagues provides additional support for the effectiveness and tolerability of metrifonate in persons with mild-to-moderate AD. The results are similar to a study of metrifonate (1) that used a variable dose (30 to 60 mg) based on body weight and suggest that a 50-mg daily dose is reasonable.

Comparisons of the effectiveness of metrifonate (an investigational drug) with other cholinesterase inhibitors (tacrine, donepezil, and rivastigmine) in systematic reviews (2, 3) and recent trials (4) suggest no substantial advantage for metrifonate except reduced adverse effects in some comparisons. All of these agents produce small positive effects on cognition, behavior, and some aspects of functional status that are globally noticeable by an expert clinician but are of debatable importance overall in terms of quality of life for the patient and caregiver. Only longer-term studies with more clinically relevant outcomes will allay serious doubts about the practicality of these agents.

In the interim, existing data justify a trial of a cholinesterase inhibitor in most patients with mild-to-moderate AD but provide no guidance on identifying "responders." The options are to continue treating all patients, including those who continue to decline, assuming that the drug may be reducing the rate of deterioration in some patients, or to set arbitrary criteria for a "response" (e.g., stable MMSE score). Publication of detailed distributions of clinical response measures and subgroup analyses could be useful in identifying potential responders and non-responders and in defining maximum expected levels of response more clearly than the average values reported in most studies.

Roger Luckmann, MD, MPH
University of Massachusetts Medical CenterWorcester, Massachusetts, USA


1. Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease. Neurology. 1998;50:1222-30.

2. Qizilbash N, Whitehead A, Higgins J, et al. Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' Collaboration. JAMA. 1998;280:1777-82.

3. Birks JS, Melzer D. Donepezil for mild and moderate Alzheimer's disease. Cochrane Review, latest version 24 Nov 1998. In: The Cochrane Library. Oxford: Update Software.

4. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ. 1999;318:633-8.