Measurement And Treatment Research To Improve Cognition In Schizophrenia Research Articles

Neurocognitive Functioning in Individuals at Clinical High Risk for Psychosis

Neurocognitive functioning is a potential biomarker to advance detection, prognosis, and preventive care for individuals at clinical high risk for psychosis (CHR-P). The current consistency and magnitude of neurocognitive functioning in individuals at CHR-P are undetermined. To provide an updated synthesis of evidence on the consistency and magnitude of neurocognitive functioning in individuals at CHR-P. Web of Science database, Cochrane Central Register of Reviews, and Ovid/PsycINFO and trial registries up to July 1, 2020. Multistep literature search compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology performed by independent researchers to identify original studies reporting on neurocognitive functioning in individuals at CHR-P. Independent researchers extracted the data, clustering the neurocognitive tasks according to 7 Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) domains and 8 CHR-P domains. Random-effect model meta-analyses, assessment of publication biases and study quality, and meta-regressions were conducted. The primary effect size measure was Hedges g of neurocognitive functioning in individuals at CHR-P (1) compared with healthy control (HC) individuals or (2) compared with individuals with first-episode psychosis (FEP) or (3) stratified for the longitudinal transition to psychosis. A total of 78 independent studies were included, consisting of 5162 individuals at CHR-P (mean [SD; range] age, 20.2 [3.3; 12.0-29.0] years; 2529 [49.0%] were female), 2865 HC individuals (mean [SD; range] age, 21.1 [3.6; 12.6-29.2] years; 1490 [52.0%] were female), and 486 individuals with FEP (mean [SD; range] age, 23.0 [2.0; 19.1-26.4] years; 267 [55.9%] were female). Compared with HC individuals, individuals at CHR-P showed medium to large deficits on the Stroop color word reading task (g = -1.17; 95% CI, -1.86 to -0.48), Hopkins Verbal Learning Test-Revised (g = -0.86; 95% CI, -1.43 to -0.28), digit symbol coding test (g = -0.74; 95% CI, -1.19 to -0.29), Brief Assessment of Cognition Scale Symbol Coding (g = -0.67; 95% CI, -0.95 to -0.39), University of Pennsylvania Smell Identification Test (g = -0.55; 95% CI, -0.97 to -0.12), Hinting Task (g = -0.53; 95% CI, -0.77 to -0.28), Rey Auditory Verbal Learning Test (g = -0.50; 95% CI, -0.78 to -0.21), California Verbal Learning Test (CVLT) (g = -0.50; 95% CI, -0.64 to -0.36), and National Adult Reading Test (g = -0.52; 95% CI, -1.01 to -0.03). Individuals at CHR-P were less impaired than individuals with FEP. Longitudinal transition to psychosis from a CHR-P state was associated with medium to large deficits in the CVLT task (g = -0.58; 95% CI, -1.12 to -0.05). Meta-regressions found significant effects for age and education on processing speed. Findings from this meta-analysis support neurocognitive dysfunction as a potential detection and prognostic biomarker in individuals at CHR-P. These findings may advance clinical research and inform preventive approaches.

Cortical morphometric correlational networks associated with cognitive deficits in first episode schizophrenia

Schizophrenia (SCZ) is a chronic cognitive and behavioral disorder associated with abnormal cortical activity during information processing. Several brain structures associated with the seven performance domains evaluated using the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) have shown cortical volume loss in first episode schizophrenia (FES) patients. However, the relationship between morphological organization and MCCB performance remains unclear. Therefore, in the current observational study, high-resolution structural MRI scans were collected from 50 FES patients, and the morphometric correlation network (MCN) using cortical volume was established to characterize the cortical pattern associated with poorer MCCB performance. We also investigated topological properties, such as the modularity, the degree and the betweenness centrality. Our findings show structural volume was directly and strongly associated with the cognitive deficits of FES patients in the precuneus, anterior cingulate, and fusiform gyrus, as well as the prefrontal, parietal, and sensorimotor cortices. The medial orbitofrontal, fusiform, and superior frontal gyri were not only identified as the predominant nodes with high degree and betweenness centrality in the MCN, but they were also found to be critical in performance in several of the MCCB domains. Together, these results suggest a widespread cortical network is altered in FES patients and that performance on the MCCB domains is associated with the core pathophysiology of SCZ.

Sex-differential associations between cognitive impairments and white matter abnormalities in first episode and drug-naïve schizophrenia.

