Functional Outcome In Schizophrenia Research Articles

Cognitive impairment and functional outcomes in schizophrenia: a narrative review

Cognitive impairment and functional outcomes in schizophrenia: a narrative review

Negative symptoms and social cognition as mediators of the relationship between neurocognition and functional outcome in schizophrenia.

In this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia. The Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome. One hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome. Our results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.

“Food for Thought”: Improving Cognition in People With Schizophrenia

We have known that cognitive difficulties are related to functional outcomes in schizophrenia for many years. However, we have only paid attention to potential treatments relatively recently. This paper describes the development of cognitive remediation treatments to improve cognitive skills and their effects on functioning. It also reviews the types of cognitive remediation with some evidence on their effects. This evidence allowed the models of treatment to be clarified and led to a landmark paper by cognitive remediation experts around the world on the ingredients of cognitive remediation to have the best chance of benefit. This expert judgement on good clinical practice was justified by a large meta-analysis that supported the extra benefit of the four ingredients: an active therapist, massed practice of cognitive skills, the teaching of cognitive strategies and additional rehabilitation to transfer skills to real life. Although there is evidence of efficacy there is little implementation of cognitive remediation, so the review ends by suggesting a pathway to establish cognitive remediation into mental health services. The paper is a summary of a lecture given to the spring conference 2023 of the Korean Society of Schizophrenia Research. This review was also published in Psychiatric Investigation by agreement between the editors.

Moderators of functional improvement after integrative cognitive remediation in schizophrenia: Toward a personalized treatment approach

Cognitive remediation is an effective intervention for improving functional outcome in schizophrenia. However, the factors that moderate this improvement are still poorly understood. The study aimed to identify moderators of functional outcome improvement after integrative cognitive remediation (REHACOP) in schizophrenia. This was a secondary analysis of data from two randomized controlled trials, which included 182 patients (REHACOP group=94; active control group=88). Hierarchical regression analyses were conducted to identify moderators of functional outcome improvement. Two baseline level groups (low-level and high-level) were created to analyze the moderating role of this baseline level cluster using repeated measures ANCOVA. The REHACOP was effective regardless of participants’ baseline level, but regression analyses indicated that the effectiveness on functional outcome was higher among those who were older, had fewer years in education, lower scores in baseline cognition and functional outcome, and more negative symptoms. Repeated measures ANOVA showed that the baseline level cluster influenced the improvement in functional outcome, with the low-level group showing greater improvements. The results reinforced the need to implement cognitive remediation programs more broadly as a treatment for schizophrenia in healthcare services. Furthermore, they provided evidence for the development of personalized cognitive remediation plans to improve benefits in different schizophrenia profiles.

Efficacy of social cognition and interaction training in outpatients with schizophrenia spectrum disorders: randomized controlled trial.

Given the relationship between social cognition and functional outcome in schizophrenia, a number of social cognitive interventions have been developed, including Social Cognition Interaction Training (SCIT), a group-based, comprehensive, manualized intervention. In the current trial, we examined SCIT efficacy as well as potential moderators of treatment effects. Fifty-one outpatients were randomized to SCIT or a wait-list-control (WLC), with assessments of social cognition, neurocognition, self-report, symptoms, and functioning conducted at baseline and end of the active phase. Relative to WLC, we did not find significant improvements for SCIT on neurocognition, social cognition, self-report, or symptoms, though there was a trend-level, medium effect favoring the SCIT condition on interpersonal and instrumental role function. Post-hoc analyses indicated that baseline neurocognition did not impact degree of social cognitive or functional change. Shorter duration of illness was significantly associated with better post-training neurocognition and self-esteem and, at trend-level with better symptoms and social functioning. We discuss the importance of outcome measure selection and the need for continued evaluation of potential treatment moderators in order to better match people to existing treatments. Clinical trial registration: Clinicaltrials.gov, Identifier NCT00587561.

