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AimAttenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated.MethodsIn this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout.ConclusionsThis trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.

Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a "less-impaired" cognitive subtype, 2 subtypes with "intermediate cognitive impairment" differentiated by executive function performance, and a "globally impaired" cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P

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.

AimComputer-based virtual reality assessments of functional capacity have shown promise as a reliable and valid way to assess individuals with multi-episode schizophrenia. However, there has been little research utilizing this innovative approach with young patients who are in the early phase of schizophrenia.MethodsOutpatients in the early course of schizophrenia (n = 42) were compared to controls (n = 13) at cross-sectional study points. Patients were within 2 years of their first psychotic episode, were an average of 22.2 years old and had an average of 12.3 years of education. We used the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) and the University of California, San Diego (UCSD) Performance-Based Skills Assessment-2 (UPSA-2) to assess functional capacity. The MATRICS Consensus Cognitive Battery (MCCB) and the Cognitive Assessment Interview (CAI) were the measures of cognitive functioning. The Global Functioning Scale: Role (GFS-R) and Social (GFS-S), and the Role Functioning Scale (RFS) were the measures of daily functioning.ResultsEarly course patients vs controls were slower (patient M = 830.41 seconds vs control M = 716.84 seconds; t = 3.0, P

Computerized tests benefit from automated scoring procedures and standardized administration instructions. These methods can reduce the potential for rater error. However, especially in patients with severe mental illnesses, the equivalency of traditional and tablet-based tests cannot be assumed. The Brief Assessment of Cognition in Schizophrenia (BACS) is a pen-and-paper cognitive assessment tool that has been used in hundreds of research studies and clinical trials, and has normative data available for generating age- and gender-corrected standardized scores. A tablet-based version of the BACS called the BAC App has been developed. This study compared performance on the BACS and the BAC App in patients with schizophrenia and healthy controls. Test equivalency was assessed, and the applicability of paper-based normative data was evaluated. Results demonstrated the distributions of standardized composite scores for the tablet-based BAC App and the pen-and-paper BACS were indistinguishable, and the between-methods mean differences were not statistically significant. The discrimination between patients and controls was similarly robust. The between-methods correlations for individual measures in patients were r>0.70 for most subtests. When data from the Token Motor Test was omitted, the between-methods correlation of composite scores was r=0.88 (df=48; p

Regulatory guidance for schizophrenia cognition clinical trials requires that the assessment of cognitive change is accompanied by a functionally meaningful endpoint. However, currently available measures are challenged by resistance to change, psychometric weaknesses, and for interview-based assessments, dependence upon the presence of an informant. The aims of the current study were to: 1) assess the validity, sensitivity, and reliability of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) as a measure of functional capacity; 2) determine the association between performance on the VRFCAT and performance on the MATRICS Consensus Cognitive Battery (MCCB); and 3) compare the metrics of the VRFCAT with the UCSD Performance-based Skills Assessment (UPSA). 167 patients with schizophrenia and 166 healthy controls completed the VRFCAT, UPSA, and the MCCB at baseline. The VRFCAT and UPSA were completed again at follow-up. The VRFCAT, MCCB, and UPSA were very sensitive to impairment in schizophrenia (d=1.16 to 1.22). High test-retest reliability was demonstrated for VRFCAT total completion time and the UPSA total score in patients (ICC=0.81 and 0.78, respectively). The UPSA demonstrated significant practice effects in patients (d=0.35), while the VRFCAT did not (d=-0.04). VRFCAT total completion time was correlated with both UPSA (r=-0.56, p

ObjectivesThis trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia.MethodsIn 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18-65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50 mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score.ResultsSANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5 mg, 2-tailed P = .159; 50 mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated.ConclusionThese results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.

Background: Interventional trials in Alzheimer's Disease (AD) are increasingly targeting early disease stages. To optimize the likelihood of successful outcomes for these trials, there is an important need for tools capable of identifying individuals prone to exhibit clinical progression throughout the course of the trial. The Expanded Brief Assessment of Cognition (Expanded‐BAC) and the Virtual Reality Functional Capacity Assessment Tool – Short List (VRFCAT‐SLx) are two computerized tests assessing cognitive and functional abilities, respectively. They offer automated instructions and scoring, which significantly improves standardization and reduces administration errors. Importantly, they minimize reliance on caregiver availability, which can be a significant barrier to trial participation. The goal of this project was to evaluate the value of the Expanded‐BAC and VRFCAT‐SLx in predicting clinical progression in individuals with early AD. Method: A total of 51 participants with clinical diagnoses of MCI or early AD (NIA‐AA clinical criteria) completed both a baseline and follow‐up visit including the CDR, Expanded‐BAC, and VRFCAT‐SLx. The mean follow‐up interval was of 9.5 months (SD = 4.7 months). Clinical progression was operationalized as a change of 0.5 or more on the CDR Sum of Boxes score (CDR SoB) over the follow‐up interval. Baseline performance on the Expanded‐BAC and the VRFCAT‐SLx was contrasted between clinical progressors and non‐progressors using ANCOVAs adjusting for follow‐up duration. Linear regression models were computed to assess the predictive value of baseline performance on the Expanded‐BAC and the VRFCAT‐SLx on CDR SoB changes over time, also adjusting for follow‐up duration. Result: At follow‐up, there were 18 clinical progressors and 33 non‐progressors. The Expanded‐BAC composite score and the VRFCAT‐SLx total adjusted time at baseline significantly differed between progressors and non‐progressors, with progressors showing poorer performance on both measures (Figure 1). In linear regression models, performance at baseline on the Expanded‐BAC (r2 = 0.24, p<0.01) and the VRFCAT‐SLx (r2 = 0.16, p<0.05) significantly predicted changes in CDR SoB over the follow‐up interval. Conclusion: These preliminary results suggest that performance on the Expanded‐BAC and the VRFCAT‐SLx can predict clinical progression in individuals with early AD. These two computerized tests might thus be useful tools to identify individuals likely to exhibit clinical progression in the course of a trial. [ABSTRACT FROM AUTHOR]

