Predictors of treatment discontinuation during an 18-month multi-site randomized trial of Cognitive Enhancement Therapy for early course schizophrenia.

Treatment discontinuation during clinical trials in schizophrenia is a critical challenge, especially for longer-term interventions in the early course. This research explored predictors of treatment discontinuation in an outpatient early course schizophrenia sample (N = 102) during an 18-month multi-site trial of Cognitive Enhancement Therapy (n = 58) and Enriched Supportive Therapy (n = 44). Fifty-three (52%) participants discontinued, with no significant difference between the treatment groups in discontinuation rate. Univariate and multivariate binary logistic regression models explored differences in key demographic and cognitive and behavioral outcomes between participants who completed and discontinued treatment. Significant multivariate predictors of discontinuation included IQ (linear) and problem solving (curvilinear). The concave shape of the problem solving prediction demonstrated that initially as scores were increasing the probability of non-completion was increasing. However, after a score of 41 (below average problem solving), the probability of being a non-completer decreased as performance increased. Non-completers had significantly lower IQ scores compared to completers. Post-hoc analyses indicated that participants who discontinued prior to mid-treatment exhibited the greatest intellectual challenges, with comparisons moderate-to-large in strength. IQ and problem solving are likely important factors to assess at pre-treatment in early course schizophrenia trials to identify those most vulnerable to discontinuation.

Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Cognitive gains as a mechanism of functional capacity improvement in schizophrenia: Results from a multi-site randomized controlled trial.

Randomized-controlled trials of Cognitive Enhancement Therapy (CET) reveal its impact on cognitive and functional improvements in schizophrenia and serve as an opportunity for causal claims of potential mediational relationships. In order to examine cognitive gains during CET as a mechanism for improving functional capacity, this secondary analysis included 86 outpatients in the early course of schizophrenia from an 18-month randomized-controlled trial of CET. Functional capacity was measured using the Brief UCSD Performance-Based Skills Assessment (UPSA-B) and cognitive performance by the MATRICS Consensus Cognitive Battery (MCCB) and additional measures of social cognition. Mixed-effects models were used to examine the effects of treatment on the UPSA-B changes and mediation through cognitive improvements. Changes in overall cognition proved to be a significant mediator of CET-related gains in functional capacity at mid-treatment and treatment completion. Exploratory models examining separable cognitive domains further found that improvements in attention, theory of mind, and emotion processing significantly mediated CET effects on functional capacity. This study suggests that CET has potential for improving functional capacity in individuals with schizophrenia, and that cognitive improvements partially mediate this relationship. This evidence can be beneficial for guiding more targeted approaches for rehabilitation in this population.

Using Experience Sampling Methodology Data to Characterize the Substance Use of Youth With or At-Risk of Psychosis.

Objectives: Psychotic-spectrum disorders emerge during adolescence and early adulthood, which corresponds with the peak period for substance use initiation. Clinical and epidemiological data provide support that substance use is associated with psychotic symptom onset and severity. Experience-sampling methodology (ESM) data may provide additional insight into dynamic associations between substance use and psychotic symptoms. This is one of the first efforts to characterize substance use frequency and dynamic associations with psychotic symptoms and negative affect from ESM data in both clinical high risk (CHR) and early psychosis (EP) individuals. Methods: Using ESM, 33 individuals, including 17 with CHR and 16 EP (age range: 15-24), provided information on substance use, negative affect, and psychotic symptoms 6 times a day across a 21-day data collection window. Psychotic symptoms and negative affect included multi-item variables rated on a seven-point Likert Scale. Participants reported recent substance use for 4 drug classes (nicotine, cannabis, depressants, stimulants) via a yes/no item. Descriptive information included data on substance use frequency, and momentary negative affect and psychotic symptoms. Exploratory analyses included multi-level and person-level dynamic structural equation models, which assessed contemporaneous and lagged associations between substance use and symptoms. Results: Twenty-seven individuals (82%) reported recurrent substance use including stimulants (n = 12, 46%), nicotine (n = 9, 27%), cannabis (n = 6, 18%), and depressants (n = 4, 12%). Individuals with any recurrent substance use indicated usage at 47.7% of answered prompts; stimulants at 23.6%; nicotine at 74.2%; cannabis at 39.1%; and depressants at 20.1%. A multi-level dynamic structural equation model reflected that substance use (any class) was associated with lagged negative affect (ß = -0.02, CI: -0.06, < -0.00) but no significant contemporaneous or lagged associations between substance use and psychotic symptoms. Person-level models suggest potentially meaningful inter-individual variability. Conclusions: CHR and EP individuals use a range of substances that may both reflect and influence other experiences in daily life experiences. Data reflected moderate to high rates of recurrent substance use with more consistent use within nicotine and cannabis classes. ESM data have the potential to increase our understanding of the dynamic relationships between substance use and symptoms and to inform treatment for individuals in early course psychosis.