Markov chain analysis indicates that positive and negative emotions have abnormal temporal interactions during daily life in schizophrenia

Abnormalities in positive and negative emotional experience have been identified in laboratory-based studies in schizophrenia (SZ) and associated with poorer clinical outcomes. However, emotions are not static in daily life–they are dynamic processes that unfold across time and are characterized by temporal interactions. Whether these temporal interactions are abnormal in SZ and associated with clinical outcomes is unclear (i.e., whether the experience of positive/negative emotions at time t increases or decreases the intensity of positive/negative emotions at time t+1). In the current study, participants with SZ (n = 48) and healthy controls (CN; n = 52) completed 6 days of ecological momentary assessment (EMA) surveys that sampled state emotional experience and symptoms. The EMA emotional experience data was submitted to Markov chain analysis to evaluate transitions among combined positive and negative affective states from time t to t+1. Results indicated that: (1) In SZ, the emotion system is more likely to stay in moderate or high negative affect states, regardless of positive affect level; (2) SZ transition to co-activated emotional states more than CN, and once emotional co-activation occurs, the range of emotional states SZ transition to is more variable than CN; (3) Maladaptive transitions among emotional states were significantly correlated with greater positive symptoms and poorer functional outcome in SZ. Collectively, these findings clarify how emotional co-activation occurs in SZ and its effects on the emotion system across time, as well as how negative emotions dampen the ability to sustain positive emotions across time. Treatment implications are discussed.

Efficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, A Phase III Randomized Controlled Trial Program

AbstractIntroductionCognitive impairment is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits in glutamatergic signaling play a key role in the neuropathology of cognitive symptoms. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamatergic signaling by increasing synaptic levels of the N-methyl-D-aspartate receptor co-agonist, glycine. A 12-week, Phase II trial (NCT02832037) in 509 patients with schizophrenia demonstrated that iclepertin was well tolerated and significantly improved cognition. The Phase III CONNEX program aims to confirm the efficacy, safety, and tolerability of iclepertin in improving cognition and functioning in a larger cohort of patients.MethodsCONNEX consists of three replicate randomized, double-blind, placebo-controlled parallel-group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit ~586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug; ≥35 days on current dose prior to treatment), who have functional impairment in day-to-day activities, and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological, or other disorders, or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centers across 32 countries in Asia, North and South America, and Europe, and randomized 1:1 to receive either oral iclepertin 10 mg (n=293), or placebo (n=293) once daily over 26 weeks. The primary efficacy endpoint is change from baseline (CfB) in the MATRICS Consensus Cognitive Battery overall composite T-score. Key secondary efficacy endpoints are CfB in Schizophrenia Cognition Rating Scale total score and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety and tolerability data will be collected in an open-label safety extension study (CONNEX-X).ResultsThe studies are currently recruiting (first patients enrolled Aug–Sept 2021), with completion expected in Q2 2024. Here we present an overview of the current study status, including any information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multi-center study.ConclusionTo date, most large, industry-sponsored studies testing various compounds to address cognitive function have failed to show proof-of-clinical concept. Demonstration of efficacy of iclepertin in improving cognition in this Phase III program would provide important insight into the role of glutamate in cognitive symptoms that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.FundingBoehringer Ingelheim International GmbH (1346-0011, NCT04846868; 1346-0012, NCT04846881; 1346-0013, NCT04860830)

Real-life functioning in women with schizophrenia living in residential facilities: Gender-based comparison.