Abstract Background Neurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs. Methods Data were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms. Results At baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied. Conclusion Processing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.

Evaluate lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy for executive dysfunction in partially or fully remitted major depressive disorder (MDD). This randomized, placebo-controlled study (NCT00985725) enrolled 143 adults (18-55 years) with mild MDD (Montgomery-Åsberg Depression Rating Scale (MADRS) score 18) and executive dysfunction (Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report Global Executive Composite (GEC) T score 60) on stable antidepressant monotherapy for 8 weeks. After 2 weeks of screening, participants were randomized to 9 weeks of double-blind LDX (20-70 mg/day) or placebo augmentation, followed by 2 weeks of single-blind placebo. The primary end point was change from baseline to week 9/end of study (EOS) in BRIEF-A Self-Report GEC T score; secondary assessments included the BRIEF-A Informant Report, MADRS, and treatment-emergent adverse events (TEAEs). Of 143 randomized participants, 119 completed double-blind treatment (placebo, n=59; LDX, n=60). Mean±standard deviation (SD) BRIEF-A GEC T scores decreased from baseline (placebo, 74.2±8.88; LDX, 76.8±9.66) to week 9/EOS (placebo, 61.4±14.61; LDX, 55.2±16.15); the LS mean (95% CI) treatment difference significantly favored LDX (−8.0 (−12.7, −3.3); P=0.0009). The LS mean (95% CI) treatment difference for MADRS total score also significantly favored LDX (−1.9 (−3.7, 0.0); P=0.0465). TEAE rates were 73.6% with placebo and 78.9% with LDX; serious TEAE rates were 4.2 and 2.8%. In this trial, LDX augmentation significantly improved executive dysfunction and depressive symptoms in participants with mild MDD. The safety profile of LDX was consistent with prior studies in adults with attention-deficit/hyperactivity disorder. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairments, such as memory deficits and executive impairment, are common among patients with major depressive disorder (MDD) and can be captured with objective or subjective assessments. The aim of this post-hoc analysis of the CONNECT study was to assess the degree of overlap between subjective and objective cognitive impairment among MDD patients, and to evaluate associated clinical characteristics., Methods: The study was conducted from April 2012 to February 2014 and enrolled a total of 602 patients with MDD who reported subjective cognitive impairment. Efficacy was assessed using a battery of objective tests of cognitive function representing multiple domains: Digit Symbol Substitution Test performance, Trail Making Test A, Trail Making Test B, Congruent and Incongruent Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task, and One-Back Task. The Cognitive and Physical Functioning Questionnaire (CPFQ) was used to capture patient-reported assessments of cognitive function., Results: Although 48% of patients with MDD met our conservative criteria for subjectively defined marked cognitive impairment, 64% of patients with MDD met our conservative criteria for objectively defined cognitive impairment. Therefore, the proportion of patients defined as having impaired cognition was somewhat similar regardless of methodology. Overall, 80% of patients with MDD in this study reported either subjective or objective cognitive impairment per subjective and objective scales. However, the proportion of patients meeting criteria for both subjectively and objectively defined cognitive impairment was only 31%. This could be explained by the fact that the CPFQ total score was only modestly-although significantly-correlated with all but one of the objective tests., Conclusions: This post-hoc study shows that approximately 80% of patients with MDD participating in an antidepressant trial reported either subjective or objective cognitive impairment.

Introduction: The Reasons for Antipsychotic Discontinuation Interview (RAD-I) was developed to assess patients' perceptions of reasons for discontinuing or continuing an antipsychotic. The current study examined reliability and validity of domain scores representing three factors contributing to these treatment decisions: treatment benefits, adverse events, and distal reasons other than direct effects of the medication., Methods: Data were collected from patients with schizophrenia or schizoaffective disorder and their treating clinicians. For approximately 25% of patients, a second rater completed the RAD-I for assessment of inter-rater reliability., Results: All patients (n = 121; 81 discontinuation, 40 continuation) reported at least one reason for discontinuation or continuation (mean = 2.8 reasons for discontinuation; 3.4 for continuation). Inter-rater reliability was supported (kappas = 0.63-1.0). Validity of the discontinuation domain scores was supported by associations with symptom measures (the Positive and Negative Syndrome Scale for Schizophrenia, the Clinical Global Impression - Schizophrenia Scale; r = 0.30 to 0.51; all P < 0.01), patients' primary reasons for discontinuation, and adverse events. However, the continuation domain scores were not significantly associated with these other indicators., Discussion: Results support the reliability, convergent validity, and known-groups validity of the RAD-I for assessing patients' reasons for antipsychotic discontinuation. Further research is needed to examine validity of the RAD-I continuation section.