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Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis.

Evidence supports associations between polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and psychosis. However, polyunsaturated fatty acid trajectories in the general population have not been characterized, and associations with psychosis spectrum outcomes in early adulthood are unknown. Plasma omega-6 to omega-3 ratio and DHA (expressed as percentage of total fatty acids) were measured by nuclear magnetic spectroscopy at 7, 15, 17, and 24 years of age in participants of ALSPAC (Avon Longitudinal Study of Parents and Children). Curvilinear growth mixture modeling evaluated body mass index–adjusted trajectories of both measures. Outcomes were assessed at 24 years. Psychotic experiences (PEs), at-risk mental state status, psychotic disorder, and number of PEs were assessed using the Psychosis-Like Symptoms interview (n = 3635; 2247 [61.8%] female). Negative symptoms score was measured using the Community Assessment of Psychic Experiences (n = 3484; 2161 [62.0%] female). Associations were adjusted for sex, ethnicity, parental social class, and cumulative smoking and alcohol use. Relative to stable average, the persistently high omega-6 to omega-3 ratio trajectory was associated with increased odds of PEs and psychotic disorder, but attenuated on adjustment for covariates (PEs adjusted odds ratio [aOR] = 1.63, 95% CI = 0.92-2.89; psychotic disorder aOR = 1.69, 95% CI = 0.71-4.07). This was also the case for persistently low DHA (PEs aOR = 1.42, 95% CI = 0.84-2.37; psychotic disorder aOR = 1.14, 95% CI = 0.49-2.67). Following adjustment, persistently high omega-6 to omega-3 ratio was associated with increased number of PEs (β = 0.41, 95% CI = 0.05-0.78) and negative symptoms score (β = 0.43, 95% CI = 0.14-0.72), as was persistently low DHA (number of PEs β = 0.45, 95% CI = 0.14-0.76; negative symptoms β = 0.35, 95% CI = 0.12-0.58). Optimization of polyunsaturated fatty acid status during development warrants further investigation in relation to psychotic symptoms in early adulthood. [ABSTRACT FROM AUTHOR]

Neurochemical dysregulations resulting from N-methyl-D-aspartate hypofunction (NMDA), are exacerbated by neuroimmune and oxidative stress and are known risk factors for neuropsychiatric disorders like schizophrenia-like diseases. Here, we investigate the protective and curative effects, and mechanisms of silymarin, a polyphenolic flavonoid with neuroprotective functions in preventive-reversal model of ketamine, an NMDA antagonist in mice. Mice were grouped into 6 cohorts (n = 9). In the pre-treatment, groups 1 and 2 received saline (10 mL/kg/p.o.), groups 3 and 4 (silymarin, 50 and 100 mg/kg/p.o.), and group 5 (risperidone, 0.5 mg/kg/p.o.) consecutively for 14 days, then combined with ketamine (20 mg/kg/i.p.) injection in groups 2–5 from days 8–14. However, mice in reversal study received intraperitoneal injection of ketamine for 14 days before silymarin (50 and 100 mg/kg, p.o) and risperidone (0.5 mg/kg, p.o.) treatment between days 8–14. The consequences on schizophrenia-like behavior, neurochemistry, inflammation, and oxidative/nitrergic stress markers were evaluated in critical brain regions of the disease. Silymarin prevented and reversed ketamine-induced increase in dopamine, 5-hydroxyltryptamine, acetylcholinesterase, malondialdehyde and nitrite levels in the striatum, prefrontal-cortex and hippocampus. These were accompanied by improvement in hyperlocomotion, stereotypy, memory, and social impairments, notably devoid of cataleptogenic potential. Complementarily, silymarin reduced myeloperoxidase, tumor-necrosis factor-α, and interleukin-6 concentrations relative to the ketamine group. Moreover, ketamine-induced decreased brain-derived neurotrophic factor, glutathione, catalase, superoxide-dismutase levels were normalized by silymarin in the brain regions relative to ketamine. Overall, these findings suggest that silymarin's antipsychotic effect might be primarily associated, among other mechanisms, with the normalization of neurochemical and neurotrophic changes in the mice brains. [ABSTRACT FROM AUTHOR]

Objective: Conceptual similarities between depressive and negative symptoms complicate biomarker and intervention development. This study employed a data-driven approach to delineate the neural circuitry underlying depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). Methods: Data from three studies were analyzed (157 participants with SSDs) to assess brain-behavior relationships: two neuroimaging studies and a randomized trial of repetitive transcranial magnetic stimulation (rTMS). Partial least squares correlation (PLSC) was used to investigate associations between resting-state functional connectivity and depressive and negative symptoms. Secondary analyses of rTMS trial data (active, N=37; sham, N=33) were used to assess relationships between PLSC-derived symptom profiles and treatment outcomes. Results: PLSC identified three latent variables (LVs) relating functional brain circuitry with symptom profiles. LV1 related a general depressive symptom factor with positive associations between and within the default mode network (DMN), the frontoparietal network (FPN), and the cingulo-opercular network (CON). LV2 related negative symptoms (no depressive symptoms) via negative associations, especially between the FPN and the CON, but also between the DMN and the FPN and the CON. LV3 related a guilt and early wakening depression factor via negative rather than positive associations with the DMN, FPN, and CON. The secondary visual network had a positive association with general depressive symptoms and negative associations with guilt and negative symptoms. Active (but not sham) rTMS applied bilaterally to the dorsolateral prefrontal cortex (DLPFC) reduced general depressive but not guilt-related or negative symptoms. Conclusions: The results clearly differentiate the neural circuitry underlying depressive and negative symptoms, and segregated across the two-factor structure of depression in SSDs. These findings support divergent neurobiological pathways of depressive symptoms and negative symptoms in people with SSDs. As treatment options are currently limited, bilateral rTMS to the DLPFC is worth exploring further for general depressive symptoms in people with SSDs. [ABSTRACT FROM AUTHOR]

