Wayne S. Fenton

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.

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.

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.

Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia

The impairments in social and vocational outcome that are common in schizophrenia are strongly related to the severity of impaired neurocognition. This observation led to the initiation of The NIMHs Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, which supports the development of pharmacological agents to improve cognition in schizophrenia. MATRICS addresses barriers to drug development through a number of activities, including the development of a consensus battery for measuring cognition in schizophrenia; the development of a consensus regarding the most promising molecular targets that should be the focus of drug development; the use of a joint meeting with representatives from the industry, academia, NIMH, and the U.S. Food and Drug Administration (FDA) to clarify guidelines for the design of clinical trials for cognition enhancing agents; and finally, to assist NIMH in developing its research agenda in this area.

Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia

Recent research suggests that deficient uptake or excessive breakdown of membrane phospholipids may be associated with schizophrenia. We review available clinical research on abnormalities in membrane fatty acid composition and metabolism in schizophrenia, and therapeutic trials of fatty acid in this disorder. All potentially relevant English-language articles were identified from the medical and psychiatric literature with the aid of computer searches using key words such as lipids, phospholipids, prostaglandins and schizophrenia. All studies which include human subjects are reviewed. Empirical studies related to membrane hypotheses of schizophrenia focus on: 1) assessment of prostaglandins (PG) and their essential fatty acid (EFA) precursors in the tissues of patients with schizophrenia; 2) evaluation of the niacin flush test as a possible diagnostic marker; 3) evaluation of phospholipase enzyme activity; 4) NMR spectroscopy studies of brain phospholipid metabolism; and 5) therapeutic trials of PG precursors for the treatment of schizophrenia. The most consistent clinical findings include red blood cell fatty acid membrane abnormalities, NMR spectroscopy evidence of increased phospholipid turnover and a therapeutic effect of omega-3 fatty acid supplementation of neuroleptic treatment in some schizophrenia patients. Studies of EFA metabolism have proved fruitful for generating and testing novel etiologic hypotheses and new therapeutic agents for schizophrenia. Greater attention to factors that influence tissue EFA levels such as diet, tobacco and alcohol are required to reconcile inconsistent findings. Treatment studies, although promising, require independent replication.

The prognostic significance of obsessive-compulsive symptoms in schizophrenia.

Obsessive-compulsive symptomatology has been described in schizophrenia for more than 60 years, but its clinical significance has yet to be explored systematically. This report details the clinical characteristics and long-term course of a group of 21 schizophrenic patients with prominent obsessive-compulsive symptoms from the Chestnut Lodge Follow-Up Study. While this group differed on admission only minimally from schizophrenic patients without obsessive-compulsive symptoms, their long-term outcome in the areas of social relations, employment, psychopathology, and global functioning was significantly, and almost uniformly, poorer. Persistent obsessive-compulsive symptoms thus appear to be a powerful predictor of poor prognosis in schizophrenia.

Functional Co-Primary Measures for Clinical Trials in Schizophrenia: Results From the MATRICS Psychometric and Standardization Study

OBJECTIVE During the consensus meetings of the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) Initiative, the U.S. Food and Drug Administration took the position that a drug for this purpose should show changes on 1) an accepted consensus cognitive performance measure and 2) an additional measure (i.e., a co-primary) that is considered functionally meaningful. The goal of the current study was to describe steps to evaluate four potential co-primary measures for psychometric properties and validity. METHOD As part of the five-site MATRICS Psychometric and Standardization Study (PASS), two measures of functional capacity and two interview-based measures of cognition were evaluated in 176 patients with schizophrenia (167 of these patients were retested 4 weeks later). RESULTS Data are presented for each co-primary measure for test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to functioning, tolerability/practicality, and number of missing data. CONCLUSIONS Psychometric properties of all of the measures were considered acceptable, and the measures were generally comparable across the various criteria, except that the functional capacity measures had stronger relationships to cognitive performance and fewer missing data. The development and evaluation of potential co-primary measures is still at an early stage, and it was decided not to endorse a single measure for clinical trials at this point. The current findings offer the initial steps to identify functionally meaningful co-primary measures in this area and will help to guide further evaluation of such measures.

