Showing papers in "Schizophrenia Bulletin in 2021"

Self-stigma in Serious Mental Illness: A Systematic Review of Frequency, Correlates, and Consequences.

Abstract: Self-stigma is associated with poor clinical and functional outcomes in Serious Mental Illness (SMI). There has been no review of self-stigma frequency and correlates in different cultural and geographic areas and SMI. The objectives of the present study were: (1) to review the frequency, correlates, and consequences of self-stigma in individuals with SMI; (2) to compare self-stigma in different geographical areas and to review its potential association with cultural factors; (3) to evaluate the strengths and limitations of the current body of evidence to guide future research. A systematic electronic database search (PubMed, Web of Science, PsycINFO, Scopus, and Ovid SP Cumulative Index to Nursing and Allied Health Literature [CINAHL]) following PRISMA guidelines, was conducted on the frequency, correlates, and consequences of self-stigma in SMI. Out of 272 articles, 80 (29.4%) reported on the frequency of self-stigma (n = 25 458), 241 (88.6%) on cross-sectional correlates of self-stigma and 41 (15.0%) on the longitudinal correlates and consequences of self-stigma. On average, 31.3% of SMI patients reported high self-stigma. The highest frequency was in South-East Asia (39.7%) and the Middle East (39%). Sociodemographic and illness-related predictors yielded mixed results. Perceived and experienced stigma-including from mental health providers-predicted self-stigma, which supports the need to develop anti-stigma campaigns and recovery-oriented practices. Increased transition to psychosis and poor clinical and functional outcomes are both associated with self-stigma. Psychiatric rehabilitation and recovery-oriented early interventions could reduce self-stigma and should be better integrated into public policy.

Brief Psychotic Disorder During the National Lockdown in Italy: An Emerging Clinical Phenomenon of the COVID-19 Pandemic

Abstract: The impact of the COVID-19 pandemic on psychosis remains to be established. Here we report 6 cases (3 male and 3 female) of first-episode psychosis (FEP) admitted to our hospital in the second month of national lockdown. All patients underwent routine laboratory tests and a standardized assessment of psychopathology. Hospitalization was required due to the severity of behavioral abnormalities in the context of a full-blown psychosis (the Brief Psychiatric Rating Scale [BPRS] = 75.8 ± 14.6). Blood tests, toxicological urine screening, and brain imaging were unremarkable, with the exception of a mild cortical atrophy in the eldest patient (male, 73 years). All patients were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout their stay, but 3 presented the somatic delusion of being infected. Of note, all 6 cases had religious/spiritual delusions and hallucinatory contents. Despite a generally advanced age (53.3 ± 15.6), all patients had a negative psychiatric history. Rapid discharge (length of stay = 13.8 ± 6.9) with remission of symptoms (BPRS = 27.5 ± 3.1) and satisfactory insight were possible after relatively low-dose antipsychotic treatment (Olanzapine-equivalents = 10.1 ± 5.1 mg). Brief psychotic disorder/acute and transient psychotic disorder diagnoses were confirmed during follow-up visits in all 6 cases. The youngest patient (female, 23 years) also satisfied the available criteria for brief limited intermittent psychotic symptoms. Although research on larger populations is necessary, our preliminary observation suggests that intense psychosocial stress associated with a novel, potentially fatal disease and national lockdown restrictions might be a trigger for FEP.

Disparities in Intensive Care Unit Admission and Mortality Among Patients With Schizophrenia and COVID-19: A National Cohort Study.

Abstract: Patients with schizophrenia (SCZ) represent a vulnerable population who have been understudied in COVID-19 research. We aimed to establish whether health outcomes and care differed between patients with SCZ and patients without a diagnosis of severe mental illness. We conducted a population-based cohort study of all patients with identified COVID-19 and respiratory symptoms who were hospitalized in France between February and June 2020. Cases were patients who had a diagnosis of SCZ. Controls were patients who did not have a diagnosis of severe mental illness. The outcomes were in-hospital mortality and intensive care unit (ICU) admission. A total of 50 750 patients were included, of whom 823 were SCZ patients (1.6%). The SCZ patients had an increased in-hospital mortality (25.6% vs 21.7%; adjusted OR 1.30 [95% CI, 1.08-1.56], P = .0093) and a decreased ICU admission rate (23.7% vs 28.4%; adjusted OR, 0.75 [95% CI, 0.62-0.91], P = .0062) compared with controls. Significant interactions between SCZ and age for mortality and ICU admission were observed (P = .0006 and P < .0001). SCZ patients between 65 and 80 years had a significantly higher risk of death than controls of the same age (+7.89%). SCZ patients younger than 55 years had more ICU admissions (+13.93%) and SCZ patients between 65 and 80 years and older than 80 years had less ICU admissions than controls of the same age (-15.44% and -5.93%, respectively). Our findings report the existence of disparities in health and health care between SCZ patients and patients without a diagnosis of severe mental illness. These disparities differed according to the age and clinical profile of SCZ patients, suggesting the importance of personalized COVID-19 clinical management and health care strategies before, during, and after hospitalization for reducing health disparities in this vulnerable population.

