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.

The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization.

OBJECTIVE: The consensus cognitive battery developed by the National Institute of Mental Health's (NIMH's) 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.

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 Health's 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.

How should DSM-V criteria for schizophrenia include cognitive impairment?

Neurocognitive impairment is considered a core component of schizophrenia and is increasingly under investigation as a potential treatment target. On average, cognitive impairment is severe to moderately severe compared with healthy controls, and almost all patients with schizophrenia demonstrate cognitive decrements compared with their expected level if they had not developed the illness. Compared with patients with affective disorders, cognitive impairment in schizophrenia appears earlier, is more severe, and tends to be more independent of clinical symptoms. While the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, description of schizophrenia includes several references to cognitive impairment, neither the diagnostic criteria nor the subtypology of schizophrenia include a requirement of cognitive impairment. We forward for consideration a proposal that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria include a specific criterion of "a level of cognitive functioning suggesting a consistent severe impairment and/or a significant decline from premorbid levels considering the patient's educational, familial, and socioeconomic background." The inclusion of this criterion may increase the "point of rarity" with affective psychoses and may increase clinicians' awareness of cognitive impairment, potentially leading to more accurate prognosis and better treatment outcomes. Future research will need to address the validity of these possibilities. The reliable determination of cognitive impairment as part of a standard diagnostic evaluation may present challenges to diagnosticians with limited resources or insufficient expertise. Various cognitive assessment methods for clinicians, including brief assessments and interview-based assessments, are discussed. Given the current emphasis on the development of cognitive treatments, the evaluation of cognition in schizophrenia is an essential component of mental health education.

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.

Recovery from schizophrenic psychoses within the northern Finland 1966 Birth Cohort.

BACKGROUND: Because of widely disparate findings from follow-up studies, the likelihood of recovery from schizophrenia remains controversial. We report the extent of recovery from schizophrenia in a population-based cohort. METHOD: Subjects with psychotic disorders were recruited from the Northern Finland 1966 Birth Cohort. Of the 91 subjects who agreed to participate, 59 were diagnosed with schizophrenia and 12 were diagnosed with schizophrenia spectrum disorders (schizophreniform psychosis, schizoaffective or delusional disorder) by DSM-III-R criteria. Diagnoses were established by interviewing the subjects, checking the Finnish Hospital Discharge Register, and reviewing their medical records. To assess recovery, we used the Clinical Global Impressions; the Positive and Negative Syndrome Scale; the Social and Occupational Functioning Assessment Scale; and information about psychiatric hospitalizations, use of antipsychotic medication, and occupational status. RESULTS: Only 1 subject (1.7%) with DSM-III-R schizophrenia and 3 subjects (25%) with schizophrenia spectrum disorders fully recovered; 1 schizophrenia subject (1.7%) and 2 schizophrenia spectrum subjects (16.7%) experienced partial recovery. CONCLUSION: The data indicate that, at least until age 35, complete recovery from schizophrenia is rare, and the prognosis for the disorder is far more serious than suggested by some follow-up studies.

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.

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.

Changing middle schoolers' attitudes about mental illness through education.

The field test of The Science of Mental Illness curriculum supplement for middle school (grades 6-8) children provided an opportunity to assess knowledge and attitudes about mental illness in more than 1,500 middle school students throughout the United States and to evaluate the impact of an educational intervention on stigma-related attitudes. Two primary questions were examined: (1) what are the baseline knowledge and attitudes about mental illness in this sample of middle school students, and (2) does participation in a curriculum about the science of mental illness increase knowledge and improve attitudes about mental illness? Consistent with findings from other studies, results indicate that students had some understanding of mental illness as a problem of the brain with biological and psychosocial causes; however, they lacked knowledge about treatment and overall were "not sure" about many aspects of mental illness. The students did not strongly endorse negative attitudes about mental illness at baseline. The curriculum produced significant improvements in both knowledge and attitudes at posttest and was most effective in improving attitudes among those with more negative baseline attitudes. These findings suggest that a brief educational program can be an effective intervention to increase knowledge and improve attitudes about mental illness.

Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder.

