The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests.

Comprehensive review of the research employing the schizophrenia cognition rating scale (SCoRS).

This review of research utilizing the Schizophrenia Cognition Rating Scale (SCoRS) outlines the development, evaluation, validation, and implementation of the SCoRS to assess whether the scale meets the criteria as a functional co-primary as defined by the MATRICS-CT initiative. Interview-based co-primary assessments should be: 1) practical and easy to administer for a clinician or researcher; 2) validated in individuals with schizophrenia; 3) contain the relevant areas of cognition and functioning applicable to schizophrenia; 4) able to assess all phases and severity levels of schizophrenia; 5) capable of monitoring disease progression; 6) minimal burden to patients; and 7) sensitive to assess treatment effects. A review of the literature was conducted to present information on the development, psychometric properties and usage of the SCoRS. Review of the development of the SCoRS followed the parameters outlined for scale development on content expert validation and feedback. The SCoRS shows good psychometric properties in various studies, and demonstrates low burden on clinicians and patients. The items measure global concepts that do not require notable cultural modification, making international use feasible. While multiple performance-based tests in cognition and functional outcomes are available, there is a need for a multi-domain, interview-based assessment of cognitive progression and treatment response in clinical trials. The SCoRS appears to meet many of the criteria for an optimal co-primary measure for schizophrenia cognition clinical trials as defined in the MATRICS-CT initiative.

Basic auditory processing deficits and their association with auditory emotion recognition in schizophrenia.

BACKGROUND: Individuals with schizophrenia are impaired in their ability to recognize emotions based on vocal cues and these impairments are associated with poor global outcome. Basic perceptual processes, such as auditory pitch processing, are impaired in schizophrenia and contribute to difficulty identifying emotions. However, previous work has focused on a relatively narrow assessment of auditory deficits and their relation to emotion recognition impairment in schizophrenia. METHODS: We have assessed 87 patients with schizophrenia and 73 healthy controls on a comprehensive battery of tasks spanning the five empirically derived domains of auditory function. We also explored the relationship between basic auditory processing and auditory emotion recognition within the patient group using correlational analysis. RESULTS: Patients exhibited widespread auditory impairments across multiple domains of auditory function, with mostly medium effect sizes. Performance on all of the basic auditory tests correlated with auditory emotion recognition at the p < .01 level in the patient group, with 9 out of 13 tests correlating with emotion recognition at r = 0.40 or greater. After controlling for cognition, many of the largest correlations involved spectral processing within the phase-locking range and discrimination of vocally based stimuli. CONCLUSIONS: While many auditory skills contribute to this impairment, deficient formant discrimination appears to be a key skill contributing to impaired emotion recognition as this was the only basic auditory skill to enter a step-wise multiple regression after first entering a measure of cognitive impairment, and formant discrimination accounted for significant unique variance in emotion recognition performance after accounting for deficits in pitch processing.

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms.

OBJECTIVE: Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. METHODS: Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). RESULTS: Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. CONCLUSIONS: Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

The Brief Assessment of Cognition In Affective Disorders (BAC-A):performance of patients with bipolar depression and healthy controls.

BACKGROUND: Cognitive deficits in bipolar disorder are significant enough to impact everyday functioning. A key question for treatments aimed at cognition is which cognitive domains are most affected by bipolar disorder and which cognitive tests have the best psychometric characteristics for this population. METHOD: 432 patients assessed at study entry in a treatment study of bipolar depression were assessed with a version of a new cognitive measure - the Brief Assessment of Cognition in Affective Disorder (BAC-A), which assesses traditional cognitive constructs with six subtests measuring memory, processing speed, working memory, and reasoning and problem solving, and a new measure of affective processing. From the cohort of 432 patients, 309 were selected based upon their demographic similarities to a previously collected healthy control sample of 309 subjects. Patients and controls completed the traditional cognitive tests and the Affective Processing Test. Results. Patients with bipolar depression and healthy controls differed significantly on all cognitive measures (P<0.001). The two alternate forms of the Affective Processing Test were very similar in both groups. The most robust discriminator of the groups was a composite score that combined the six core cognitive subtests of the Brief Assessment of Cognition (BAC) with two of the measures from the Affective Processing Test. LIMITATIONS: Test-retest reliabilities of the individual Affective Processing Test measures were low. CONCLUSION: The BAC-A is sensitive to the cognitive impairments in bipolar disorder patients in traditional neuropsychological domains and in cognitive processes believed to be specifically impaired in affective disorders.

Standardizing the use of the Continuous Performance Test in schizophrenia research: a validation study.