COVID-19 Prevalence and Mortality Among Schizophrenia Patients: A Large-Scale Retrospective Cohort Study.

Abstract: Objective Individuals with schizophrenia may be at an increased risk for COVID-19 morbidity due to the disease characteristics. In this study, we aimed to explore the odds of significant COVID-19 morbidity and mortality among schizophrenia patients while controlling for potential sociodemographic and medical confounders. Methods Schizophrenia patients and age-and-sex matched controls (total n = 51 078) were assessed for frequency of COVID-19 positivity, hospitalizations, and mortality. The odds for COVID-19-associated hospitalization and mortality were calculated using logistic regression models, while controlling for age, sex, marital status, sector, socioeconomic status, diabetes, ischemic heart disease, hypertension, hyperlipidemia, obesity, smoking, and chronic obstructive pulmonary disease. Results Individuals with schizophrenia were less likely to test positive for COVID-19; however, they were twice as likely to be hospitalized for COVID-19 (OR 2.15 95% CI 1.63-2.82, P Conclusions We found evidence of associations between schizophrenia and increased COVID-19 morbidity and mortality compared to controls regardless of sociodemographic and medical factors. As these patients present with a combination of potential risk factors for mortality, efforts should be made to minimize the effects of the pandemic on this vulnerable population.

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA).

Abstract: The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min-1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

The Self in the Spectrum: A Meta-analysis of the Evidence Linking Basic Self-Disorders and Schizophrenia.

Abstract: Disturbed self-experience has been reported as a characteristic feature of schizophrenia since the first formulation of its diagnostic concept; however, only in the last 2 decades an explicit notion of basic Self-disturbance, or Self-Disorders (SD), has emerged as target for a systematic research program We conducted systematic searches in bibliographical databases to identify cross-sectional studies that explored SD across different diagnostic groups and explored diagnostic ascription within or outside schizophrenia spectrum disorders (SSD) as main outcome Data were pooled using fixed- and random-effects meta-analysis models Heterogeneity was assessed using stratified meta-analyses and meta-regression Of 218 identified studies, 32 were included in the systematic review and 27 in the meta-analysis Patients diagnosed with SSD scored higher on measures of SD than healthy controls (HC) (Hedges' g = 18; 95% CI = 15 to 20), individuals diagnosed with other mental illness (OMI) (19; 16 to 22), bipolar or affective disorders (18; 14 to 22), and clinical high risk for psychosis (CHR) (16; 09 to 24) Patients with schizotypy or schizotypal personality disorder scored higher on measures of SD than OMI (15; 13 to 18) and HC (14; 11 to 17) Patients with first-episode psychosis scored higher on measures of SD than HC (25; 21 to 29) and OMI (16; 12 to 21) Subjects at CHR scored higher on measures of SD than HC (20; 17 to 22) and OMI (19; 16 to 22) Overall, heterogeneity ranged from negligible to high, especially in comparisons of the target group with OMI, probably as a reflection of the immanent diagnostic heterogeneity of this group The findings suggest that SD selectively aggregate within schizophrenia spectrum disorders as compared to other mental disorders and that they could be a central phenotypic marker of vulnerability to schizophrenia across the different shades of severity of its spectrum of disorders

A Meta-analysis of Cognitive Remediation for Schizophrenia: Efficacy and the Role of Participant and Treatment Factors.

