Michael F. Green

The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity.

OBJECTIVE The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National Institute of Mental Healths Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. METHOD The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. RESULTS The expert panel ratings are presented for the initially selected 36 tests. For the beta battery tests, data on test-retest reliability, practice effects, relationships to functional status, practicality, and tolerability are presented. Based on these data, 10 tests were selected to represent seven cognitive domains in the MATRICS Consensus Cognitive Battery. CONCLUSIONS The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. It may also aid evaluation of cognitive remediation strategies.

Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS

It is generally accepted that cognitive deficits in schizophrenia are related to functional outcome. However, support for longitudinal relationships between cognition and functional outcome has not been as well documented. The current paper presents a review of 18 recently published longitudinal studies (minimum 6-month follow up) of the relationships between cognition and community outcome in schizophrenia. Results from these studies reveal considerable support for longitudinal associations between cognition and community outcome in schizophrenia. These studies demonstrate that cognitive assessment predict later functional outcome and provide a rationale for psychopharmacological interventions for cognitive deficits in schizophrenia. Although the relationships between cognition and community outcome are well-supported, it is clear that community functioning is also affected by a host of factors apart from cognition that are usually not considered in clinical trial studies (e.g., psychosocial rehabilitation and educational/vocational opportunities). In the second part of the paper, we consider intervening steps between cognitive performance measures and community outcome. These steps are apt to have important implications for clinical trials of cognition-enhancing agents in schizophrenia.

Identification of separable cognitive factors in schizophrenia

One of the primary goals in the NIMH initiative to encourage development of new interventions for cognitive deficits in schizophrenia, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), has been to develop a reliable and valid consensus cognitive battery for use in clinical trials. Absence of such a battery has hampered standardized evaluation of new treatments and, in the case of pharmacological agents, has been an obstacle to FDA approval of medications targeting cognitive deficits in schizophrenia. A fundamental step in developing such a battery was to identify the major separable cognitive impairments in schizophrenia. As part of this effort, we evaluated the empirical evidence for cognitive performance dimensions in schizophrenia, emphasizing factor analytic studies. We concluded that seven separable cognitive factors were replicable across studies and represent fundamental dimensions of cognitive deficit in schizophrenia: Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning and Memory, Visual Learning and Memory, Reasoning and Problem Solving, and Verbal Comprehension. An eighth domain, Social Cognition, was added due to recent increased interest in this area and other evidence of its relevance for clinical trials aiming to evaluate the impact of potential cognitive enhancers on cognitive performance and functional outcome. Verbal Comprehension was not considered appropriate for a cognitive battery intended to be sensitive to cognitive change, due to its resistance to change. The remaining seven domains were recommended for inclusion in the MATRICS-NIMH consensus cognitive battery and will serve as the basic structure for that battery. These separable cognitive dimensions also have broader relevance to future research aimed at understanding the nature and structure of core cognitive deficits in schizophrenia.

Approaching a consensus cognitive battery for clinical trials in schizophrenia: The NIMH-MATRICS conference to select cognitive domains and test criteria

To stimulate the development of new drugs for the cognitive deficits of schizophrenia, the National Institute of Mental Health (NIMH) established the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. This article presents an overview of decisions from the first MATRICS consensus conference. The goals of the meeting were to 1) identify the cognitive domains that should be represented in a consensus cognitive battery and 2) prioritize key criteria for selection of tests for the battery. Seven cognitive domains were selected based on a review of the literature and input from experts: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition. Based on discussions at this meeting, five criteria were considered essential for test selection: good test-retest reliability, high utility as a repeated measure, relationship to functional outcome, potential response to pharmacologic agents, and practicality/tolerability. The results from this meeting constitute the initial steps for reaching a consensus cognitive battery for clinical trials in schizophrenia.

Anhedonia in schizophrenia: distinctions between anticipatory and consummatory pleasure.

Research on anhedonia in schizophrenia has revealed mixed results, with patients reporting greater anhedonia than healthy controls on self-report measures and semi-structured interviews, but also reporting comparable experiences of positive emotions in response to pleasurable stimuli. Basic science points to the importance of distinguishing between anticipatory and consummatory (or in-the-moment) pleasure experiences, and this distinction may help to reconcile the mixed findings on anhedonia in schizophrenia. In two studies, we tested the hypothesis that anhedonia in schizophrenia reflects a deficit in anticipatory pleasure but not consummatory pleasure. In Study 1, we used experience sampling methodology to assess reported experiences of consummatory and anticipated pleasure among schizophrenia patients and controls. In Study 2, schizophrenia patients and controls completed a self-report trait measure of anticipatory and consummatory pleasure and interviews that assessed negative symptoms, including anhedonia, and community functioning. In both studies, we found evidence for an anticipatory but not a consummatory pleasure deficit in schizophrenia. In addition, anticipatory pleasure was related to clinical ratings of anhedonia and functional outcome. Clinical and research implications of these findings are discussed.