Previous evidence has suggested that schizophrenia patients may display sex differences in cognitive impairments and cognitive impairments are related to disrupted white matter (WM) microstructure. The current research aims to address the intriguing possibility for the sex-specific association between cognitive deficits and WM abnormalities in first-episode and drug-naïve schizophrenia. Cognitive performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) was measured in 39 FEND patients (females:males=23:16) and 30 healthy controls (females:males=17:13), together with whole-brain WM fractional anisotropy (FA) values determined using voxel-based diffusion tensor imaging. Correlations between cognitive performance and FA values were assessed. Patients performed significantly worse than healthy controls in the total score and most of the subscores of MCCB. Female patients displayed better cognitive performance than male patients on the Trail Making A Test, the Hopkins Verbal Learning Test and the Spatial Span Test in the Wechsler Memory Scale. More importantly, sex-differential association between cognitive performance and FA values was found in patients, but not in healthy controls. In particular, FA values in the cerebellum were negatively correlated with the continuous performance and digital sequence scores in male patients but positively correlated with the performance on the Spatial Span Test in the Wechsler Memory Scale in female patients. These findings suggest sex-specific neurobiological substrates involved in cognitive deficits in early-onset schizophrenia and have important implications for differentially targeted interventions between males and females.

Sex differences in association between clinical correlates and cognitive impairment in patients with chronic schizophrenia

Schizophrenia is a heterogeneous disorder with sex differences in clinical manifestations and cognitive function. However, the nature of its sex-specific relationship between clinical manifestations and cognitive impairment remains equivocal. This study aimed to explore the sex differences in the association between cognitive function and clinical features of hospitalized patients with schizophrenia. A total of 251 schizophrenia patients (males/females = 167/84) and 178 healthy controls (males/females = 84/94) were enrolled. Cognitive function was assessed through the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). The Positive and Negative Syndrome Scale (PANSS) was used to evaluate psychiatric symptoms in patients. Both male and female patients performed more impaired than their counterparts on all MCCB tests. However, only the scores of category fluency, attention and reasoning/problem solving of female patients were significantly lower than those of male patients. Multivariate regression analyses demonstrated that attention was independently associated with negative symptoms in female patients, and general psychopathology in male patients. Negative symptoms were also independently associated with verbal learning and memory and social cognition only in male patients, while general psychopathology was independently associated with symbol coding only in female patients. Our results suggest that there are noticeable sex differences in clinical features, cognitive impairment and their associations in schizophrenia patients. These sex-specific associations may provide useful information for future studies aimed at predicting and interfering with the outcome of schizophrenia from a sex perspective.

M108. CONCA: AN ONLINE COGNITIVE ASSESSMENT FOR USE WITH PATIENTS WITH PSYCHOSIS

BackgroundCognition is impaired in patient with psychosis and is predictive of functional outcomes. Despite this, cognitive function is not routinely assessed in clinical services in the United Kingdom. Collecting cognitive data for research is also labour-intensive and expensive. Web-based assessments may be a solution for these issues but to date, these have not been utilised in patients with psychosis or other psychiatric disorders.MethodsWe have developed an online cognitive battery for use in psychosis research (and broader mental health research) in collaboration with The Many Brains Project, website developers, patients and clinicians (Cardiff ONline Cognitive Assessment, CONCA). Tasks were selected to measure the domains outlined by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. We have undertaken a cross-validation study in those with schizophrenia (N=15), bipolar disorder (N=16), depression (N=15) and healthy controls (N=19) to compare the online tasks with the MATRICS battery. Following validation, we invited participants from the Cardiff Cognition in Schizophrenia Study (CardiffCOGS) and the National Centre for Mental Health (NCMH) to complete CONCA.ResultsCorrelations between CONCA and MATRICS tasks ranged from 0.25 to 0.73 in our validation sample (N=65). A total of 6960 individuals were invited to participate and 1227 consented to take part. There was a better response rate from NCMH participants (who were recruited more recently) compared to those from CardiffCOGS. Online participants recruited from NCMH were more highly educated (W=1171600, p<0.001) and more likely to be professionals (χ2(1)=5.4, p=0.02) than the original NCMH cohort. In CardiffCOGS, online participants were more highly educated than non-responders (W=7786.5, p=0.003). A total of 887 individuals met inclusion criteria for our analyses including 43 participants with schizophrenia, 146 with bipolar disorder, 261 with unipolar depression, 187 controls and 250 participants with other psychiatric disorders. Consistent with studies using offline assessments, participants with schizophrenia were the most severely impaired group (compared to controls: g=1.36, p<0.001), exhibiting greater impairments than participants with depression (g=1.04, p<0.001) and bipolar disorder (g=0.71, p=0.002). Of note, lower performance on the battery was associated with poorer functional outcome as assessed using the World Health Organisation’s Disability Assessment Scale (B=-1.77, SE=0.3, p=5.8 x 10–9).DiscussionWeb-based cognitive testing is a suitable method for collecting large-scale data in psychiatric populations, although there was some evidence of recruitment bias. The results of the validation and recruitment phases were used to inform selection of the final battery. We consulted with patients and health professionals from a youth psychosis service and NCMH’s patient involvement group to create a user-friendly interface and will continue to work with these groups to develop clinically useful feedback to facilitate patient monitoring in early intervention psychosis services.