Abstract: The number of randomized, controlled studies of cognitive remediation (CR) for schizophrenia, a therapeutic approach designed to improve cognitive skills and function, has grown substantially over the past 20 years. Active elements of CR treatment, however, remain unknown. The current meta-analysis investigated treatment, study, and participant factors in the size of observed treatment effects. Electronic databases were searched up to May 2020 using variants of the key words "cognitive remediation," "clinical trials," and "schizophrenia." This search produced 73 unique, randomized, controlled trials. Data were independently extracted by 3 reviewers with excellent reliability. Random-effects models were used to assess primary cognitive and secondary symptom and functional outcomes. Moderator analyses investigated the role of a variety of treatment, study, and participant factors. The meta-analysis (4594 participants) revealed that CR produced significant small-to-moderate size improvements in all domains of cognition studied (Hedge's gs = .19-.33). and a significant small improvement in function (Hedge's g = .21). CR programs that included a discussion ("bridging") group to help apply acquired cognitive skills to everyday life produced larger effects on global cognition and verbal memory. CR programs with strategy-coaching produced larger effects on episodic memory. Sample age, gender, positive, negative, and overall symptoms, and medication dose did not serve as barriers to treatment gains. CR produces small-to-moderate improvements in cognition and function in schizophrenia. Programs of CR that utilize bridging groups and strategy-coaching are more cognitively potent. Future research should focus on ways to modify CR to bolster generalization of cognitive improvements to function.

A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse.

Abstract: The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication-from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade "evenly"): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3-6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.

Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in Schizophrenia.

Abstract: Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.

Understanding Language Abnormalities and Associated Clinical Markers in Psychosis: The Promise of Computational Methods.

Abstract: The language and speech of individuals with psychosis reflect their impairments in cognition and motor processes. These language disturbances can be used to identify individuals with and at high risk for psychosis, as well as help track and predict symptom progression, allowing for early intervention and improved outcomes. However, current methods of language assessment-manual annotations and/or clinical rating scales-are time intensive, expensive, subject to bias, and difficult to administer on a wide scale, limiting this area from reaching its full potential. Computational methods that can automatically perform linguistic analysis have started to be applied to this problem and could drastically improve our ability to use linguistic information clinically. In this article, we first review how these automated, computational methods work and how they have been applied to the field of psychosis. We show that across domains, these methods have captured differences between individuals with psychosis and healthy controls and can classify individuals with high accuracies, demonstrating the promise of these methods. We then consider the obstacles that need to be overcome before these methods can play a significant role in the clinical process and provide suggestions for how the field should address them. In particular, while much of the work thus far has focused on demonstrating the successes of these methods, we argue that a better understanding of when and why these models fail will be crucial toward ensuring these methods reach their potential in the field of psychosis.

The Self and Its Prolonged Intrinsic Neural Timescale in Schizophrenia.

Abstract: Schizophrenia (SCZ) can be characterized as a basic self-disorder that is featured by abnormal temporal integration on phenomenological (experience) and psychological (information processing) levels. Temporal integration on the neuronal level can be measured by the brain's intrinsic neural timescale using the autocorrelation window (ACW) and power-law exponent (PLE). Our goal was to relate intrinsic neural timescales (ACW, PLE), as a proxy of temporal integration on the neuronal level, to temporal integration related to self-disorder on psychological (Enfacement illusion task in electroencephalography) and phenomenological (Examination of Anomalous Self-Experience [EASE]) levels. SCZ participants exhibited prolonged ACW and higher PLE during the self-referential task (Enfacement illusion), but not during the non-self-referential task (auditory oddball). The degree of ACW/PLE change during task relative to rest was significantly reduced in self-referential task in SCZ. A moderation model showed that low and high ACW/PLE exerted differential impact on the relationship of self-disorder (EASE) and negative symptoms (PANSS). In sum, we demonstrate abnormal prolongation in intrinsic neural timescale during self-reference in SCZ including its relation to basic self-disorder and negative symptoms. Our results point to abnormal relation of self and temporal integration at the core of SCZ constituting a "common currency" of neuronal, psychological, and phenomenological levels.

Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals

Abstract: INTRODUCTION: Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. METHODS: All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. RESULTS: Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = -3.56, P = .0004) and IL-12(p70) (t = -2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. CONCLUSIONS: We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.

Predictors of Treatment-Resistant and Clozapine-Resistant Schizophrenia: A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders.

Abstract: Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes.

Cognitive Predictors of Social and Occupational Functioning in Early Psychosis: A Systematic Review and Meta-analysis of Cross-Sectional and Longitudinal Data.