Recovery is a hot topic in current psychosis literature. However, popular models on recovery, like CHIME-DTAR, fail to address the relationship with factors that might hamper recovery, like experiencing negative symptoms. This study explores how narratives can play a role in recovery from negative symptoms. As a mixed team of researchers, some with lived experience of psychosis, others with a background in clinical psychology or special needs education, we co-constructed an understanding of how narratives played a role in the experiences of Pete and Tanguy. Two major themes stood out: narratives can serve as points of support; and the importance of claiming ownership over your own narrative practice. The authors conclude that recovery can be promoted by creating opportunities for service users to articulate personal narratives and get recognition for these. Our collaborative approach not only highlighted these aspects, but also provided an opportunity for articulating narratives. POINTS OF INTEREST: This article explores how narratives can play a role in the recovery from negative symptoms of psychosis. This study is the result of a collaboration between researchers with and without lived experience of psychosis. Developing a personal narrative practice can help to regain a grip on life and as such to get out of a crisis. Narratives are especially helpful when you are able to claim ownership/authorship of them. Current mental health care still too often fails to recognize service users as active meaning making subjects, but rather approaches them as passive recipients of care. We believe such an attitude might unwittingly promote negative symptoms. Creating opportunities to develop and get recognition for one's narratives might foster recovery. [ABSTRACT FROM AUTHOR]

Blunted affect is associated with severe mental illness, particularly schizophrenia. Mechanisms of blunted affect are poorly understood, potentially due to a lack of phenomenological clarity. Here, we examine clinician rated blunted affect and computerized facial metrics derived from ambulatory video assessment using machine learning. With high predictive accuracy (80–82%), we found that head orientation, eye movement, and facets of mouth movement were associated with clinical ratings of blunted affect. Features denoting larger muscle movements were associated with social cognition (R2 = 0.37) and cognition (R2 = 0.40). Findings provide potential insights on psychological and pathophysiological contributors to blunted affect. [ABSTRACT FROM AUTHOR]

Site-independent ratings derived from audio-digital recordings of site-based interviews are often used for quality assurance monitoring to affirm ratings reliability in CNS clinical trials. The present study of subjects with schizophrenia and persistent negative symptoms used video instead of audio recordings of site-based interviews and thereby facilitated visual observation of the subject by the remote rater. "Paired" site-independent scores of the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS) were obtained from video-recordings of site-based interviews. The intraclass correlation between site-based and paired site-independent ratings was r = 0.839 for the total PANSS scores (n = 1006) and r = 0.871 for the total BNSS scores (n = 892); <5 % of paired scores deviated outside the acceptable confidence intervals. Ratings "outliers" were identified and remediated. We examined the pattern of paired scoring deviations for the BNSS, total PANSS, PANSS symptom subscales, and the Marder negative symptom factor. Each metric revealed a bidirectional pattern of scoring deviations such that mean site-based ratings were higher than site-independent ratings when symptom severity was high but lower than site-independent ratings when symptom severity was low. The pattern of bidirectional paired scoring deviations observed in this analysis has previously been noted in paired ratings analyses of subjects experiencing an acute exacerbation of psychosis in schizophrenia and major depressive disorder as well. The bidirectional pattern may reflect inherent differences between live ratings and remotely scored recorded ratings. This analysis affirms the utility of video-recordings of site-based ratings for surveillance in trials with subjects with schizophrenia and persistent negative symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Predictors of functioning are well-studied in schizophrenia, but much less so in treatment-resistant schizophrenia (TRS). In this study, we aim to investigate contributions of schizophrenia symptom domains and neurocognition to predict functioning in a TRS population (n = 146). Methods: Participants were assessed on the Positive and Negative Syndrome Scale (PANSS), to calculate scores for five symptomfactors (Positive, Negative, Cognitive, Depressive and Hostility) and two negative symptom constructs (Diminished Expressivity (DE), and Social Anhedonia (SA) as part of the Motivation and Pleasure-related dimension), based on a previously validated model, modified in accordance with EPA guidelines on negative symptoms assessment. Neurocognition was assessed with symbol coding and digit sequencing tasks from the Brief Assessment of Cognition in Schizophrenia (BACS). Functioning was assessed with the Social and Occupational Functioning Assessment Scale (SOFAS), employment status andWorld Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Multiple regression analyses were performed on psychopathology scores and BACS scores against all three measures of functioning, controlling for age and sex. For WHODAS, regression with PANSS scores of significant symptom factors were also performed. Results: A lower severity of negative symptoms in the SA dimension was the strongest predictor of higher functioning across all three functioning measures. Neurocognition, in particular processing speed and attention assessed on the symbol coding task, predicted employment. A lower severity of somatic concerns and depressive symptoms was associated with lesser self-reported disability on WHODAS. Discussion: This study represents a first attempt at elucidating significant predictors of functioning in TRS. We highlight negative symptoms and neurocognition as important treatment targets to improve functioning in TRS, consistent with previous studies in general schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic psychotic disorder comprising positive symptoms, negative symptoms, and cognitive deficits. Negative symptoms are associated with stigma, worse functional outcomes, and a significant deterioration in quality of life. Clinical diagnosis is challenging despite its significance, and current treatments offer little improvement in the burden of negative symptoms. This article reviews current pharmacological strategies for treating negative symptoms. Dopaminergic, glutamatergic, serotonergic, noradrenergic, cholinergic, anti-inflammatory compounds, hormones, and psychostimulants are explored. Finally, we review pharmacological global treatment guidelines for negative symptoms. In general, switching to a second-generation antipsychotic seems to be most often recommended for patients with schizophrenia on first-generation antipsychotics, and an add-on antidepressant is considered when depression is also present. However, the treatment of negative symptoms remains an unmet need. Future, larger clinical studies and meta-analyses are needed to establish effective pharmacological agents for the effective treatment of negative symptoms. [ABSTRACT FROM AUTHOR]