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

Altered working memory-related brain activity in children at familial high risk for psychosis: A preliminary study.

BACKGROUND: Schizophrenia spectrum disorders are heritable illnesses that usually manifest in early adulthood but are increasingly viewed as neurodevelopmental disorders. Functional magnetic resonance imaging (fMRI) studies show altered brain activity during performance of working memory (WM) tasks in both individuals with schizophrenia and their first-degree relatives as compared to healthy controls (HC). This study examined whether similar changes are already present in pre-adolescent children at familial high-risk (FHR) for psychosis. METHODS: 37 children (17 FHR, 20 HC) between 7 and 12 years old participated in this study. WM performance was assessed using the Wechsler Intelligence Scale for Children-IV (WISC-IV). To assess brain activation during WM performance, participants completed a visual block-designed n-back task with 2 conditions (2-back and 0-back) during scanning. fMRI data was preprocessed and analyzed using FSL Feat. RESULTS: Compared to HC, FHR children showed significantly lower WISC-IV WM scores. In addition, FHR children exhibited hypoactivation in the 2-back (versus 0-back) condition in a cluster encompassing bilateral precuneus and cuneus and right posterior cingulate cortex. There were no significant group-differences in n-back task performance and brain activation. The precuneus cluster was not correlated with n-back performance or WISC WM scores. CONCLUSIONS: The current results provide preliminary evidence of impaired WM function and altered brain activity during WM performance in children with a familial predisposition for psychosis. Longitudinal studies are needed to determine whether these findings are related to abnormal brain development and predictive of cognitive deficits and psychosis later in life.

Confirmatory Efficacy of Cognitive Enhancement Therapy for Early Schizophrenia: Results From a Multisite Randomized Trial.

OBJECTIVE: Cognitive enhancement therapy (CET) is an 18-month comprehensive cognitive remediation intervention designed to improve cognition and functioning among patients with schizophrenia. The current study sought to confirm previously observed benefits of CET on cognitive and behavioral outcomes in the early course of the condition in a large multisite trial. METHODS: Overall, 102 outpatients with early-course schizophrenia were randomly assigned to 18 months of CET (N=58) or enriched supportive therapy (EST; N=44). Participants completed cognitive, social adjustment, and symptom assessments at baseline and at 9 and 18 months. Composite indices were calculated for these outcomes. Mixed-effects models investigated differential changes in outcomes between CET and EST. Because of a high attrition rate, sensitivity analyses of data from treatment completers (N=49) were conducted. RESULTS: The effects of CET on improved overall cognition were confirmed and tentatively confirmed for social cognition in both intent-to-treat and completer analyses, and beneficial effects on attention/vigilance were also observed. An effect of CET on social adjustment was not confirmed in the analyses, because both CET and EST groups had considerably improved social adjustment. Although not statistically significant, the between-group effect size for CET's effect on social adjustment doubled from the intent-to-treat (Cohen's d=0.23) to completer analyses (Cohen's d=0.51) (p=0.057). Both groups displayed similar symptom improvements. CONCLUSIONS: CET effectively improved cognition among patients with early-course schizophrenia. The functional benefits of CET appeared to increase with treatment retention. Further research is needed to understand predictors of attrition and mechanisms of change during CET for this population.

Functional connectivity associated with improvement in emotion management after cognitive enhancement therapy in early-course schizophrenia.