Despite many patients with schizophrenia being able to achieve good functional outcomes, the number of patients with poor functional outcome estimates at over 25 percent. One of the wider constructs, reflecting functional outcomes in schizophrenia, is real-life functioning, whose key domains include ability to live relatively autonomously, productive activity and social interaction. Negative symptoms are seen among independent predictors of real-life functioning. As most researchers agree that schizophrenia is a disease with gender differences in terms of both clinical and functional outcomes, the goal of our observational study was to examine real-life functioning of women with schizophrenia, living in residential care facilities, and study the relationship between daily functioning and negative symptoms. Using the Standardized Protocol of Clinical Interview and observation for 1 or more weeks, we examined 46 females with schizophrenia, living in psychiatric residential facilities and compared them with 54 males with schizophrenia, living in the same facilities. In a pilot study 21 subjects with schizophrenia (13 females and 8 males), were evaluated by the Russian version of the Brief Negative Symptom Scale (BNSS). To the results, more females with schizophrenia, compared to males with schizophrenia, remained active and took initiative in their physical care, vocational activities, involvement in cultural events, and maintained friendly relationships with other inmates. We have identified a group of inmates, in which females prevailed, with less pronounced negative symptoms and a higher level of social functioning, who did not need residential social care in the institutions. Limitations of residential social care in the institutions for psychiatric patients are discussed.

Emotion-behaviour decoupling and experiential pleasure deficits predict negative symptoms and functional outcome in first-episode schizophrenia patients.

Emotion-behaviour decoupling refers to the failure to translate emotion into motivated behaviour, and is a putative marker for schizophrenia. The heterogeneity of experiential pleasure and emotion expressivity deficits has been reported in schizophrenia patients. These three constructs are believed to contribute to negative symptoms, but very few studies have examined their predictive ability for clinical and functional outcome of schizophrenia. This study aimed to clarify whether these three constructs influence clinical and functional outcome of schizophrenia. At baseline, 127 first-episode schizophrenia patients completed a behavioural paradigm for emotion-behaviour decoupling, and self-report scales for experiential pleasure and emotion expressivity deficits. Cluster-analysis was applied to characterize schizophrenia subgroups based on these three constructs. At end-point (mean follow-up = 5.37 years, SD = 1.03 years), 85 schizophrenia patients were reassessed using the Clinical Assessment Interview for Negative Symptoms (CAINS) and a clinician-rated social functioning scale. Cluster 1 (n=74) did not show emotion-behaviour decoupling, and had intact experiential pleasure and emotion expressivity. Cluster 2 (n=29) showed emotion-behaviour decoupling and experiential pleasure deficits. Cluster 3 (n=24) showed emotion expressivity deficits. At endpoint, the three clusters differed significantly in CAINS MAP factor (p=0.016) and social functioning (p=0.019), but not CAINS EXP factor. Specifically, Cluster 2 (n=18) showed more severe negative symptoms of CAINS MAP factor (p=0.046) and poorer social functioning (p=0.022) than Cluster 1 (n=49). Cluster 3 (n=18) did not differ from Cluster 1 and Cluster 2 in negative symptoms and social functioning. Emotion-behaviour decoupling and experiential pleasure deficits predicted clinical and functional outcome of schizophrenia.

Human stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review.

Cognitive impairment is the strongest predictor of functional outcomes in schizophrenia and is hypothesized to result from synaptic dysfunction. However, targeting synaptic plasticity and cognitive deficits in patients remains a significant clinical challenge. A comprehensive understanding of synaptic plasticity and the molecular basis of learning and memory in a disease context can provide specific targets for the development of novel therapeutics targeting cognitive impairments in schizophrenia. Here, we describe the role of synaptic plasticity in cognition, summarize evidence for synaptic dysfunction in schizophrenia and demonstrate the use of patient derived induced-pluripotent stem cells for studying synaptic plasticity in vitro. Lastly, we discuss current advances and future technologies for bridging basic science research of synaptic dysfunction with clinical and translational research that can be used to predict treatment response and develop novel therapeutics.