Abstract: Many individuals with early psychosis experience impairments in social and occupational function. Identification of modifiable predictors of function such as cognitive performance has the potential to inform effective treatments. Our aim was to estimate the strength of the relationship between psychosocial function in early psychosis and different domains of cognitive and social cognitive performance. We conducted a systematic review and meta-analysis of peer-reviewed, cross-sectional, and longitudinal studies examining cognitive predictors of psychosocial function. Literature searches were conducted in PsycINFO, PubMed, and reference lists of relevant articles to identify studies for inclusion. Of the 2565 identified, 46 studies comprising 3767 participants met inclusion criteria. Separate meta-analyses were conducted for 9 cognitive domains. Pearson correlation values between cognitive variables and function were extracted. All cognitive domains were related to psychosocial function both cross-sectionally and longitudinally. Importantly, these associations remained significant even after the effects of symptom severity, duration of untreated psychosis, and length of illness were accounted for. Overall, general cognitive ability and social cognition were most strongly associated with both concurrent and long-term function. Associations demonstrated medium effect sizes. These findings suggest that treatments targeting cognitive deficits, in particular those focusing on social cognition, are likely to be important for improving functional outcomes in early psychosis.

Comorbid Major Depressive Disorder in Schizophrenia: A Systematic Review and Meta-Analysis.

Abstract: Comorbid major depressive disorder (MDD) in schizophrenia (SZ; SZ-MDD) has been identified as a major prognostic factor. However, the prevalence and associated factors of SZ-MDD have never been explored in a meta-analysis. All studies assessing the prevalence of SZ-MDD in stabilized outpatients with a standardized scale or with structured interviews were included. The Medline, Web of Science, PsycINFO, and Google Scholar databases were searched. Using random effects models, we calculated the pooled estimate of the prevalence of SZ-MDD. We used meta-regression and subgroup analyses to evaluate the potential moderators of the prevalence estimates, and we used the leave-one-out method for sensitivity analyses. Of the 5633 potentially eligible studies identified, 18 studies (n = 6140 SZ stabilized outpatients) were retrieved in the systematic review and included in the meta-analysis. The pooled estimate of the prevalence of SZ-MDD was 32.6% (95% CI: 27.9-37.6); there was high heterogeneity (I2 = 92.6%), and Egger's test did not reveal publication bias (P = .122). The following factors were found to be sources of heterogeneity: publication in or after 2015, the inclusion of patients from larger studies, the assessment tools, the inclusion of patients with substance use disorder or somatic chronic diseases, age, education level, the lifetime number of hospitalizations, and antidepressant use. Two-thirds of the extracted variables could not be explored due to an insufficient amount of published data. The prevalence of MDD is high among SZ individuals. Healthcare providers and public health officials should have an increased awareness of the burden of SZ-MDD.

Digital phenotyping of negative symptoms: the relationship to clinician ratings.

Abstract: Negative symptoms are a critical, but poorly understood, aspect of schizophrenia. Measurement of negative symptoms primarily relies on clinician ratings, an endeavor with established reliability and validity. There have been increasing attempts to digitally phenotype negative symptoms using objective biobehavioral technologies, eg, using computerized analysis of vocal, speech, facial, hand and other behaviors. Surprisingly, biobehavioral technologies and clinician ratings are only modestly inter-related, and findings from individual studies often do not replicate or are counterintuitive. In this article, we document and evaluate this lack of convergence in 4 case studies, in an archival dataset of 877 audio/video samples, and in the extant literature. We then explain this divergence in terms of "resolution"-a critical psychometric property in biomedical, engineering, and computational sciences defined as precision in distinguishing various aspects of a signal. We demonstrate how convergence between clinical ratings and biobehavioral data can be achieved by scaling data across various resolutions. Clinical ratings reflect an indispensable tool that integrates considerable information into actionable, yet "low resolution" ordinal ratings. This allows viewing of the "forest" of negative symptoms. Unfortunately, their resolution cannot be scaled or decomposed with sufficient precision to isolate the time, setting, and nature of negative symptoms for many purposes (ie, to see the "trees"). Biobehavioral measures afford precision for understanding when, where, and why negative symptoms emerge, though much work is needed to validate them. Digital phenotyping of negative symptoms can provide unprecedented opportunities for tracking, understanding, and treating them, but requires consideration of resolution.