BACKGROUND: The ability to manage emotions is an important social-cognitive domain impaired in schizophrenia and linked to functional outcome. The goal of our study was to examine the impact of cognitive enhancement therapy (CET) on the ability to manage emotions and brain functional connectivity in early-course schizophrenia. METHODS: Participants were randomly assigned to CET (n = 55) or an enriched supportive therapy (EST) control group (n = 45). The resting-state functional magnetic resonance imaging scans and measures of emotion management performances were collected at baseline, 9, and 18 months follow-up. The final sample consisted of 37 CET and 25 EST participants, including 19 CET and 12 EST participants with imaging data. Linear mixed-effects models investigated the impact of treatment on emotion management and functional connectivity from the amygdala to ventrolateral and dorsolateral prefrontal cortex (dlPFC). RESULTS: The CET group showed significant improvement over time in emotion management compared to EST. Neither functional connectivity changes nor main group differences were observed following treatment. However, a significant between-group interaction showed that improved emotion management ability was associated with increased functional connectivity between the left amygdala and the left dlPFC in the CET group exclusively. CONCLUSION: Our results replicate the previous work demonstrating that CET is effective at improving some aspects of social cognition in schizophrenia. We found evidence that improvement in emotion management may be associated with a change in amygdala-dlPFC connectivity. This fronto-limbic circuit may provide a mechanistic link between the biology of emotion management processes that can be enhanced in individuals with schizophrenia.

Are we ready for a name change for schizophrenia? A survey of multiple stakeholders.

About one in 100 people worldwide are diagnosed with schizophrenia. Many people advocate for a name change for the condition, pointing to the stigma and discrimination associated with the term "schizophrenia", as well as to how the name poorly characterizes features of the illness. The purpose of this project was to collect opinions from a broad, diverse sample of stakeholders about possible name changes for schizophrenia. The project represented a partnership between researchers, clinicians, and those with lived experience with psychosis. The group developed a survey to assess opinions about the need for change in the name schizophrenia as well as potential alternate names. We accumulated 1190 responses from a broad array of community stakeholders, including those with lived experience of mental illness, family members, clinicians, researchers, government officials, and the general public. Findings indicated that the majority of respondents (74.1%) favored a name change for schizophrenia. Most (71.4%) found the name stigmatizing. Of the proposed alternate names, those with the most support included "Altered Perception Syndrome", "Psychosis Spectrum Syndrome", and "Neuro-Emotional Integration Disorder". Survey findings provide strong support for renaming schizophrenia. Most expressed hope that a name change will reduce stigma and discrimination.

Association of white matter microstructure and extracellular free-water with cognitive performance in the early course of schizophrenia.

Schizophrenia (SZ) is proposed as a disorder of dysconnectivity underlying cognitive impairments and clinical manifestations. Although previous studies have shown extracellular changes in white matter of first-episode SZ, little is known about the transition period towards chronicity and its association with cognition. Free-water (FW) imaging was applied to 79 early course SZ participants and 29 controls to detect white matter axonal and extracellular differences during this phase of illness. Diffusion-weighted images were collected from two sites, harmonized, and processed using a pipeline separately modeling water diffusion in tissue (FAt) and extracellular space (FW). Tract-Based Spatial Statistics was performed using the ENIGMA-DTI protocols. SZ showed FAt reductions in the posterior thalamic radiation (PTR) and FW elevations in the cingulum compared to controls, suggesting FAt and FW changes in the early course of SZ. In SZ, greater FAt of the fornix & stria terminalis (FXST) was positively associated with Theory of Mind performance; average whole-brain FAt, FAt of the FXST and the PTR were positively associated with greater working memory performance; average whole-brain FAt was positively associated with visual learning. Further studies are necessary to better understand the neurobiological mechanisms of SZ for developing intervention strategies to preserve brain structure and function.

Longitudinal evaluation of visual P300 amplitude in clinical high-risk subjects: An event-related potential study.