BACKGROUND: Prior reports of decreased levels of essential fatty acids among schizophrenic patients have generated several hypotheses proposing inherent abnormalities in phospholipid and fatty acid metabolism and have provided the basis for treatment trials; however, these essential fatty acid aberrations may be attributable to uncontrolled factors, such as smoking, rather than abnormalities inherent to schizophrenia. METHODS: Erythrocyte fatty acid compositions were quantified in 72 medicated schizophrenic or schizoaffective patients both at baseline and after 16 weeks of supplementation with 3 g/day of either ethyl-eicosapentaenoic acid or placebo. Current smoking status, gender, dietary survey, and Montgomery Asburg Depression Rating Scale, Repeatable Battery for the Assessment of Neuropsychological Status, Abnormal Involuntary Movement Scale, and Positive and Negative Syndrome Scale scores were assessed. RESULTS: Schizophrenic patients who smoked had lower baseline erythrocyte docosahexaenoic acid percent (2.98 +/-.7 vs. 3.59 +/- 1.2, p <.005) and eicosapentaenoic acid (EPA) percent (.39 +/-.13 vs. 47 +/-.22, p <.05), compared with nonsmokers, with a significant gender interaction (p <.01) in multivariate analyses of variance. Baseline arachidonic acid did not differ. Smokers reported lower dietary intake (percent total fat) of linolenic acid (F = 10.1, p <.003) compared with nonsmokers. Nonsmoking women reported greater dietary intake of EPA compared with smoking men or nonsmokers of either gender. CONCLUSIONS: Smoking status, gender, and dietary intake significantly predicted erythrocyte polyunsaturated fatty acid status among schizophrenic patients. No evidence was found for subgroups of schizophrenia or relationships to specific symptom severity on the basis of erythrocyte fatty acids. Prior reports of abnormalities of essential fatty acid metabolism among schizophrenic patients may have been an artifact of patients' smoking behavior and differences in dietary intake of omega-3 fatty acids.

Test-retest stability of the Repeatable Battery for the Assessment of Neuropsychological Status in schizophrenia.

OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was designed as a cognitive screening test, providing both a total scale score and five specific cognitive ability index scores. This study examined the test-retest stability of the RBANS in individual patients with schizophrenia relative to a healthy comparison group. METHOD: A total of 181 patients with schizophrenia or schizoaffective disorder were recruited from three clinical settings. Healthy comparison subjects were recruited as part of the RBANS standardization. Participants were administered one form of the RBANS on one occasion and another form at a later date, with intervals ranging from 1 to 134 days. RESULTS: Intraclass correlation coefficients for the RBANS total scale were 0.84 for the patients with schizophrenia and 0.77 for the healthy comparison subjects. Confidence intervals and percentile data for the total scale change scores were similar for both groups. CONCLUSIONS: The RBANS demonstrated reasonable intraclass correlation coefficient test-retest reliability for both schizophrenia patients and healthy comparison subjects. Confidence intervals are comparable to those previously published for the WAIS-R and Wechsler Memory Scale-Revised, suggesting that retest measurement error is not dramatically increased in the RBANS, despite the brevity of the test. These data may serve as an informative guide for using the RBANS to evaluate neuropsychological change on the level of the individual subject.

Cost and cost-effectiveness of hospital vs residential crisis care for patients who have serious mental illness.

BACKGROUND: This study evaluates the cost and cost-effectiveness of a residential crisis program compared with treatment received in a general hospital psychiatric unit for patients who have serious mental illness in need of hospital-level care and who are willing to accept voluntary treatment. METHODS: Patients in the Montgomery County, Maryland, public mental health system (N = 119) willing to accept voluntary acute care were randomized to the psychiatric ward of a general hospital or a residential crisis program. Unit costs and service utilization data were used to estimate episode and 6-month treatment costs from the perspective of government payors. Episodic symptom reduction and days residing in the community over the 6 months after the episode were chosen to represent effectiveness. RESULTS: Mean (SD) acute treatment episode costs was $3046 ($2124) in the residential crisis program, 44% lower than the $5549 ($3668) episode cost for the general hospital. Total 6-month treatment costs for patients assigned to the 2 programs were $19,941 ($19,282) and $25,737 ($21,835), respectively. Treatment groups did not differ significantly in symptom improvement or community days achieved. Incremental cost-effectiveness ratios indicate that in most cases, the residential crisis program provides near-equivalent effectiveness for significantly less cost. CONCLUSIONS: Residential crisis programs may be a cost-effective approach to providing acute care to patients who have serious mental illness and who are willing to accept voluntary treatment. Where resources are scarce, access to needed acute care might be extended using a mix of hospital, community-based residential crisis, and community support services.