Elevated serum anti-NMDA receptor antibody levels in first-episode patients with schizophrenia

Accumulating evidence has shown that N-methyl-D-aspartate (NMDA) glutamate receptors (NMDAR) are implicated in the pathophysiology of neurological and psychiatric disorders, and that patients with NMDAR antibody encephalitis develop psychopathological symptoms. Therefore, we hypothesized that NMDAR antibodies play a key role in the etiology of schizophrenia. In this study, we enrolled 110 first-episode patients with schizophrenia (FEP) and 50 healthy controls (HC). Cognitive function and psychopathology were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS), respectively. NMDAR antibody levels were measured using enzyme-linked immunosorbent assay. Our results showed that FEP with schizophrenia exhibited cognitive deficits in all domains of the MCCB and had elevated levels of serum anti-NMDAR antibody compared with the healthy controls (9.2 ± 3.5 vs. 7.3 ± 2.9 ng/ml, t = 3.10, p = 0.002). Furthermore, serum antibody levels were positively correlated with PANSS positive, negative and total score, and inversely correlated with performances of verbal learning and memory, working memory, speed of processing and MCCB total score in the patient group. These results indicate that elevated levels of NMDAR antibody may play a role in the pathogenesis of schizophrenia, leading to NMDAR dysfunction, thereby inducing symptoms of psychosis and cognitive impairment. Therefore, NMDAR antibodies may serve as a biomarker and provide a new avenue for treatment of schizophrenia.

Estudio de una nueva técnica psicoterapéutica grupal en esquizofrenia basada en el cine de ficción: efectos sobre síntomas positivos y negativos

IntroductionSchizophrenia is one of the mental disorders that generate the greatest human disability in the world. The treatment of negative symptoms in schizophrenia is still far from being resolved satisfactorily. The unique ability of cinema to activate attention, imagination and memory, as well as to activate complex mental processes in viewers leads one to think that it can be an effective therapeutic tool for the treatment of certain mental disorders. ObjectiveTo evaluate the efficacy of a new psychotherapeutic technique (designed ad hoc) based on the analysis of film sequences and double viewed using fiction films in patients diagnosed with spectrum disorders of schizophrenia and other psychotic disorders. MethodsA multicentre, randomised and parallel group clinical trial was conducted on 48 patients with a diagnosis of psychotic disorders of the schizophrenia spectrum. The effects of the application of a psychotherapeutic group therapy technique, based on the use of fiction films, were compared to a control group that also worked with fiction films, but using a non-specific technique. Three film analysis techniques with potential therapeutic properties were selected for the development of the new group psychotherapy technique: 1) the segmentation of the cinematic material into sequences, 2) the analysis by sequences of the contents of the film, 3) the double viewing of the cinematographic material. The intervention consisted of 26 sessions, which involved the double viewing of the 13 episodes of the first season of the television series Los Soprano. The primary outcome measures were the changes obtained in the Positive and Negative Syndrome Scale (PANSS) subscales, according to Wallwork's five-factor model, between the baseline and final situation after treatment. Cognitive outcome measurements included changes in the cognition scales included in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) and in social cognition scales, like MSCEIT, FEIT, and FBS (Mayer-Salovey-Caruso Emotional Intelligence Test, Facial Emotion Identification Test, and Frankfurt self-assessment scale for persons with schizophrenia, respectively), before and after treatment. ResultsThe results showed a statistically significant improvement in the experimental group versus the control group in the positive [P=.01; d=0.82 (95% CI; 0.2-1.43)], negative [P=.005; d=0.89 (95% CI; 0.26-1.51)] and disorganised symptoms [P=.013; d=0.49 (95% CI; 0.11-1.09)]. In the “post-hoc” analysis of the negative factor, statistically significant improvements were found in the following variables: blunted effect (P=.041, d=0.64 (95% CI; 0.03-1.24)], emotional withdrawal (P=.012, d=0.80 (95% CI; 0.18-1.41)], poor contact (P=.000, d=1.18 (95% CI; 0.52-1.82)], and motor retardation (P=.003, d=0.96 (95% CI; 0.33-1.58).] In the “post-hoc” analysis of the positive factor there was a significant improvement in the delusions subdomain [P=.01; d=0.82 (95% CI; 0.2-1.4).] No significant differences were found between groups in affective symptoms or in any of the cognitive domains. ConclusionsThe proposed new psychotherapy technique is applicable and well accepted by patients with schizophrenia and other psychotic disorders. The use of this new psychotherapy technique inspired in film analysis is effective in leading to improvements in the positive, negative, and disorganised symptoms in patients with schizophrenia.

