The Effects of Metrifonate on the Cognitive, Behavioral, and Functional Performance of Alzheimer's Disease Patients

Murray A. Raskind, M.D.; Pamela A. Cyrus, M.D.; Bianca B. Ruzicka, Ph.D.; and Barbara I. Gulanski, M.D., for the Metrifonate Study Group

Background: The objective of this study was to evaluate the efficacy and safety of metrifonate, a long-acting acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease of mild-to-moderate severity.

Method: This was a prospective, multicenter, 26-week, double-blind, parallel group study. The 264 randomized patients met diagnostic criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association for probable Alzheimer's disease. Patients had Mini-Mental State Examination (MMSE) scores of 10-26 and ischemic scores (Rosen modification) of < 4. Metrifonate-treated patients received a single 50-mg dose once daily. The efficacy of metrifonate was investigated with respect to 3 symptom domains. Cognitive performance was analyzed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the MMSE. Psychiatric and behavioral disturbances were analyzed using the Neuropsychiatric Inventory (NPI) and the ADAS-Noncognitive subscale (ADAS-Noncog). The ability to perform instrumental and basic activities of daily living was evaluated using the Disability Assessment for Dementia (DAD) scale. Additionally, global state was assessed using the Clinician Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus) scale.

Results: After 26 weeks of metrifonate therapy, a statistically significant benefit of metrifonate was observed in the cognitive performance of Alzheimer's disease patients (ADAS-Cog, t = 2.55, df = 237, p = .012; MMSE, t = 4.60, df = 237, p = .0001). Metrifonate also significantly attenuated the deterioration in activities of daily living of the patients (DAD total score, t = -2.11, df = 233, p = .036) and relieved patients' psychiatric and behavioral disturbances (NPI total score, t = 2.51, df = 233, p = .013). In addition, metrifonate significantly improved the scores for the global state of the patients (CIBIC-Plus, t = 2.07, df = 232, p = .039). Metrifonate was well tolerated; adverse events were predominantly mild in intensity, and no hepatotoxicity was observed.

Conclusion: In this study, metrifonate was safe and well tolerated. It benefited the cognitive decline, psychiatric and behavioral disturbances, impaired ability to perform instrumental and basic activities of daily living, and global state of patients diagnosed with mild-to-moderate Alzheimer's disease.

(J Clin Psychiatry 1999;60:318-325)

Received Oct. 24, 1997; accepted July 29, 1998. From the Department of Veterans Affairs, Northwest Mental Illness Research, Education and Clinical Center, Seattle, Wash. (Dr. Raskind), and Bayer Corporation, Pharmaceutical Division, West Haven, Conn. (Drs. Cyrus, Ruzicka, and Gulanski).

A complete list of the members of the Metrifonate Study Group appears at the end of this article.

This report includes data from protocol D96-010 sponsored by Bayer Corporation, Pharmaceutical Division. Dr. Raskind and the members of the Metrifonate Study Group do not own stock or options in Bayer Corporation, but have received research support from Bayer Corporation. Additionally, Dr. Raskind has served as a consultant in the field of Alzheimer's disease to Bayer Corporation. Drs. Cyrus, Ruzicka, and Gulanski were employees of Bayer Corporation at the time of this study.

The authors gratefully acknowledge the patients and their caregivers for their participation in the study. They also acknowledge the contribution of Andrea Nadel, Ph.D., in the preparation of this manuscript.

Reprint requests to: Murray A. Raskind, M.D., VA Puget Sound Health Care System (116), 1660 South Columbian Way, Seattle, WA 98108.