High Mobility Group Protein 1 and Dickkopf-Related Protein 1 in Schizophrenia and Treatment-Resistant Schizophrenia: Associations With Interleukin-6, Symptom Domains, and Neurocognitive Impairments.

Abstract: Background Schizophrenia (SCZ) and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased high mobility group protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-related protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain barrier and induce neurotoxic effects and neurocognitive deficits. Aim The present study aims to examine HMGB1 and DDK1 in nonresponders to treatments (NRTT) with antipsychotics (n = 60), partial RTT (PRTT, n = 55), and healthy controls (n = 43) in relation to established markers of SCZ, including interleukin (IL)-6, IL-10, and CCL11 (eotaxin), and to delineate whether these proteins are associated with the SCZ symptom subdomains and neurocognitive impairments. Results HMGB1, DKK1, IL-6, and CCL11 were significantly higher in SCZ patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls, while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that SCZ was best predicted by increased DDK1 and HMGB1, while NRTT (vs PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism, and negative (PHEMN) symptoms and formal thought disorders was explained by HMGB1, IL-6, and CCL11, while most neurocognitive functions were predicted by HMGB1, DDK1, and CCL11. Conclusions The neurotoxic effects of HMGB1, DKK1, IL-6, and CCL11 including the effects on the blood-brain barrier and the Wnt/β-catenin signaling pathway may cause impairments in executive functions and working, episodic, and semantic memory and explain, in part, PHEMN symptoms and a nonresponse to treatment with antipsychotic drugs.

Changes in Brain Glutamate on Switching to Clozapine in Treatment-Resistant Schizophrenia

Abstract: It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naive), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P = .01) but not in the ACC (n = 24, F = 0.02, P = .59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r = .42, P = .04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment.

Metabolomic Identification of Exosome-Derived Biomarkers for Schizophrenia: A Large Multicenter Study.

Abstract: Exosomes have been suggested as promising targets for the diagnosis and treatment of neurological diseases, including schizophrenia (SCZ), but the potential role of exosome-derived metabolites in these diseases was rarely studied. Using ultra-performance liquid chromatography-tandem mass spectrometry, we performed the first metabolomic study of serum-derived exosomes from patients with SCZ. Our sample comprised 385 patients and 332 healthy controls recruited from 3 clinical centers and 4 independent cohorts. We identified 25 perturbed metabolites in patients that can be used to classify samples from patients and control participants with 95.7% accuracy (95% CI: 92.6%-98.9%) in the training samples (78 patients and 66 controls). These metabolites also showed good to excellent performance in differentiating between patients and controls in the 3 test sets of participants, with accuracies 91.0% (95% CI: 85.7%-96.3%; 107 patients and 62 controls), 82.7% (95% CI: 77.6%-87.9%; 104 patients and 142 controls), and 99.0% (95% CI: 97.7%-100%; 96 patients and 62 controls), respectively. Bioinformatic analysis suggested that these metabolites were enriched in pathways implicated in SCZ, such as glycerophospholipid metabolism. Taken together, our findings support a role for exosomal metabolite dysregulation in the pathophysiology of SCZ and indicate a strong potential for exosome-derived metabolites to inform the diagnosis of SCZ.

Understanding Identity Changes in Psychosis: A Systematic Review and Narrative Synthesis

Abstract: Background and objective: Experiencing psychosis can be associated with changes in how people see themselves as individuals and in relation to others (i.e., changes in their identity). However, identity changes receive little attention in treatment, possibly due to a lack of clarity or consensus around what identity change means in people with psychosis. We aimed to create a conceptual framework synthesizing how identity changes are understood in the psychosis literature. Methods: Electronic databases were searched up to April 2020. Studies about identity changes among people with psychotic disorders were analyzed using narrative synthesis by a collaborative review team, including researchers from different disciplines, clinicians, and people who have experienced psychosis. Results: Of 10,389 studies screened, 59 were eligible. Identity changes are understood in five ways: as 1) characteristics of psychosis, 2) consequences of altered cognitive functioning, 3) consequences of internalized stigma, 4) consequences of lost roles and relationships, and 5) reflections of personal growth. These five understandings are not mutually exclusive. Across a heterogeneous literature, identity changes were mostly framed in terms of loss. Conclusions: Our conceptual framework, comprising five understandings, highlights the complexity of studying identity changes and suggests important implications for practice and research. For clinicians, this framework can inform new therapeutic approaches where the experience and impact of identity changes are acknowledged and addressed as part of treatment. For researchers, the conceptual framework offers a way of locating their understandings of identity changes when undertaking research in this area.