Collaborating with the people who experience psychosis: From subjects to partners

IntroductionDespite the critical role of motivation in psychosocial treatment and rehabilitation, as well as functional outcomes in schizophrenia, service user voices are not always present in setting research agendas on this topic. This is important since the service user’s involvement in the research process helps prioritize research questions (Wykes et al., 2015).ObjectivesWe have begun a consultation process to bridge the gap between research and practice on ‘motivation in schizophrenia.’ The study’s main objective was to produce the means to increase motivation in schizophrenia from the perspective of users.MethodsIn the current study, we asked the service users about the priorities for ‘motivation and schizophrenia’ research and also suggested involving service users in research itself as partners. Expert Panels with peer leaders previously involved in psychosocial rehabilitation programs took place. A total of 12 Panels (group meetings) were held during the year with three users (schizophrenia spectrum outpatients) aged 45, 47, and 50, male. The reports were analysed using content analysis to generate main themes and findings (Braun & Clarke, 2006).ResultsThe users’ elements of motivation may differ from organizationally defined ones; this may be related to different opinions and ethical standards among clinicians on patients’ autonomy and right to refuse treatment. A discussion of the topics patients have developed to improve the motivation, engagement, and management of patients with schizophrenia in psychosocial treatment and rehabilitation is presented.ConclusionsThe approach successfully generated items for questionnaires that usesr participants declared with a sence of pride in and ownership of. It is, therefore, possible to create measures of motivation that users feel reflect their understanding and experiences. The outcome of this research is that other Russian researchers will be inspired to follow the same patrnership path and encourage service users to participate rather than be subjected to research.Disclosure of InterestNone Declared

Interactions between dopamine transporter and N-methyl-D-aspartate receptor-related amino acids on cognitive impairments in schizophrenia

IntroductionCognitive impairments, the main determinants of functional outcomes in schizophrenia, had limited treatment responses and need a better understanding of the mechanisms. Dysfunctions of the dopamine system and N-methyl-D-aspartate receptor (NMDAR), the primary pathophysiologies of schizophrenia, may impair cognition.ObjectivesThis study explored the effects and interactions of striatal dopamine transporter (DAT) and plasma NMDAR-related amino acids on cognitive impairments in schizophrenia.MethodsWe recruited 36 schizophrenia patients and 36 age- and sex-matched healthy controls (HC). All participants underwent cognitive assessments of attention, memory, and executive function. Single-photon emission computed tomography with 99mTc-TRODAT and ultra-performance liquid chromatography were applied to determine DAT availability and plasma concentrations of eight amino acids, respectively.ResultsCompared with HC, schizophrenia patients had lower cognitive performance, higher methionine concentrations, decreased concentrations of glutamic acid, cysteine, aspartic acid, arginine, the ratio of glutamic acid to gamma-aminobutyric acid (Glu/GABA), and DAT availability in the left caudate nucleus (CN) and putamen. Regarding memory scores, Glu/GABA and the DAT availability in left CN and putamen exhibited positive relationships, while methionine concentrations showed negative associations in all participants. The DAT availability in left CN mediated the methionine-memory relationship. An exploratory backward stepwise regression analysis for the four biological markers associated with memory indicated that DAT availability in left CN and Glu/GABA remained in the final model.ConclusionsThis study demonstrated the interactions of striatal DAT and NMDAR-related amino acids on cognitive impairments in schizophrenia. Future studies to comprehensively evaluate their complex interactions and treatment implications are warranted.Disclosure of InterestNone Declared

Gene Expression and Epigenetic Regulation in the Prefrontal Cortex of Schizophrenia.

Schizophrenia pathogenesis remains challenging to define; however, there is strong evidence that the interaction of genetic and environmental factors causes the disorder. This paper focuses on transcriptional abnormalities in the prefrontal cortex (PFC), a key anatomical structure that determines functional outcomes in schizophrenia. This review summarises genetic and epigenetic data from human studies to understand the etiological and clinical heterogeneity of schizophrenia. Gene expression studies using microarray and sequencing technologies reported the aberrant transcription of numerous genes in the PFC in patients with schizophrenia. Altered gene expression in schizophrenia is related to several biological pathways and networks (synaptic function, neurotransmission, signalling, myelination, immune/inflammatory mechanisms, energy production and response to oxidative stress). Studies investigating mechanisms driving these transcriptional abnormalities focused on alternations in transcription factors, gene promoter elements, DNA methylation, posttranslational histone modifications or posttranscriptional regulation of gene expression mediated by non-coding RNAs.