S30. COMBINING PHARMACOTHERAPY OF BI 425809 WITH COMPUTERIZED COGNITIVE TRAINING IN PATIENTS WITH SCHIZOPHRENIA: A RANDOMIZED TRIAL METHODOLOGY

Trials of pharmacotherapies targeting cognition in schizophrenia have produced mainly negative results, and there are no approved cognition-enhancing pharmacological treatments available for patients with schizophrenia. This may be due in part to varying levels of concurrent cognitive stimulation, particularly for pharmacotherapies targeting neuroplasticity, which is activity-dependent (i.e. responds to cognitive demand). Often, the surroundings and environment of patients with schizophrenia provide only a low level of cognitive demand. At-home computerized cognitive training (CCT) can be one way to increase the level of environmental cognitive stimulation for these patients. BI 425809, a glycine transporter 1 inhibitor, increases glycine in the synaptic cleft and thus should lead to improved glutamatergic neurotransmission, synaptic neuroplasticity, and cognition. We describe a large randomized multicenter trial conducted across several countries that aims to explore whether enhanced cognitive stimulation through at-home CCT combined with BI 425809 pharmacotherapy could significantly improve cognition in patients with schizophrenia. This double-blind, parallel group trial plans to recruit patients with schizophrenia on stable antipsychotic therapy, across approximately 40 centers in 7 countries. We plan to randomize 200 patients who are compliant with CCT during a 2-week run-in period in a 1:1 ratio to either BI 425809 or placebo once daily for 12 weeks. The at home CCT should be optimally performed across 3–5 sessions (approximately 2.5 hours in total) per week. The primary endpoint will be change from baseline in neurocognitive function, measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 12 weeks of treatment. The neurocognitive composite score was selected specifically because it excludes the social cognition domain, which is typically targeted by separate training procedures. Novel exploratory endpoints include the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) to assess skills for daily functioning and the Balloon Effort task to assess the role of motivation in cognitive performance and also in patients’ willingness to comply with at-home CCT. Scores from the Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS), which is being developed to assess patients’ subjective experiences of cognitive impairment in schizophrenia, will also be assessed in a subset of patients. Initiation of the trial is planned for February 2019 and the last patient out is planned for December 2020. Results are expected in early 2021. This trial is critical to the field for several reasons. Firstly, the results will show if there is an enhanced benefit to combining pharmacotherapy with increased cognitive stimulation through at-home CCT in patients with schizophrenia. Second, the trial will evaluate the impact of BI 425809 with adjunctive CCT on outcomes relating to patients’ daily functioning, including the novel virtual reality test, VRFCAT. Third, the role of motivation in cognition, CCT compliance, and CCT performance will be explored. Finally, this trial will demonstrate if at-home CCT can be effectively implemented in a large trial across many centers and several countries. One key strength of this trial is the relatively large sample size which should result in robust data. Funding: Boehringer Ingelheim International GmbH (1346.38)

Association between Thalamocortical Functional Connectivity Abnormalities and Cognitive Deficits in Schizophrenia