A White Matter Connection of Schizophrenia and Alzheimer's Disease.

Abstract: Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter "regional vulnerability index" (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen's d = 0.44, P = 1·10-5, N = 173 patients/230 control) and replication (Cohen's d = 0.78, P = 9·10-7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.

Voice-Hearing and Personification: Characterizing Social Qualities of Auditory Verbal Hallucinations in Early Psychosis

Abstract: Recent therapeutic approaches to auditory verbal hallucinations (AVH) exploit the person-like qualities of voices. Little is known, however, about how, why, and when AVH become personified. We aimed to investigate personification in individuals' early voice-hearing experiences. We invited Early Intervention in Psychosis (EIP) service users aged 16-65 to participate in a semistructured interview on AVH phenomenology. Forty voice-hearers (M = 114.13 days in EIP) were recruited through 2 National Health Service trusts in northern England. We used content and thematic analysis to code the interviews and then statistically examined key associations with personification. Some participants had heard voices intermittently for multiple years prior to clinical involvement (M = 74.38 months), although distressing voice onset was typically more recent (median = 12 months). Participants reported a range of negative emotions (predominantly fear, 60%, 24/40, and anxiety, 62.5%, 26/40), visual hallucinations (75%, 30/40), bodily states (65%, 25/40), and "felt presences" (52.5%, 21/40) in relation to voices. Complex personification, reported by a sizeable minority (16/40, 40%), was associated with experiencing voices as conversational (odds ratio [OR] = 2.56) and companionable (OR = 3.19) but not as commanding or trauma-related. Neither age of AVH onset nor time since onset related to personification. Our findings highlight significant personification of AVH even at first clinical presentation. Personified voices appear to be distinguished less by their intrinsic properties, commanding qualities, or connection with trauma than by their affordances for conversation and companionship.

Using Natural Language Processing on Electronic Health Records to Enhance Detection and Prediction of Psychosis Risk.

Abstract: Background Using novel data mining methods such as natural language processing (NLP) on electronic health records (EHRs) for screening and detecting individuals at risk for psychosis. Method The study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and Maudsley (SLaM) NHS Foundation Trust between January 1, 2008, and July 28, 2018. Least Absolute Shrinkage and Selection Operator (LASSO)-regularized Cox regression was used to refine and externally validate a refined version of a five-item individualized, transdiagnostic, clinically based risk calculator previously developed (Harrell's C = 0.79) and piloted for implementation. The refined version included 14 additional NLP-predictors: tearfulness, poor appetite, weight loss, insomnia, cannabis, cocaine, guilt, irritability, delusions, hopelessness, disturbed sleep, poor insight, agitation, and paranoia. Results A total of 92 151 patients with a first index diagnosis of nonorganic and nonpsychotic mental disorder within the SLaM Trust were included in the derivation (n = 28 297) or external validation (n = 54 716) data sets. Mean age was 33.6 years, 50.7% were women, and 67.0% were of white race/ethnicity. Mean follow-up was 1590 days. The overall 6-year risk of psychosis in secondary mental health care was 3.4 (95% CI, 3.3-3.6). External validation indicated strong performance on unseen data (Harrell's C 0.85, 95% CI 0.84-0.86), an increase of 0.06 from the original model. Conclusions Using NLP on EHRs can considerably enhance the prognostic accuracy of psychosis risk calculators. This can help identify patients at risk of psychosis who require assessment and specialized care, facilitating earlier detection and potentially improving patient outcomes.

Reducing Stigma Toward Individuals With Schizophrenia Using a Brief Video: A Randomized Controlled Trial of Young Adults