History of learning disorders is associated with worse cognitive and functional outcomes in schizophrenia: results from the multicentric FACE-SZ cross-sectional dataset.

Schizophrenia is associated with early neurodevelopmental disorders, including most frequently learning disorders (LD), among them dyslexia and dyspraxia. Despite the demonstrated links between schizophrenia and LD, specific clinical patterns of the schizophrenia with a history of LD subgroup remain unknown. The aim of the present study was to investigate cognitive impairment, symptoms and functional outcome associated with a history of LD in a large cross-sectional, multicentric, sample of schizophrenia subjects. 492 community-dwelling subjects with schizophrenia (75.6% male, mean age 30.8years) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. The 51 (10.4%) subjects identified with a history of LD had significantly impaired general cognitive ability (Wechsler Adult Intelligence Scale Full Scale Total IQ: Cohen's d = 0.50, p = 0.001), processing speed (d = 0.19), verbal comprehension (d = 0.29), working memory (d = 0.31), cognitive inhibition and flexibility (d = 0.26), central executive functioning (d = 0.26), phonemic verbal fluency (d = 0.22) and premorbid intellectual ability (d = 0.48), as well as with a worse functional outcome (Global Assessment of Functioning, d = 0.21), independently of age, sex, education level, symptoms, treatments, and addiction comorbidities. These results indicate that a history of LD is associated with later cognitive impairment and functional outcome in schizophrenia. This suggests that history of LD is a relevant clinical marker to discriminate subgroups of patients with schizophrenia with different profiles in a precision psychiatry framework.

Understanding the relationship between apathy, cognition and functional outcome in schizophrenia: The significance of an ecological assessment.

In recent years there has been an increasing interest in understanding the role apathy plays in mediating the relationship between cognitive impairment and functional outcome. In general, most studies measure cognition with traditional cognitive tests that give explicit instructions and guide the participants toward generating a response. However, given that apathy is defined by a decrease in self-initiated behavior, it is crucial to evaluate cognition with ecological tasks that do not explicitly direct the patient´s motivation to generate behaviors to assess the actual effect. This study investigated whether an ecological cognitive assessment (the Jansari Executive Function Assessment, JEF©) would uniquely contribute to the relationship between cognition, apathy, and functional outcome in schizophrenia. The Apathy Evaluation Scale (AES), neuropsychological tests and the JEF© were administered to 20 patients with schizophrenia. Hierarchical multiple regression and mediation analysis were performed to test the associations between the variables of interest. Results showed that JEF© explained a significant portion of the variance in AES (25%). In addition, apathy explained 36% of the variance in functional outcome. However, AES did not mediate between cognition and functional outcome. Our results highlight the importance of assessing cognition with tasks that require integration of cognitive functions needed for real life demands.

Relation between frontal pole volumes and cognitive insight in Schizophrenia.

Cognitive insight comprising self-reflection and self-certainty is an important determinant of functional outcomes in Schizophrenia. The neural correlates of cognitive insight in Schizophrenia are underexamined. The frontal pole (FP) is implicated in metacognitive function in healthy individuals, but its role is not well examined in Schizophrenia. We had earlier reported the relationship between Frontal pole volumes and cognitive insight in a small sample of only male patients. Hence, we studied this relationship in an independent sample of schizophrenia patients and healthy controls. We examined 41 healthy volunteers (HV) and 57 patients with Schizophrenia (SCZ). We used a previously validated manual morphometric method to perform FP parcellation on images obtained from a 3T scanner and calculated the volumes. Cognitive insight was measured using Beck's Cognitive insight scale (BCIS). To assess the relationship between FP volumes and BCIS scores, multiple linear regression analyses were performed. In the overall sample, age, years of education, and intracranial volume were significant predictors of BCIS scores. Within the SCZ group, age and left FP volume were significant predictors of BCIS composite scores and age, ICV for BCIS-self certainty. There was no significant relationship between age and FP volumes in either SCZ or HV group. The current study in an independent sample further supports the critical role of the frontal pole in cognitive insight, earlier reported by us. As cognitive insight has a vital role in functional outcome, our findings have potential clinical implications.

