Therapeutic Nihilism: Widespread Yet Passé? AD Acetylcholinesterase Inhibitors Are Better Than Their Reputation
John C. Morris, Murray Raskind, and Martin Farlow led this live discussion on 14 October 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
View Transcript of Live Discussion — Posted 26 August 2006
Background Text: Update on Approved Drugs for the Symptomatic Treatment of Alzheimer Disease: Introduction
By John C. Morris, M.D., Harvey A. and Dorismae Hacker Friedman Distinguished Professor
of Neurology and Professor of Pathology and Immunology, Washington
University School of Medicine, St. Louis, MO.
Reference: Neurolog. 2003 Sep;9(5):223-4:
Posting courtesy of Lippincott William & Wilkins. The Alzheimer Research Forum gratefully acknowledges their
permission to make this series available to a wider audience.
Tacrine in 1993 was the initial drug approved by the Food
and Drug Administration (FDA) for symptomatic therapy
for Alzheimer disease (AD). Subsequent FDA approval was
obtained for donepezil (1996), rivastigmine (2000), and galantamine
(2001). All four drugs are centrally acting cholinesterase
inhibitors (cholinesterase inhibitors) and all consistently demonstrate
efficacy for mild-moderate AD. Therapeutic benefit, although
modest, is clinically meaningful and generally equivalent for
all four drugs. Tacrine no longer is marketed by its manufacturer
in the United States as the newer drugs (donepezil, rivastigmine,
and galantamine) have superior tolerability and safety
profiles and are easier to use (e.g., bid or qd dosing for the
newer drugs versus qid dosing for tacrine).
Are there clinically relevant differences in the therapeutic
ratios of donepezil, rivastigmine, and galantamine? There is no
definitive answer to this question. Only a very few limited
studies have attempted to directly compare these agents. Comparing
published findings of pivotal trials for each drug is
problematic because variable patient selection criteria and study
designs, rather than actual drug effect, may be responsible for
any small differences in results. Clinical experience suggests that
several factors will determine which drug(s) ultimately will
emerge as the most favored: 1) therapeutic superiority (symptomatic
benefit is very nearly equal for all three, but it is possible
that 1 or more may demonstrate additional disease-modifying
effects); 2) tolerability and safety profiles (all are safe but share
peripheral and central cholinergic side effects; distinctions may
rest on the frequency rather than type of side effects); 3) ease of
use (including dosing frequency and dose escalation requirements);
and 4) cost (currently, all three drugs cost about $150/mo).
Clinical experience with rivastigmine and galantamine still is
insufficient to know how well they compare with donepezil, the
current industry "leader" by virtue of the fact that it was
launched several years before rivastigmine and galantamine
Several features are shared in common by donepezil,
rivastigmine, and galantamine. All have therapeutic benefit in
AD. Modest efficacy consistently is shown for each drug in
the multiple domains affected by AD: cognition, performance
of activities of daily living, behavior, and "global" function.
Duration of benefit varies but can be demonstrated in some
cases for at least a year. The cholinesterase inhibitors may be efficacious for
patients with either less or more severe stages of AD than the
mild-moderate stage for which the drugs are approved. They
also may be beneficial in dementing disorders that overlap
with AD, including dementia with Lewy bodies and vascular
and mixed dementia.
Although the cholinesterase inhibitors are efficacious, safe, and readily
available in the United States, many patients with AD are
untreated with these drugs; those who are often discontinue
therapy after only brief drug exposure. Because the drugs
generally are well tolerated by patients with AD, especially
with current dose escalation paradigms, it is unlikely that
unacceptable side effects explain the underutilization of the
drugs. Instead, the high nontreatment and discontinuation
rates may relate to unwarranted therapeutic nihilism ("the
drugs don't work") and to unrealistic expectations of drug
benefit (anticipating clinical improvement rather than "stability"
This group of papers is intended to provide up-to-date,
clinically relevant information for each agent. The Neurologist is
fortunate to have each of the three cholinesterase inhibitors discussed by highly
regarded clinical investigators. Drs. Doody, Farlow, and Raskind
are leaders in dementia research with extensive experience
in the pharmacotherapy of AD. As such, their advice frequently
has been sought by companies involved in drug discovery and
development for AD. They (and I) have served as consultants,
advisory panel members, and site investigators in clinical trials
for several companies, including those that manufacture and
market the drugs that are the focus of the present contributions.
See the following articles (.pdfs) also posted courtesy of Lippincott William & Wilkins.
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