Abstract: OBJECTIVE Stigma decreases healthcare seeking and treatment adherence and increases the duration of untreated psychosis among people with first-episode psychosis (FEP). This study evaluated the efficacy of a brief video-based intervention in reducing stigma among youth toward individuals with FEP and schizophrenia. We hypothesized that the social-contact-based video intervention group would reduce stigma more than written vignette and control groups, and the vignette more than the control group. METHODS Using Amazon Mechanical Turk, we recruited and assigned 1203 individuals aged 18-30 to either (a) video intervention, (b) written description of the same content ("vignette"), or (c) nonintervention control arm. In the 90-second video intervention, an empowered young woman with schizophrenia described her FEP and the aspects of successful coping with her everyday life difficulties, exposing the viewer to schizophrenia in the context of her personal narrative. Web-based self-report questionnaires assessed stigma domains, including social distance, stereotyping, separateness, social restriction, and perceived recovery. RESULTS A MANOVA showed a significant between-group effects for all 5 stigma-related subscales (P < .001). Post hoc pairwise tests showed significant differences between video and vignette vs control for all 5 stigma domains. Video and vignette groups differed significantly on social distance, stereotyping, and social restriction. Secondary analyses revealed gender differences across stigma domains in the video group only, with women reporting lower stigma. CONCLUSIONS A very brief social contact-based video intervention efficaciously reduced stigma toward individuals with FEP. This is the first study to demonstrate such an effect. Further research should examine its long-term sustainability.

A Review of Multimodal Hallucinations: Categorization, Assessment, Theoretical Perspectives, and Clinical Recommendations

Abstract: Hallucinations can occur in different sensory modalities, both simultaneously and serially in time. They have typically been studied in clinical populations as phenomena occurring in a single sensory modality. Hallucinatory experiences occurring in multiple sensory systems-multimodal hallucinations (MMHs)-are more prevalent than previously thought and may have greater adverse impact than unimodal ones, but they remain relatively underresearched. Here, we review and discuss: (1) the definition and categorization of both serial and simultaneous MMHs, (2) available assessment tools and how they can be improved, and (3) the explanatory power that current hallucination theories have for MMHs. Overall, we suggest that current models need to be updated or developed to account for MMHs and to inform research into the underlying processes of such hallucinatory phenomena. We make recommendations for future research and for clinical practice, including the need for service user involvement and for better assessment tools that can reliably measure MMHs and distinguish them from other related phenomena.

Overcoming Rest-Task Divide-Abnormal Temporospatial Dynamics and Its Cognition in Schizophrenia.

Abstract: Schizophrenia is a complex psychiatric disorder exhibiting alterations in spontaneous and task-related cerebral activity whose relation (termed "state dependence") remains unclear. For unraveling their relationship, we review recent electroencephalographic (and a few functional magnetic resonance imaging) studies in schizophrenia that assess and compare both rest/prestimulus and task states, ie, rest/prestimulus-task modulation. Results report reduced neural differentiation of task-related activity from rest/prestimulus activity across different regions, neural measures, cognitive domains, and imaging modalities. Together, the findings show reduced rest/prestimulus-task modulation, which is mediated by abnormal temporospatial dynamics of the spontaneous activity. Abnormal temporospatial dynamics, in turn, may lead to abnormal prediction, ie, predictive coding, which mediates cognitive changes and psychopathological symptoms, including confusion of internally and externally oriented cognition. In conclusion, reduced rest/prestimulus-task modulation in schizophrenia provides novel insight into the neuronal mechanisms that connect task-related changes to cognitive abnormalities and psychopathological symptoms.

Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study.

Abstract: Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. For this, we followed up a national cohort of first-episode psychosis patients in Finland for up to 18 years. Stratified Cox proportional hazards regressions were conducted for "within-participant" risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most prescribed antipsychotic in this cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated. Among 3343 participants followed up for a mean of 8 years (SD = 4.93), the median number of continuous treatment episodes was 6 (interquartile range [IQR] = 3-11) with a median duration of 11.4 months (IQR = 5.3-25.6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30.12 (95% CI = 29.89-30.35) events per 100 participant-years, decreasing to 8.90 (95% CI = 8.75-9.05) in the 10th year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR = 0.30; 95% CI = 0.20-0.46 for episodes after the 15th compared to the first). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR = 0.33; 95% CI = 0.27-0.41). Treatment for schizophrenia over the long term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Greater utilization of long-acting injectable formulations earlier in the course of illness may facilitate the continuity of antipsychotic treatment in schizophrenia.

Online Social Cognition Training in Schizophrenia: A Double-Blind, Randomized, Controlled Multi-Site Clinical Trial.