Cognitive deficits are considered a core component of schizophrenia and may predict functional outcome. However, the neural underpinnings of neuropsychological impairment remain to be fully elucidated. Data of 59 schizophrenia patients and 72 healthy controls from a public resting-state fMRI database was employed in our study. Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery was used to measure deficits of cognitive abilities in schizophrenia. Neural correlates of cognitive deficits in schizophrenia were examined by linear regression analysis of the thalamocortical network activity with scores of seven cognitive domains. We confirmed the combination of reduced prefrontal-thalamic connectivity and increased sensorimotor-thalamic connectivity in patients with schizophrenia. Correlation analysis with cognition revealed that in schizophrenia (1) the thalamic functional connectivity in the bilateral pre- and postcentral gyri was negatively correlated with attention/vigilance and speed of processing (Pearson’s r ≤ −0.443, p ≤ 0.042, FWE corrected), and positively correlated with patients’ negative symptoms (Pearson’s r ≥ 0.375, p ≤ 0.003, FWE corrected); (2) the thalamic functional connectivity in the right cerebellum was positively correlated with speed of processing (Pearson’s r = 0.388, p = 0.01, FWE corrected). Our study demonstrates that thalamic hyperconnectivity with sensorimotor areas is related to the severity of cognitive deficits and clinical symptoms, and extends our understanding of the neural underpinnings of “cognitive dysmetria” in schizophrenia.

Cognitive deficits in subjects at risk for psychosis, first-episode and chronic schizophrenia patients

Background: Identifying the types and characteristics of cognitive deficits before the onset of schizophrenia and during its subsequent course could improve early detection and contribute to our understanding of the evolution of the core behavioral deficits underlying this disorder. Methods: This study used the Measurement and Treatment Research to Improve Cognition In Schizophrenia (MATRICS) battery to identify cognitive deficits and their progression during the course of schizophrenia from genetic high risk (HRF) subjects, subjects with prodromal symptoms (prodromal), and patients with first episode (FSCZ) and multi-episode (CSCZ) schizophrenia, compared to controls, in a Chinese Han population of 267 subjects. Results: There were statistically significant cognitive deficits which first appeared in prodromal subjects which were also present in FSCZ and CSCZ. There were no statistically significant differences between controls and HRF on any cognitive measure. Deficits in Visual Learning, Speed of Processing, and Overall Cognition were significantly correlated with some symptom measures on PANSS or SIPS. There were no statistically significant differences in cognitive deficits between FSCZ and CSCZ, and on most measures the patients with schizophrenia did not show a progression to more severe cognitive deficits than the prodromal subjects. Conclusions: In this sample of Chinese subjects, prodromal subjects showed significant cognitive deficits which were similar in most domains to those found in patients with schizophrenia. Whether the pattern of cognitive deficits on the MATRICS battery found in prodromal subjects will help predict conversion to diagnosed schizophrenia or other psychotic disorders would help determine how useful this profile of cognitive deficits is as a potential endophenotype for schizophrenia.

Guanfacine Augmentation of a Combined Intervention of Computerized Cognitive Remediation Therapy and Social Skills Training for Schizotypal Personality Disorder.

Impaired cognition is a hallmark of schizophrenia spectrum disorders, including schizotypal personality disorder, and it is the best predictor of functional outcome. Cognitive remediation therapy has demonstrated efficacy for improving cognition, augmenting other rehabilitation efforts in schizophrenia, and effecting gains in real-world functioning. Pharmacological augmentation of cognitive remediation has been attempted, but the effects of augmentation on combined therapies, such as cognitive remediation and social skills training, have not been studied. Twenty-eight participants with schizotypal personality disorder enrolled in an 8-week, randomized, double-blind, placebo-controlled trial of guanfacine plus cognitive remediation and social skills training (15 guanfacine, 13 placebo). Cognition was assessed with the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB), social cognition with the Movie for the Assessment of Social Cognition (MASC), and functional capacity with the University of California San Diego Performance-Based Skills Assessment (UPSA). A statistically significant pre- versus posttreatment effect was observed for MCCB speed of processing, verbal learning, and visual learning and UPSA total score. A significant time-by-medication (guanfacine, placebo) interaction was observed for MCCB reasoning and problem solving and UPSA total score; the time-by-treatment interaction approached significance for MASC hypomentalizing errors. Both guanfacine and cognitive remediation plus social skills training were well tolerated, with no side effects or dropouts. Participants treated with cognitive remediation, social skills training, and guanfacine demonstrated statistically significant improvements in reasoning and problem solving, as well as in functional capacity and possibly social cognition, compared with those treated with cognitive remediation, social skills training, and placebo. Cognitive remediation plus social skills training may be an appropriate intervention for individuals with schizotypal personality disorder, and guanfacine appears to be a promising pharmaceutical augmentation to this psychosocial intervention.

Effectiveness of Integrated Neurocognitive Therapy on Cognitive Impairment and Functional Outcome for Schizophrenia Outpatients.