Social Cognition in Schizophrenia: An NIMH Workshop on Definitions, Assessment, and Research Opportunities

Social cognition has become a high priority area for the study of schizophrenia. However, despite developments in this area, progress remains limited by inconsistent terminology and differences in the way social cognition is measured. To address these obstacles, a consensus-building meeting on social cognition in schizophrenia was held at the National Institute of Mental Health in March 2006. Agreement was reached on several points, including definitions of terms, the significance of social cognition for schizophrenia research, and suggestions for future research directions. The importance of translational interdisciplinary research teams was emphasized. The current article presents a summary of these discussions.

Training and quality assurance with the structured clinical interview for DSM-IV (SCID-I/P)

Accuracy in psychiatric diagnosis is critical for evaluating the suitability of the subjects for entry into research protocols and for establishing comparability of findings across study sites. However, training programs in the use of diagnostic instruments for research projects are not well systematized. Furthermore, little information has been published on the maintenance of interrater reliability of diagnostic assessments. At the UCLA Research Center for Major Mental Illnesses, a Training and Quality Assurance Program for SCID interviewers was used to evaluate interrater reliability and diagnostic accuracy. Although clinically experienced interviewers achieved better interrater reliability and overall diagnostic accuracy than neophyte interviewers, both groups were able to achieve and maintain high levels of interrater reliability, diagnostic accuracy, and interviewer skill. At the first quality assurance check after training, there were no significant differences between experienced and neophyte interviewers in interrater reliability or diagnostic accuracy. Standardization of training and quality assurance procedures within and across research projects may make research findings from study sites more comparable.

Baseline neurocognitive deficits in the CATIE schizophrenia trial

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An ‘all-comer’ approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13–0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an ‘all-comer’ clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Biosocial pathways to functional outcome in schizophrenia.

UNLABELLED Biosocial models are preeminent in the study of schizophrenia, yet there has been little empirical testing of these models. OBJECTIVE This study provided the first test of a biosocial causal model of functional outcome in schizophrenia, using neurocognition, social cognition, social competence and social support as predictors of both global and specific domains of functional outcome. METHOD The design used baseline variables to predict both concurrent functional status and prospective 12-month functional outcome. Subjects were recruited upon admission to outpatient community-based psychosocial rehabilitation programs shown in previous studies to be effective in improving functional outcomes. 139 individuals diagnosed with schizophrenia or schizoaffective disorder participated in the study; 100 participants completed the 12-month assessments. Face-to-face interviews assessed neurocognitive functioning (with five neuropsychological measures), social cognition (as perception of emotion), social competence, social support, and functional outcome which consisted of items covering the domains of social, independent living, and work functioning. RESULTS Path analysis modeling showed that the proposed biosocial models had strong fit with the data, for both concurrent and 12-month global functional outcomes, with fit indices ranging from .95 to .98. The model explained 21% of the variance in concurrent global functional outcome, and 14% of the variance in 12-month prospective outcome. CONCLUSIONS The support for this model was strong, and it has implications for understanding the causal factors related to functional outcome, as well as for intervention strategies for improving functional outcomes in schizophrenia.

The MATRICS Consensus Cognitive Battery, Part 2: Co-Norming and Standardization

OBJECTIVE The consensus cognitive battery developed by the National Institute of Mental Healths (NIMHs) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative includes 10 independently developed tests that are recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia. To facilitate interpretation of results from the MATRICS Consensus Cognitive Battery using a common scaling across tests, normative data were obtained from a single representative U.S. community sample with the battery administered as a unit. METHOD The MATRICS Consensus Cognitive Battery was administered to 300 individuals from the general community at five sites in differing geographic regions. For each site, recruitment was stratified by age, gender, and education. A scientific survey sampling method was used to help avoid sampling bias. The battery was administered in a standard order to each participant in a single session lasting approximately 60 minutes. Descriptive data were generated, and age, gender, and education effects on performance were examined. RESULTS Prominent age and education effects were observed across tests. The results for gender differed by measure, suggesting the need for age and gender corrections in clinical trials. The MATRICS Consensus Cognitive Battery components were co-normed, with allowance for demographic corrections. CONCLUSIONS Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. 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.