Abstract: Social cognition (SC), the mental operations underlying social functioning, are impaired in schizophrenia. Their direct link to functional outcome and illness status have made them an important therapeutic target. However, no effective treatment for these deficits is currently applied as a standard of care. To address this need, we have developed SocialVille-an online, plasticity-based training program that targets SC deficits in schizophrenia. Here we report the outcomes of a double-blind, controlled, randomized, multi-site clinical trial of SocialVille. Outpatients with schizophrenia were randomized to complete 40 sessions of either SocialVille (N = 55 completers) or active control (computer games; N = 53 completers) from home. The a priori co-primary outcome measures were a social cognitive composite and a functional capacity outcome (UCSD Performance-based Skills Assessment [UPSA-2]). Secondary outcomes included a virtual functional capacity measure (VRFCAT), social functioning, quality of life, and motivation. Linear mixed models revealed a group × time interaction favoring the treatment group for the social cognitive composite (b = 2.81; P < .001) but not for the UPSA-2 measure. Analysis of secondary outcome measures showed significant group × time effects favoring the treatment group on SC and social functioning, on the virtual functional capacity measure and a motivation subscale, although these latter findings were nonsignificant with FDR correction. These results provide support for the efficacy of a remote, plasticity-based social cognitive training program in improving SC and social functioning in schizophrenia. Such treatments may serve as a cost-effective adjunct to existing psychosocial treatments. Trial Registration: NCT02246426.

The Latent Structure of Negative Symptoms in Individuals With Attenuated Psychosis Syndrome and Early Psychosis: Support for the 5 Consensus Domains.

Abstract: Negative symptoms are prevalent in the prodromal and first-episode phases of psychosis and highly predictive of poor clinical outcomes (eg, liability for conversion and functioning). However, the latent structure of negative symptoms is unclear in the early phases of illness. Determining the latent structure of negative symptoms in early psychosis (EP) is of critical importance for early identification, prevention, and treatment efforts. In the current study, confirmatory factor analysis was used to evaluate latent structure in relation to 4 theoretically derived models: 1. a 1-factor model, 2. a 2-factor model with expression (EXP) and motivation and pleasure (MAP) factors, 3. a 5-factor model with separate factors for the 5 National Institute of Mental Health (NIMH) consensus development conference domains (blunted affect, alogia, anhedonia, avolition, and asociality), and 4. a hierarchical model with 2 second-order factors reflecting EXP and MAP, as well as 5 first-order factors reflecting the 5 consensus domains. Participants included 164 individuals at clinical high risk (CHR) who met the criteria for a prodromal syndrome and 377 EP patients who were rated on the Brief Negative Symptom Scale. Results indicated that the 1- and 2-factor models provided poor fit for the data. The 5-factor and hierarchical models provided excellent fit, with the 5-factor model outperforming the hierarchical model. These findings suggest that similar to the chronic phase of schizophrenia, the latent structure of negative symptom is best conceptualized in relation to the 5 consensus domains in the CHR and EP populations. Implications for early identification, prevention, and treatment are discussed.

Obesity as a Risk Factor for Accelerated Brain Ageing in First-Episode Psychosis-A Longitudinal Study.

Abstract: Background Obesity is highly prevalent in schizophrenia, with implications for psychiatric prognosis, possibly through links between obesity and brain structure. In this longitudinal study in first episode of psychosis (FEP), we used machine learning and structural magnetic resonance imaging (MRI) to study the impact of psychotic illness and obesity on brain ageing/neuroprogression shortly after illness onset. Methods We acquired 2 prospective MRI scans on average 1.61 years apart in 183 FEP and 155 control individuals. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants and calculated BrainAGE by subtracting chronological from the estimated brain age. Results Individuals with FEP had a higher initial BrainAGE than controls (3.39 ± 6.36 vs 1.72 ± 5.56 years; β = 1.68, t(336) = 2.59, P = .01), but similar annual rates of brain ageing over time (1.28 ± 2.40 vs 1.07±1.74 estimated years/actual year; t(333) = 0.93, P = .18). Across both cohorts, greater baseline body mass index (BMI) predicted faster brain ageing (β = 0.08, t(333) = 2.59, P = .01). For each additional BMI point, the brain aged by an additional month per year. Worsening of functioning over time (Global Assessment of Functioning; β = -0.04, t(164) = -2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (β = 0.11, t(175) = 3.11, P = .002) were associated with faster brain ageing in FEP. Conclusions Brain alterations in psychosis are manifest already during the first episode and over time get worse in those with worsening clinical outcomes or higher baseline BMI. As baseline BMI predicted faster brain ageing, obesity may represent a modifiable risk factor in FEP that is linked with psychiatric outcomes via effects on brain structure.