Cognitive impairment is highly prevalent in patients with schizophrenia and schizoaffective disorder. Many interventions have been developed to treat cognitive deficit, since it has a strong impact on functional outcome; however, there are no integrated interventions targeting multiple neuro- and social-cognitive domains with a particular focus on the generalization of the effects of therapy on the functional outcome. Recently, a group of experts has developed a cognitive remediation group therapy approach called Integrated Neurocognitive Therapy (INT), which includes exercises to improve the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) neuro- and social-cognitive domains. This systematic review and meta-analysis aimed to assess the efficacy of this approach. We conducted a search of PubMed, Scopus, Web of Science, and PsycINFO to select primary studies evaluating INT in schizophrenic and schizoaffective patients. The primary outcomes of the meta-analysis included negative and positive symptoms and global functioning. Two randomized controlled trials met inclusion criteria. A total of 217 participants were included. Based on the results from the Positive and Negative Syndrome Scale (PANSS), a significant pooled effect size was observed for negative symptoms, which demonstrated not only an improvement in the patients treated immediately after therapy but also a permanence of positive results at a 9–12-month follow-up. On the other hand, no significant effect size was observed for positive symptoms. In addition, a significant pooled effect size was found for Global Assessment of Functioning (GAF), which shows how INT's integrated approach has lasting positive implications on patients' functional outcome. We concluded that INT might be an effective treatment for negative symptoms and global functioning in patients with schizophrenia, compared to treatment as usual (TAU).

Healthy Adolescent Performance With Standardized Scoring Tables for the MATRICS Consensus Cognitive Battery: A Multisite Study.

ObjectiveThe aim of this study was to develop standardized scores and scoring tables for test performance in healthy adolescents for the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for each year from 11 to 19 years of age, by sex, with T scores and percentile ranks.MethodsA total of 502 healthy participants (aged 11–19 years) from 7 cohorts from Ireland, Norway, Sweden, and United States, were included in this multisite study. Regression-predicted means for the MCCB tests, except the social cognition subtest, were calculated using the MCCB test scores as outcome variables and age, age2, sex, age × sex as predictors. The regression-predicted means for each combination of age and sex were added with the residuals from the entire cohort to yield the expected distribution of that group. Age effects were examined using regression models with age and age2 as predictors. Sex differences were examined using Student’s t-tests.ResultsSignificant positive age effects were found for all tests, except for the Brief Visuospatial Memory Test, revised (BVMT-R; measure of visual learning). Females performed significantly better than males on BACS Symbol coding (measure of speed of processing) and BVMT-R, while males performed significantly better than females on NAB Mazes (measure of reasoning and problem solving). Based on the regression-predicted distributions of scores, 19 standardized scoring tables for each test and domain were created.ConclusionsWith the results from this study, we have developed an accessible standardized data set of healthy adolescent test performance for the MCCB.

Examining cognition across the bipolar/schizophrenia diagnostic spectrum.

Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia. We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia (n = 558), schizoaffective disorder depressive type (n = 112), schizoaffective disorder type (n = 76), bipolar disorder (n = 78) and healthy participants (n = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis. Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance (d = 0.07, p = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, p < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, p < 0.001). There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups. Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.

An approach to directly link ICA and seed-based functional connectivity: Application to schizophrenia

Independent component analysis (ICA) and seed-based analyses are widely used techniques for studying intrinsic neuronal activity in task-based or resting scans. In this work, we show there is a direct link between the two, and show that there are some important differences between the two approaches in terms of what information they capture. We developed an enhanced connectivity-matrix independent component analysis (cmICA) for calculating whole brain voxel maps of functional connectivity, which reduces the computational complexity of voxel-based connectivity analysis on performing many temporal correlations. We also show there is a mathematical equivalency between parcellations on voxel-to-voxel functional connectivity and simplified cmICA. Next, we used this cost-efficient data-driven method to examine the resting state fMRI connectivity in schizophrenia patients (SZ) and healthy controls (HC) on a whole brain scale and further quantified the relationship between brain functional connectivity and cognitive performances measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Current results suggest that SZ exhibit a wide-range abnormality, primarily a decrease, in functional connectivity both between networks and within different network hubs. Specific functional connectivity decreases were associated with MATRICS performance deficits. In addition, we found that resting state functional connectivity decreases was extensively associated with aging regardless of groups. In contrast, there was no relationship between positive and negative symptoms in the patients and functional connectivity. In sum, we have developed a novel mathematical relationship between ICA and seed-based connectivity that reduces computational complexity, which has broad applicability, and showed a specific application of this approach to characterize connectivity changes associated with cognitive scores in SZ.