AIM: We previously reported abnormal P300 and N200 in a visual oddball task, and progressive P300 amplitude reduction at 1-year follow-up in patients with first-episode schizophrenia. P300 reduction as well as intact P1/N1 were also observed in clinical high-risk subjects (CHR), but whether or not these components change over time is unknown. This study evaluates, longitudinally, the visual P300, as well as P1, N1, and N200, in CHR. METHODS: Visual event-related potentials (ERP) were recorded twice, once at baseline and once at 1-year follow-up in CHR (n = 19) and healthy comparison subjects (HC; n = 28). Participants silently counted infrequent target stimuli ('x') among standard stimuli ('y') presented on the screen while the 64-channel electroencephalogram was recorded. RESULTS: No CHR converted to psychosis from baseline to 1-year follow-up in this study. Visual P300 amplitude was reduced and the latency was delayed significantly in CHR at both time points compared with HC. Furthermore, CHR subjects who had more positive symptoms showed more amplitude reduction at both time points. P1, N1, and N200 did not differ between groups. CONCLUSION: Visual P300 amplitude was found to be reduced in CHR individuals compared with HC. We note that this finding is in subjects who did not convert to psychosis at 1-year follow-up. The association between visual P300 amplitude and symptoms suggests that for CHR who often experience clinical symptoms and seek medical care, visual P300 may be an important index that reflects the pathophysiological impairment underlying such clinical states.

Transdiagnostic validity of the MATRICS Consensus Cognitive Battery across the autism-schizophrenia spectrum.

BACKGROUND: Autism Spectrum Disorder (ASD) and schizophrenia are neurodevelopmental disorders which share substantial overlap in cognitive deficits during adulthood. However, treatment evaluation in ASD and treatment comparisons across ASD and schizophrenia are limited by a dearth of empirical work establishing the validity of a standard cognitive battery across ASD and schizophrenia. Promisingly, the MATRICS Consensus Cognitive Battery (MCCB) has been validated in schizophrenia and encompasses cognitive domains that are impacted in ASD. Thus, this study aimed to establish MCCB's generalizability from schizophrenia to ASD. METHODS: Community-residing adults with schizophrenia (N = 100) and ASD (N = 113) underwent MCCB assessment. Using multigroup confirmatory factor analysis, MCCB's transdiagnostic validity was evaluated by examining whether schizophrenia and ASD demonstrate the same configuration, magnitude, and directionality of relationships within and among measures and their underlying cognitive domains. RESULTS: Across schizophrenia and ASD, the same subsets of MCCB measures inform three cognitive domains: processing speed, attention/working memory, and learning. Except for group means in category fluency, continuous performance, and spatial span, both groups show vastly comparable factor structures and characteristics. CONCLUSIONS: To our knowledge, this study is the first to establish the validity of a standard cognitive battery in adults with ASD and furthermore the first to establish a cognitive battery's comparability across ASD and schizophrenia. Cognitive domain scores can be compared across new samples using weighted sums of MCCB scores resulting from this study. These findings highlight MCCB's applicability to ASD and support its utility for standardizing treatment evaluation of cognitive outcomes across the autism-schizophrenia spectrum.

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

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

Abnormal Frequency Mismatch Negativity in Early Psychosis Outpatient Subjects.

Background. Abnormalities of mismatch negativity (MMN), an event-related potential, indexing preattentive mechanisms, are consistently reported in schizophrenia (SZ). MMN abnormalities elicited to different deviant types have been recently shown to distinguish among patients according to length of their illness as well as inpatient versus outpatient status, and to be modulated by premorbid IQ. The objective of this study was to evaluate the MMN elicited by both frequency and duration deviant stimuli in patients with early schizophrenia (EP) recruited from an outpatient clinic in Boston, Massachusetts. Methods. Twenty-two healthy controls (HC) and 22 age-, handedness-, and gender-matched EP were tested using a frequency and duration MMN paradigm. Clinical data were also collected. Results. Frequency MMN amplitude but not duration MMN was significantly reduced in EP relative to HC subjects (P = .015). Conclusions. These results indicate that in this sample of early psychosis outpatient group, reductions in frequency MMN but not in duration MMN index clinical status. The relationship between age at first hospitalization and MMN frequency and duration amplitude and latency indicates that neurodevelopmental stage, auditory function, and clinical status are tightly linked.

Cingulum bundle abnormalities and risk for schizophrenia.