BACKGROUND: The Continuous Performance Test (CPT) has emerged as the most commonly administered measure of sustained attention, but use of discrepant versions reduces the ability of researchers and clinicians to accurately draw cross-study conclusions. In an effort to standardize use of the CPT, this study compared four versions of the Identical Pairs CPT for their reliability and ability to discriminate between patients with schizophrenia and healthy volunteers. The relationship of performance on the different versions of the CPT with measures of psychopathology, functioning, and other aspects of cognition was also examined. METHODS: Performance on the 2-digit, 3-digit, 4-digit, and Shapes Identical Pairs CPT was assessed at three test sessions over five weeks, during which subjects also completed the Brief Assessment of Cognition in Schizophrenia (BACS) and questionnaires assessing psychopathology and functioning. RESULTS: All four CPTs discriminated between patients with schizophrenia and healthy volunteers, but there were no statistical differences in sensitivity among the versions. The 3-digit CPT showed non-statistical advantages in that it had high test-retest reliability, low potential for a ceiling effect, and a very low rate of false alarms. There were also moderate correlations between CPT performance and performance of the BACS subtests, but no significant correlations between CPT performance and measures of psychopathology and functioning. CONCLUSIONS: While all versions of the CPT tested here had good psychometric characteristics, the 3-digit CPT-IP has some advantages in repeated measures studies such as clinical trials.

Feasibility and pilot efficacy results from the multisite Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) randomized controlled trial.

BACKGROUND: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established. METHOD: 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010. RESULTS: During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 (95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F(1,46) = 4.16, P = .047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F(1,47) = 2.26, P = .14). CONCLUSION: Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00930150.

Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS).

According to the recommendations of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Neurocognition Committee, one of the desired characteristics of a cognitive battery for assessing cognition in schizophrenia studies and clinical trials is the availability of normative data. This report describes normative data collected on the Brief Assessment of Cognition in Schizophrenia (BACS) from 404 healthy controls with demographic characteristics matching the 2005 United States Census of English-speakers. The six test measures demonstrated the expected pattern of correlations with age, gender, and education. Individual test scores were converted into standardized (T and z) scores and composite scores that were corrected for age and gender. An education-correction factor was calculated and recommended only for non-schizophrenia patients. Eight different verbal memory tests were found to have equivalent levels of difficulty.

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.

The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity.

OBJECTIVE: Interview-based measures of cognition may serve as potential coprimary measures in clinical trials of cognitive-enhancing drugs for schizophrenia. However, there is no such valid scale available. Interviews of patients and their clinicians are not valid in that they are unrelated to patients' levels of cognitive impairment as assessed by cognitive performance tests. This study describes the reliability and validity of a new interview-based assessment of cognition, the Schizophrenia Cognition Rating Scale (SCoRS), that involves interviews with patients and informants. METHOD: Sixty patients with schizophrenia were assessed with the SCoRS and three potential validators of an interview-based measure of cognition: cognitive performance, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS); real-world functioning, as measured by the Independent Living Skills Inventory; and functional capacity, as measured by the University of California, San Diego, Performance-Based Skills Assessment (UPSA). RESULTS: The SCoRS global ratings were significantly correlated with composite scores of cognitive performance and functional capacity and with ratings of real-world functioning. Multiple regression analyses suggested that SCoRS global ratings predicted unique variance in real-world functioning beyond that predicted by the performance measures. CONCLUSIONS: An interview-based measure of cognition that included informant reports was related to cognitive performance as well as real-world functioning. Interview-based measures of cognition, such as the SCoRS, may be valid coprimary measures for clinical trials assessing cognitive change and may also aid clinicians desiring to assess patients' level of cognitive impairment.

The relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome.

The Brief Assessment of Cognition in Schizophrenia (BACS) assesses five different domains of cognitive function with six tests, and takes about 30-35 minutes to complete in patients with schizophrenia. Previous work has demonstrated the reliability of this measure, and its sensitivity to the deficits of schizophrenia. However, the relationship of this brief cognitive measure to functional outcome has not been determined. Further, future registration trials for potentially cognitive enhancing compounds may not only assess efficacy with cognitive performance measures, but with assessments of real-world functional outcome and functional capacity. The purpose of this study was to determine the relationship between the BACS and a potential co-primary measure for treatment studies of cognition in schizophrenia, and to determine if such a measure accounts for significant variance in functioning beyond that provided by cognitive function. The current study assessed 60 patients with schizophrenia over the course of six months. Cognitive functions were measured with the BACS. Functional capacity was measured with the UCSD Performance-based Skills Assessment (UPSA). Real-world functional outcome was measured with the Independent Living Skills Inventory (ILSI). BACS composite scores were significantly correlated with functional capacity as measured by the UPSA (r = .65, df = 55, p < .001), and real-world functional outcome as assessed by the ILSI (r = .37, df = 56, p = .005). In multiple regression analyses, UPSA scores did not account for additional variance in real-world functioning beyond that accounted for by the BACS. These data suggest that brief cognitive assessments such as the BACS are able to assess aspects of cognition that are related to important functional measures in clinical trials of cognitive enhancement. They also suggest that the measures being considered as potential co-primary indicators of cognitive function for registration trials are significantly correlated with cognition as assessed by brief cognitive assessments.