Drug's Effect on Cognition Could Be Treatment Advance
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 of cognition.
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 Psychiatry.
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 poorer outcome.
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.
'Allosteric' Modulator Credited for Benefits
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 placebo.
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 memory measures.
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?”
New Era in Research Beginning
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 medications.
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, 2006).
The principal investigator for the MATRICS project is Steven Marder, M.D., director of the Section on Psychosis at the UCLA Neuropsychiatric Institute.
“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 process.”
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.
“Galantamine for the Treatment of Cognitive Impairments in People With Schizophrenia” will be posted November 15 at<http://ajp.psychiatryonline.org>.▪
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Published online: 5 October 2007
Published in print: October 5, 2007
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A break with the tradition of “me too” agents that act on the dopamine system may lead schizophrenia drug development in a new direction.
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