Brief cognitive assessment in schizophrenia: normative data for the Repeatable Battery for the Assessment of Neuropsychological Status.

BACKGROUND The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, standardized cognitive screening instrument that assesses several domains of interest and offers an efficient approach to screening for cognitive impairment in schizophrenia (SC). Prior studies have established the clinical validity and test-retest reliability of the RBANS in SC. AIMS The purpose of the current study was to guide clinical interpretation by providing normative data for the use of the RBANS as a measure of cognitive impairment in SC. We also sought to evaluate the role of demographic factors and to present percentile data accordingly. METHODS 575 patients (391 male, 184 female) meeting the diagnostic criteria for SC or schizoaffective disorder were recruited from 4 inpatient (n=117) and 6 outpatient (n=458) sites in 2 different mental health treatment systems. All participants were administered the RBANS according to standardized instructions and a subgroup of 242 patients were also administered the Wide Range Achievement Test (3rd Edition) (WRAT-3) Reading subtest. RESULTS RBANS Total Scale score for patients with SC was approximately 2 standard deviations below the normal mean, was approximately 1 standard deviation below WRAT-3 Reading scores, and expected patterns of impairment were observed: measures of language and visuospatial ability were preserved relative to those of memory and attention. Aside from weak associations with Language (0.139) and Attention (0.112), age was not significantly associated with RBANS Index scores (which are age adjusted in healthy controls). Education was significantly associated with all RBANS scores and one-way ANOVA indicates that those with more than high school education scored consistently higher than the other two groups (less than and equal to a complete high school education). Normative tables with age and education based percentiles are presented. CONCLUSIONS The RBANS is an efficient screening tool for assessing cognitive impairment in patients with SC thereby making it a useful instrument for clinical and research applications.

Mood disorders: cardiovascular and diabetes comorbidity.

Purpose of review Depression is often associated with medical comorbidity. New research quantifies patterns of mood disorder in illnesses such as cardiovascular disease and diabetes, evaluates the prognostic significance of mood symptoms, and seeks to identify common mechanisms for both mood and medical disease. This review provides recent findings on comorbidity, summarizes mechanistic hypotheses, and outlines developments in treatment and services. Recent findings Depression occurs in up to one-quarter of patients with cardiovascular disease and diabetes. Depressed patients with heart disease have poorer medical outcomes including increased risk of reinfarction and all-cause mortality. Patients with diabetes and depression have poorer glycemic control, more diabetes symptoms, and greater all-cause mortality. Depression is associated with both biological (hypothalamic–pituitary–adrenal axis dysregulation) and psychosocial processes (adherence, poorer diet, and exercise) that may mediate adverse medical outcomes. Antidepressant treatments are effective in treating depression in medically ill patients, but their impact on medical outcomes remains to be quantified. Summary Depression, cardiovascular disease, and diabetes are among the most common chronic illnesses affecting an aging population. Depression is treatable in patients with medical illnesses, and collaborative care models can yield better detection and depression treatment in primary care settings in which most patients with depression are seen.

Line drawing as a possible measure of lateralized motor performance in schizophrenia

In this paper we suggest a new method, conceived by Maher, to assess lateralized motor performance in schizophrenia. Subjects draw two straight lines with each hand. The lines are scanned into a computer, and a regression is run on the points of the line. The root mean squared error (RMS) of the regression equation indicates the deviation from straightness of the line. The average RMS of all four lines is taken as an overall measure of motor disorder, and the difference in performance between the two hands serves as an index of motoric laterality. Scores on the motor disorder index were significantly positively related to clinical ratings of Parkinsonism among schizophrenic inpatients. A marginal relation was found to ratings of voluntary movement disorders, and the task was not associated with dyskinetic movements. Scores on the motor disorder measure were significantly worse for schizophrenic subjects than for staff controls. The laterality index significantly differentiated right- and left-handed subjects, but did not differentiate schizophrenic from control subjects. Mahers simple line drawing task yields objective continuous ratings of motor disorder and handedness and may be a useful tool for examining associations between motor functioning and cognition and symptomatology in schizophrenia.