Marlene Busko
Medscape Medical News 2008. © 2008 Medscape
February 13, 2008 — The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, funded by the National Institute of Mental Health (NIMH), has selected and tested a battery of 10 tests to evaluate cognition in schizophrenia. The MATRICS Consensus Cognitive Battery has been accepted by the US Food and Drug Administration (FDA) for use in clinical trials to evaluate cognition-enhancing treatments in schizophrenia.
In addition, MATRICS investigators have determined normal values for the cognitive test battery and have appraised 4 measures of functional capacity in schizophrenia.
This work is discussed in 3 articles and an editorial in the February 2008 issue of the American Journal of Psychiatry.
"Developing a method to evaluate the efficacy of treatments that target cognitive impairment in schizophrenia has been a timely and critical task, especially given that the central role of cognition in long-term disability has become increasingly apparent," Philip D. Harvey, PhD, from Emory University School of Medicine, in Atlanta, Georgia, and Barbara A. Cornblatt, PhD, from the Zucker Hillside Hospital, in Glen Oaks, New York, write in an accompanying editorial.
Need for Accepted Test Series
Despite the importance of cognitive deficits in schizophrenia, no drug has yet been approved to treat this aspect of this illness, and 1 of the major impediments has been the lack of an accepted cognitive battery of tests, write the authors of the first article, led by Keith H. Nuechterlein, PhD, from the University of California, Los Angeles Semel Institute for Neuroscience and Human Behavior.
One of the primary goals of the MATRICS initiative was to develop such a series of tests.
Part 1: Choosing, Validating Cognition Test Battery
The MATRICS Neurocognition Committee first surveyed experts to determine the desirable characteristics of a battery of tests of cognition in schizophrenia, Dr. Nuechterlein and colleagues write. One criterion was that the test battery would optimally not exceed 90 minutes.
At a consensus conference, scientists from academia, government, and the pharmaceutical industry agreed on cognitive domains and selection criteria for these tests.
The 7 cognitive domains were speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The 5 selection criteria were reliability, utility, relationship to functional status, potential changeability in response to pharmacological agents, and practicality for clinical trials and tolerability for patients.
From more than 90 nominated tests, the committee identified the 36 most promising ones, and an expert panel then evaluated how well the tests met the selection criteria, to determine the 20 tests that would constitute the beta version of the test battery.
The beta version of the test battery was administered to individuals with schizophrenia at 5 study sites in the United States. A total of 176 individuals with schizophrenia were assessed at baseline, and 167 were assessed again 4 weeks later. Participants had a mean age of 44 years, and most were male (76%). A total of 59% were white and 29% were African American, and 86% had a diagnosis of schizophrenia while 14% had a diagnosis of schizoaffective disorder, depressed type.
From the results of the beta test, the investigators came to a consensus for the 10 tests to represent the 7 cognitive domains. It is expected that it will take no more than 1 day of training to learn how to administer the test battery. The total testing time (without rest breaks) is estimated to be 65 minutes.
The MATRICS report recommended that these tests be used as the standard cognitive performance battery for clinical trials of potential cognitive-enhancing interventions. This was endorsed by the NIMH Mental Health Advisory Council in 2005 and accepted by the FDA's Division of Neuropharmacological Drug Products. To facilitate use, the tests were placed in a kit form by MATRICS Assessment Inc, a nonprofit company.
Part 2: Establishing Normal Values
In the next step, investigators used a single representative US community sample to establish normal data simultaneously for all 10 measures in the MATRICS Consensus Cognitive Battery administered as a unit, a process called "conorming." They identified age, sex, and education effects.
"These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores," the group, led by Robert S. Kern, PhD, from the Greater Los Angeles Healthcare Center, in California, writes.
They recruited 300 participants intended to represent the sex, age, and racial/ethnic composition of the 2000 US census from communities around the 5 study sites.
An equal number of participants were drawn from 3 age groups: 20 to 39 years, 40 to 49 years, and 50 to 59 years. A total of 47% of the participants were men; 76% were white, and 18% were African American.
The investigators administered the test battery (with tests given in the same order) to each participant in a single session lasting about 1 hour. From the results, they developed a computer-based scoring program.
Higher education levels were associated with higher test performance and might affect symptom severity. Age and sex differences should be adjusted for, the group writes, adding that age and sex are part of the default scoring program.
But How Well Can the Patient Function?
The US FDA indicated at MATRICS meetings that a significant improvement on a consensus cognitive performance end point would be necessary but not sufficient for approval of cognition-enhancing drugs for schizophrenia.
It stated that it would also require improvement in an additional measure (a co-primary measure) that would reveal a patient's ability to function in the real world.
Based on expert recommendations, the MATRICS investigators looked at 2 types of measures of functional ability: a patient's ability to simulate performing key tasks of daily living (eg, taking public transportation) or an interview-based assessment of cognition.
They evaluated the same patients with schizophrenia: 176 patients at baseline and 167 patients 4 weeks later. All 4 co-primary test measures performed reasonably well, and the investigators did not recommend any particular measure. The FDA indicated that any 1 of the 4 measures would be acceptable at this point for use in clinical trials.
"The results presented in the current article should be viewed as a good starting point for evaluation, comparison, and discussion of potential functionally meaningful co-primary measures, with expectations that future developments will lead to improved tools in this domain," the team, led by Michael F. Green, PhD, from the University of California, Los Angeles Semel Institute for Neuroscience and Human Behavior, concludes.
"Major Beneficiaries: Our Patients"
Multiple constituencies — members of the scientific community, pharmaceutical companies, and the FDA — will benefit from the MATRICS project, Drs. Harvey and Cornblatt write in their editorial. "It is clear, however, that the major beneficiaries of MATRICS process will be our patients. They are the ones with disability, poverty, and social isolation . . . [who face] negative assumptions made about those who are not employed, self sufficient, or independent." Not only will patients with schizophrenia benefit when treatments for cognition are developed, but patients with bipolar disorder and major depression who have cognitive deficits that persist when their symptoms are in remission will also benefit, they add.
Dr. Nuechterlein has a leadership position but no financial interest in MATRICS Assessment Inc. He was a developer of but has no financial interest in the 3-7 Continuous Performance Test and has received a grant from Janssen LLP. Dr. Green has consulted for Abbott, Astella, Bristol-Myers Squibb, Eli Lilly, Lundbeck, Memory Pharmaceuticals, Otsuka, Pfizer, Roche, Sanofi-Aventis, and Solvay. He has a leadership position but no financial interest in MATRICS Assessment Inc. Dr. Kern receives financial support from MATRICS Assessment Inc. Dr. Harvey has received research or contract support from or served as an advisor or consultant to AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Memory Pharmaceuticals, Novartis, Pfizer, SolvayWyeth Alliance, and the Sanofi-Aventis Group. Dr. Cornblatt was a developer of and receives royalties from the Continuous Performance Test—Identical Pairs version.
Am J Psychiatry. 2008;165:203-213 Abstract, 214-220 Abstract, 221-228 Abstract, 163-165. Abstract
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