Antipsychotic Augmentation With N-Acetylcysteine for Patients With Schizophrenia.

N-acetylcysteine (NAC) augmentation of antipsychotic medication is one of very many antipsychotic augmentation strategies that have been studied in schizophrenia. A recent systematic review and meta-analysis of 6 randomized controlled trials (RCTs) found that NAC (median dose, 2,000 mg/d) improved several clinical outcomes at different time points with medium to large effect sizes; however, many of the significant findings in this meta-analysis are suspect because they appeared to be influenced by 2 short-term (8-week) RCTs with outlying characteristics. Important findings not influenced by the 2 outlying RCTs were significant attenuation by NAC of negative symptom (3 RCTs) and total psychopathology (2 RCTs) ratings at ≥ 24 weeks and improvement in working memory but not processing speed (3 RCTs). Of these findings, reduction in psychopathology ratings, though statistically significant, appeared too small to be clinically meaningful. Finally, a newly published, moderately large RCT of NAC (2,000 mg/d) in schizophrenia patients refractory to clozapine found that 1 year of treatment with NAC did not outperform placebo for any clinical, cognitive, or quality of life outcome. The take-home message is that it is premature to recommend the use of NAC to treat schizophrenia for any target domain in routine clinical practice and that there does not appear to be a role for NAC for any indication in clozapine-refractory schizophrenia. However, it may be worth studying whether NAC, dosed at 2,000 mg/d or higher for 6 months or longer, improves functional outcomes in schizophrenia.

Interactions between dopamine transporter and N-methyl-d-aspartate receptor-related amino acids on cognitive impairments in schizophrenia

BackgroundCognitive impairments, the main determinants of functional outcomes in schizophrenia, had limited treatment responses and need a better understanding of the mechanisms. Dysfunctions of the dopamine system and N-methyl-d-aspartate receptor (NMDAR), the primary pathophysiologies of schizophrenia, may impair cognition. This study explored the effects and interactions of striatal dopamine transporter (DAT) and plasma NMDAR-related amino acids on cognitive impairments in schizophrenia. MethodsWe recruited 36 schizophrenia patients and 36 age- and sex-matched healthy controls (HC). All participants underwent cognitive assessments of attention, memory, and executive function. Single-photon emission computed tomography with 99mTc-TRODAT and ultra-performance liquid chromatography were applied to determine DAT availability and plasma concentrations of eight amino acids, respectively. ResultsCompared with HC, schizophrenia patients had lower cognitive performance, higher methionine concentrations, decreased concentrations of glutamic acid, cysteine, aspartic acid, arginine, the ratio of glutamic acid to gamma-aminobutyric acid (Glu/GABA), and DAT availability in the left caudate nucleus (CN) and putamen. Regarding memory scores, Glu/GABA and the DAT availability in left CN and putamen exhibited positive relationships, while methionine concentrations showed negative associations in all participants. The DAT availability in left CN mediated the methionine-memory relationship. An exploratory backward stepwise regression analysis for the four biological markers associated with memory indicated that DAT availability in left CN and Glu/GABA remained in the final model. ConclusionsThis study demonstrated the interactions of striatal DAT and NMDAR-related amino acids on cognitive impairments in schizophrenia. Future studies to comprehensively evaluate their complex interactions and treatment implications are warranted.