S80. NEUROCOGNITIVE FUNCTIONING IN YOUTH AT RISK OF SERIOUS MENTAL ILLNESS

BackgroundNeurocognitive deficits are associated with many serious mental illnesses (SMI), including schizophrenia, bipolar disorder, and major depressive disorder, and have been found to negatively impact social and occupational outcomes, clinical prognosis, and overall quality of life. These deficits have also been observed in people in earlier phases of schizophrenia, specifically in young people at clinical high risk (CHR) of psychosis. In these youth, neurocognitive deficits present at a level intermediate to healthy controls and those with early psychosis, indicating that mild impairments in neurocognitive functioning may be early markers of illness development. It is possible that neurocognitive deficits may be present in young people at risk of a range of SMI beyond the psychosis-spectrum, including affective and anxiety disorders. The aim of this study was to compare neurocognitive functioning in a sample of youth at risk of SMI across the different clinical stages described by McGorry and colleagues and compare them to healthy controls (HCs). It was hypothesized that participants in the later stages of risk, characterized by the presence of subthreshold psychiatric symptoms or attenuated syndromes, would exhibit impairments in neurocognitive performance compared to HCs and asymptomatic youth at familial high risk.MethodsThis was an observational, cross-sectional study of 243 male and female individuals between the ages of 12–26. The sample consists of participants in the Canadian Psychiatric Risk and Outcome Study (PROCAN) and included: asymptomatic participants at familial high risk for SMI (Stage 0; n=41); youth with early mood or anxiety symptoms (Stage 1a; n=52); youth with attenuated psychotic or affective syndromes and distress (Stages 1b; n=108); and HCs (n=42). The neurocognitive battery included the WRAT-4 reading task, WASI Vocabulary and WASI Matrix Reasoning tasks, and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). All neurocognitive tasks were administered at baseline. Group differences in neurocognitive performance were analyzed using MANCOVA/ANCOVA analyses. Covariates included age and sex.ResultsSubjects in Stage 0 and Stage 1a did not significantly differ from any group. Subjects in Stage 1b (attenuated syndromes) had significantly lower neurocognitive scores in the domains of speed of processing, working memory, attention/vigilance and reasoning and problem solving, and on composite scores of neurocognitive performance and full-scale IQ compared to HCs. A secondary analysis demonstrated that subjects in Stage 1b who met CHR status according to Criteria of Psychosis-risk Syndromes (n=83) had lower scores in the domains of working memory, verbal learning, and reasoning and problem solving and on the overall composite score than the other participants in Stage 1b who did not meet CHR criteria.DiscussionThis study provides evidence for a growing literature which suggests that neurocognitive deficits may be markers of susceptibility for SMI development. It also increases what is known about neurocognitive performance associated with different stages of risk for SMI. Identification of such impairments could aid with detection of early mental health problems prior to illness onset.

O9.8. STRESS AND COGNITIVE FUNCTION AMONG INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS: FINDINGS FROM THE NAPLS COHORT

BackgroundAccumulated evidence from non-human animal studies suggests that the prominent deficits in memory and executive function that characterise individuals with psychosis may, at least in part, be due to the effects of stress on the brain regions that support these functions. However, studies of patients with established psychosis have yielded inconsistent findings with regards to the relationship between stress and cognition, and research in high-risk populations is notably lacking. Utilising data from the North American Prodrome Longitudinal Study 2 (NAPLS 2), we aimed to further elucidate the relationship between stress (daily stressors, life events, and childhood trauma) and cognitive function in clinical high-risk (CHR) individuals and healthy controls (HC). We additionally explored the role of potential mediators [hypothalamic-pituitary-adrenal (HPA) axis function] and moderators (group status, sex, family history of illness).MethodsThe sample comprised 885 participants (CHR=646; HC=239) who completed measures of stress and cognitive function at the NAPLS 2 baseline assessment. Stress measures included the Daily Stress Inventory and a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale, both of which provided continuous measures of stress exposure (number of events) and distress (subjective feelings of distress). Participants were also interviewed using the Childhood Trauma and Abuse Scale to determine any exposure to childhood trauma (abuse, neglect, and bullying occurring prior to age 16 years). Basal HPA axis activity was determined via salivary cortisol samples obtained at the baseline assessment and standardised scores from selected subtests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) were used to derive two cognitive domain scores (memory and executive function). To examine relationships between stress and cognitive domain scores, linear regression analyses were performed on standardised variables.ResultsDaily stressor exposure, daily stressor distress, and life event exposure exhibited negative quadratic (i.e., inverted U-shaped) associations with both memory and executive function (P < 0.01 for all). In contrast, the reverse pattern (i.e., a negative linear relationship and a positive quadratic relationship) was shown in the model for life event distress and memory domain scores (P < 0.01) whilst trauma history showed only a trend-level association with poorer memory performance (P = 0.084). These relationships, which did not differ across CHR and healthy control groups, were largely unchanged after adjusting for demographic factors and salivary cortisol. Exploratory analyses suggested that trauma exposure and a family history of psychosis may moderate the relationship between daily stressors/life events and cognitive function.DiscussionIn this large sample of predominately CHR individuals, we observed that the association between stress and cognition is complex and differs across stressor types. The negative quadratic associations that we observed for daily stressor exposure, daily stressor distress, and life event exposure imply that whist lower levels of stress may facilitate memory and executive function, there may be a negative impact on cognition when these stressors become more frequent and distressing. Interventions aiming to minimise stress exposure and promote effective coping strategies might feasibly improve cognition in CHR individuals.