BACKGROUND: The cingulum bundle (CB) is a major white matter fiber tract of the limbic system that underlies cingulate cortex, passing longitudinally over the corpus callosum. The connectivity of this white matter fiber tract plays a major role in emotional expression, attention, motivation, and working memory, all of which are affected in schizophrenia. Myelin related CB abnormalities have also been implicated in schizophrenia. The purpose of this study is to determine whether or not CB abnormalities are evident in individuals at clinical high risk (CHR) for psychosis, and whether or not cognitive deficits in the domains subserved by CB are related to its structural abnormalities. METHODS: Diffusion Tensor Imaging (DTI) was performed on a 3 T magnet. DT tractography was used to evaluate CB in 20 individuals meeting CHR criteria (13 males/7 females) and 23 healthy controls (12 males/11 females) group matched on age, gender, parental socioeconomic status, education, and handedness. Fractional anisotropy (FA), a measure of white matter coherence and integrity, radial diffusivity (RD), thought to reflect myelin integrity, trace, a possible marker of atrophy, and axial diffusivity (AD), thought to reflect axonal integrity, were averaged over the entire tract and used to investigate CB abnormalities in individuals at CHR for psychosis compared with healthy controls. RESULTS: Significant group differences were found between individuals at CHR for psychosis and controls for FA (p = 0.028), RD (p = 0.03) and trace (p = 0.031), but not for AD (p = 0.09). We did not find any significant correlations between DTI measures and clinical symptoms. CONCLUSION: These findings suggest abnormalities (possibly myelin related) in the CB in individuals at CHR for psychosis.

Establishing a standard emotion processing battery for treatment evaluation in adults with autism spectrum disorder: Evidence supporting the Mayer-Salovey-Caruso Emotion Intelligence Test (MSCEIT).

Autism spectrum disorder (ASD) and schizophrenia are neurodevelopmental disorders which show markedly similar deficits in emotion processing, yet treatment evaluation in ASD and treatment comparisons across ASD and schizophrenia are constrained by a lack of empirical work validating a standard emotion processing battery across ASD and schizophrenia. Encouragingly, the Mayer-Salovey-Caruso Emotion Intelligence Test, version 2.0 (MSCEIT (Mayer et al., 2003) spans the range of emotion processing deficits in schizophrenia and ASD. This study therefore aimed to establish MSCEIT's factorial, measurement, and structural invariance in community-residing adults with schizophrenia (N = 103) and ASD (N = 113) using multigroup confirmatory factor analysis. Consistent with prior studies in normative populations, a two-factor structure comprised of emotional experiencing and emotional reasoning was supported in ASD and schizophrenia. Both groups operationalize MSCEIT measures similarly, with all measures except for Facilitation and Management showing comparability across groups. To our knowledge, this study is not only the first to establish the measurement and structural invariance of a standard emotion perception battery in adults with ASD, it is also the first to establish its comparability across ASD and schizophrenia. Ultimately, these findings underscore MSCEIT's utility for standardizing treatment evaluation of social cognitive outcomes across the autism-schizophrenia spectrum.

Progressive reduction of auditory evoked gamma in first episode schizophrenia but not clinical high risk individuals.

The early auditory-evoked gamma band response (EAGBR) may serve as an index of the integrity of fast recurrent inhibition or synaptic connectivity in the auditory cortex, where abnormalities in individuals with schizophrenia have been consistently found. The EAGBR has been rarely investigated in first episode schizophrenia patients (FESZ) and individuals at clinical high risk (CHR) for schizophrenia, and never been compared directly between these populations nor evaluated longitudinally. Here we examined the EAGBR in FESZ, CHR, and matched healthy controls (HC) at baseline and 1-year follow-up assessments to determine whether the EAGBR was affected in these clinical groups, and whether any EAGBR abnormalities changed over time. The electroencephalogram was recorded with a dense electrode array while subjects (18 FESZ, 18 CHR, and 40 HC) performed an auditory oddball task. Event-related spectral measures (phase locking factor [PLF] and evoked power) were computed on Morlet-wavelet-transformed single epochs from the standard trials. At baseline, EAGBR PLF and evoked power did not differ between groups. FESZ showed progressive reductions of PLF and evoked power from baseline to follow-up, and deficits in PLF at follow-up compared to HC. EAGBR peak frequency also increased at temporal sites in FESZ from baseline to follow-up. Longitudinal effects on the EAGBR were not found in CHR or HC, nor did these groups differ at follow-up. In conclusion, we detected neurophysiological changes of auditory cortex function in FESZ during a one-year period, which were not observed in CHR. These findings are discussed within the context of neurodevelopmental models of schizophrenia.