Efficacy of Integrated Social Cognitive Remediation vs. Neurocognitive Remediation in Improving Functional Outcome in Schizophrenia: Concept and Design of a Multicenter, Single-Blind RCT (The ISST Study).

BackgroundAlthough clinically effective treatment is available for schizophrenia, recovery often is still hampered by persistent poor psychosocial functioning, which in turn is limited by impairments in neurocognition, social cognition, and social behavioral skills. Although cognitive remediation has shown general efficacy in improving cognition and social functioning, effects still need to be improved and replicated in appropriately powered, methodologically rigorous randomized controlled trials (RCTs). Existing evidence indicates that effects can most likely be optimized by combining treatment approaches to simultaneously address both social cognitive and social behavioral processes.ObjectivesTo assess whether Integrated Social Cognitive and Behavioral Skill Therapy (ISST) is more efficacious in improving functional outcome in schizophrenia than the active control treatment Neurocognitive Remediation Therapy (NCRT).MethodsThe present study is a multicenter, prospective, rater-blinded, two-arm RCT being conducted at six academic study sites in Germany. A sample of 180 at least partly remitted patients with schizophrenia are randomly assigned to either ISST or NCRT. ISST is a compensatory, strategy-based program that targets social cognitive processes and social behavioral skills. NCRT comprises mainly drill and practice-oriented neurocognitive training. Both treatments consist of 18 sessions over 6 months, and participants are subsequently followed up for another 6 months. The primary outcome is all-cause discontinuation over the 12-month study period; psychosocial functioning, quality of life, neurocognitive and social cognitive performance, and clinical symptoms are assessed as secondary outcomes at baseline before randomization (V1), at the end of the six-month treatment period (V6), and at the six-month follow-up (V12).DiscussionThis RCT is part of the German Enhancing Schizophrenia Prevention and Recovery through Innovative Treatments (ESPRIT) research network, which aims at using innovative treatments to enhance prevention and recovery in patients with schizophrenia. Because this study is one of the largest and methodologically most rigorous RCTs on the efficacy of cognitive remediation approaches in schizophrenia, it will not only help to identify the optimal treatment options for improving psychosocial functioning and thus recovery in patients but also allow conclusions to be drawn about factors influencing and mediating the effects of cognitive remediation in these patients.Trial RegistrationClinicalTrials.gov NCT 02678858, German Study Register DRKS 00010033

Shape features of working memory-related deep-brain regions differentiate high and low community functioning in schizophrenia

We have previously shown that schizophrenia (SCZ) participants with high community functioning demonstrate better verbal working memory (vWM) performance relative to those with low community functioning. In the present study, we investigated whether neuroanatomical differences in regions supporting vWM also exist between schizophrenia groups that vary on community functioning. Utilizing magnetic resonance imaging, shape features of deep-brain nuclei known to be involved in vWM were calculated in samples of high functioning (HF-SCZ, n = 23) and low functioning schizophrenia participants (LF-SCZ, n = 18), as well as in a group of healthy control participants (CON, n = 45). Large deformation diffeomorphic metric mapping was employed to characterize surface anatomy of the caudate nucleus, globus pallidus, hippocampus, and thalamus. Statistical analyses involved linear mixed-effects models and vertex-wise contrast mapping to assess between-group differences in structural shape features, and Pearson correlations to evaluate relationships between shape metrics and vWM performance. We found significant between-group main effects in deep-brain surface anatomy across all structures. Post-hoc comparisons revealed HF-SCZ and LF-SCZ groups significantly differed on both caudate and hippocampal shape, however, significant correlations with vWM were only observed in hippocampal shape for both SCZ groups. Specifically, more abnormal hippocampal deformation was associated with lower vWM suggesting hippocampal shape is both a neural substrate for vWM deficits and a potential biomarker to predict or monitor the efficacy of cognitive rehabilitation. These findings add to a growing body of literature related to functional outcomes in schizophrenia by demonstrating unique shape patterns across the spectrum of community functioning in SCZ.