Galantamine, an agent used to treat Alzheimer's disease, appears to have
selective benefits for some aspects of cognition in patients with
schizophrenia, pointing the way for future research on breakthrough drugs to
treat cognitive deficits.
Galantamine is sold under the trade names of Razadyne and Reminyl.
A randomized, placebo-controlled trial of galantamine using a range of
neuropsychological measures to assess cognition found that the agent had no
global effect, but did have significant beneficial effects on certain measures
In particular, subjects randomized to receive galantamine scored
significantly better than those receiving placebo on scores of"
processing speed," as measured by the Wechsler Adult Intelligence
Scale (WAIS) III Digit Symbol Test. The report will be published online next
month as part of the advance edition of the American Journal of
Study author Robert Buchanan, M.D., told Psychiatric News that
performance on the WAIS III Digit Symbol Test has been shown in previous
studies to be the cognitive measure that most clearly distinguishes good
vocational outcome among patients with schizophrenia from those who have a
However, galantamine had no apparent effect on other measures of cognition
and appears even to have interfered with performance on at least one test of
cognition. Buchanan added that it would be premature to recommend the clinical
use of galantamine for schizophrenia.
"The real importance of this lies in the fact that it marks a new
direction in the study of drugs for schizophrenia, one that is geared toward
treating a discrete aspect of the disease that has been shown to be crucial in
overall outcome," Buchanan said.
In addition, he said it marks a departure from the approach favored by drug
manufacturers for many decades of tweaking existing compounds for their
effects on positive symptoms of schizophrenia via the dopamine system. That
approach has led to a long-line of "me too" antipsychotic
medications, sold to a niche market for their side-effect profile but offering
little in the way of improvement in function and outcome.
In the study, 86 people with schizophrenia were entered into a 12-week,
double-blind, placebo-controlled, randomized clinical trial. Forty-two
subjects were randomized to galantamine, and 44 were randomized to
Subjects were administered an eight-test neuropsychological battery at
baseline and study completion for working memory, verbal memory, visual
memory, motor speed, and processing speed. The battery included WAIS-III
Letter-Number Sequencing, Brief Assessment of Cognition in Schizophrenia,
Number Sequencing, California Verbal Learning, Brief Visuospatial Memory,
Grooved Pegboard, WAIS-III Digit Symbol and WAIS-III Symbol Search, and the
Gordon Diagnostic System Continuous Performance Test.
The treatment effect for the overall composite score was not significant,
but follow-up analyses revealed that subjects randomized to galantamine
exhibited significant improvements on the WAIS-III digit symbol and verbal
The digit symbol test consists of up to seven rows of numbers from 1 to 9,
each paired with a blank box. Above these rows is a printed key that pairs
each number with a different nonsense symbol. Following a practice trial, the
task is to fill in the blank spaces with the symbol that is paired to the
number above the blank space as quickly as possible for 120 seconds.
Buchanan explained that galantamine is an acetylcholinesterase inhibitor
that works to enhance cholinergic function in the brain.
Galantamine is also an "allosteric modulator," a term
describing the capacity of some agents to enhance the function of a receptor
by acting at sites on the receptor other than the site to which the
neurotransmitter for the receptor binds. Such a drug binds to an"
allosteric" site (allostery, derived from the Greek, means"
other site") and enhances the potency of an agonist; in the case
of acetylcholine, galantamine prolongs the activation of the receptor.
Buchanan said he believes it is this allosteric-modulating property of
galantamine that accounts for its selectively beneficial effects on cognition.
Moreover, since there are agents that are substantially more potent as
allosteric modulators, the results of the current study point the way toward
more potent drugs for enhancing cognition.
The results of the study also raise a challenge for future research: Will
other, more potent allosteric modulators have a global effect on cognition?"
Or are the results of our study more typical, in that agents for
cognition will have heterogenous effects on specific cognitive
functions?" Buchanan asked. "In that case, the clinical question
will be, Which drug is best for which patient?"
In any case, Buchanan believes the work on galantamine represents a new era
in schizophrenia drug research whose fruit will be a new class of
He credited the National Institute of Mental Health MATRICS (Measurement
and Treatment Research to Improve Cognition in Schizophrenia) project, which
is designed to close what the late Wayne Fenton, M.D., called "the
translational gap" between the very large body of basic research on
cognition in schizophrenia and the paucity of clinical studies on drugs
targeting cognitive impairments (Psychiatric News, January 20,
The principal investigator for the MATRICS project is Steven Marder, M.D.,
director of the Section on Psychosis at the UCLA Neuropsychiatric
"That initiative is motivating drug companies to be much more
interested in developing drugs for cognition," Buchanan said."
Companies are now investing money in this area of research. I think we
are a number of years away from a drug being marketed for cognition, but we
are much further along than we would have been without the MATRICS
The study was funded in part by the VA Capitol Network Mental Illness
Research, Education, and Clinical Center and the Stanley Medical Research
Institute. Double-blind medications were provided by Ortho-McNeil Neurologics
Inc., a sister company to Janssen Pharmaceuticals, which manufactures
"Galantamine for the Treatment of Cognitive Impairments in
People With Schizophrenia" will be posted November 15 at<http://ajp.psychiatryonline.org>.▪