Dose reduction of risperidone and olanzapine can improve cognitive function and negative symptoms in stable schizophrenic patients: A single-blinded, 52-week, randomized controlled study.

The long-term effects of dose reduction of atypical antipsychotics on cognitive function and symptomatology in stable patients with schizophrenia remain unclear. We sought to determine the change in cognitive function and symptomatology after reducing risperidone or olanzapine dosage in stable schizophrenic patients. Seventy-five stabilized schizophrenic patients prescribed risperidone (≥4 mg/day) or olanzapine (≥10 mg/day) were randomly divided into a dose-reduction group ( n=37) and a maintenance group ( n=38). For the dose-reduction group, the dose of antipsychotics was reduced by 50%; for the maintenance group, the dose remained unchanged throughout the whole study. The Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery were measured at baseline, 12, 28, and 52 weeks. Linear mixed models were performed to compare the Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects and MATRICS Consensus Cognitive Battery scores between groups. The linear mixed model showed significant time by group interactions on the Positive and Negative Syndrome Scale negative symptoms, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, attention/vigilance, working memory and total score of MATRICS Consensus Cognitive Battery (all p<0.05). Post hoc analyses showed significant improvement in Positive and Negative Syndrome Scale negative subscale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, working memory and total score of MATRICS Consensus Cognitive Battery for the dose reduction group compared with those for the maintenance group (all p<0.05). This study indicated that a risperidone or olanzapine dose reduction of 50% may not lead to more severe symptomatology but can improve speed of processing, working memory and negative symptoms in patients with stabilized schizophrenia.

Right unilateral electroconvulsive therapy does not cause more cognitive impairment than pharmacologic treatment in treatment‐resistant bipolar depression: A 6‐month randomized controlled trial follow‐up study

Electroconvulsive therapy is an effective treatment for bipolar depression, but there are concerns about whether it causes long-term neurocognitive impairment. In this multicenter randomized controlled trial, in-patients with treatment-resistant bipolar depression were randomized to either algorithm-based pharmacologic treatment or right unilateral electroconvulsive therapy. After the 6-week treatment period, all of the patients received maintenance pharmacotherapy as recommended by their clinician guided by a relevant treatment algorithm. Patients were assessed at baseline and at 6months. Neurocognitive functions were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and autobiographical memory consistency was assessed using the Autobiographical Memory Interview-Short Form. Seventy-three patients entered the trial, of whom 51 and 26 completed neurocognitive assessments at baseline and 6months, respectively. The MATRICS Consensus Cognitive Battery composite score improved by 4.1 points in both groups (P=.042) from baseline to 6months (from 40.8 to 44.9 and from 41.9 to 46.0 in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively). The Autobiographical Memory Interview-Short Form consistency scores were reduced in both groups (72.3% vs 64.3% in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively; P=.085). This study did not find that right unilateral electroconvulsive therapy caused long-term impairment in neurocognitive functions compared to algorithm-based pharmacologic treatment in bipolar depression as measured using standard neuropsychological tests, but due to the low number of patients in the study the results should be interpreted with caution. ClinicalTrials.gov: NCT00664976.

P.1.j.006 - Examining cognition across the bipolar/schizophrenia diagnostic spectrum

BACKGROUND: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia. METHODS: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia (n = 558), schizoaffective disorder depressive type (n = 112), schizoaffective disorder type (n = 76), bipolar disorder (n = 78) and healthy participants (n = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis. RESULTS: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance (d = 0.07, p = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, p < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, p < 0.001). LIMITATIONS: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups. CONCLUSION: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.