Background: Variable benefits have been reported from the adjunctive use of simvastatin and the 5HT3 receptor antagonist, ondansetron, in patients with schizophrenia. We investigated their independent efficacy and possible synergy to improve negative symptoms of schizophrenia within a single trial. Methods: A 6-month, randomised, double-blind, placebo-controlled trial with a 4-arm, 2 × 2 factorial design, in three centres in Pakistan. In total, 303 people with stable treated schizophrenia aged 18–65 were randomly allocated to add-on ondansetron, simvastatin, both or neither. The primary outcome was a Positive and Negative Syndrome Scale (PANSS) negative score at 3 and 6 months. Results: Mixed model analysis and analysis of covariance revealed no main effects of simvastatin or ondansetron but a significant negative interaction between them (p = 0.03); when given alone, both drugs significantly reduced negative symptoms compared to placebo but they were ineffective in combination. Individual treatment effects versus placebo were −1.9 points (95%CIs −3.23, −0.49; p = 0.01) for simvastatin and −1.6 points for ondansetron (95%CIs −3.00, −0.14; p = 0.03). Combined treatment significantly increased depression and side effects. In those with less than the median 5 years of treatment, ondansetron improved all PANSS subscales, global functioning measures and verbal learning and fluency, whereas simvastatin did not. Conclusion: Small improvement in negative symptoms on simvastatin and ondansetron individually are not synergistic in combination in treating negative symptoms of schizophrenia. Ondansetron showed broad efficacy in patients on stable antipsychotic treatment within 5 years of illness. The findings suggest that ondansetron should be evaluated in patients at risk of psychosis or early in treatment. [ABSTRACT FROM AUTHOR]

Social anhedonia is a hallmark symptom of schizophrenia. Discrepancies in anticipated versus consummatory pleasure for non-social stimuli are well-documented. Thus, a similar emotional paradox may underlie social anhedonia. If so, our understanding of social anhedonia—including how to treat it in schizophrenia—could be enhanced. This project used a 5-day experience sampling method (ESM) to measure discrepancies between anticipated and consummatory pleasure for real-world social activities in people with schizophrenia and healthy controls (n = 30/group). ESM results were compared to laboratory assessments of negative symptoms and neurocognition. The schizophrenia group exhibited similar levels of anticipated and consummatory social pleasure as controls throughout daily life, and both groups were accurate in their short-term predictions of pleasure. Clinical interviews revealed those with schizophrenia showed significant deficits in long-term social pleasure prediction (i.e., a 1-week timeframe). Thus, people with schizophrenia may exhibit differences in ability to predict pleasure in the short-term versus the long-term. Negative symptoms and neurocognition were related to anticipated, but not consummatory, social pleasure, suggesting anhedonia is driven by deficits in thinking about pleasure, rather than inability to experience pleasure. Clinical implications include focusing on building upon short-term ability to predict pleasure in therapy to increase social motivation in schizophrenia. • People with schizophrenia report as much social pleasure in daily life as controls. • Those with schizophrenia can accurately predict social pleasure in the short-term. • Those with schizophrenia show deficits in long-term social pleasure prediction. • Cognitive impairment is implicated in ability to predict social pleasure. [ABSTRACT FROM AUTHOR]

Paranoid ideation is a transdiagnostic construct that is associated with social impairment and often occurs in psychotic spectrum disorders. Little research has examined how paranoid ideation is related to social behaviors that underlie social impairment and may ultimately lead to social rejection. It is important to consider that negative symptoms and sleep problems also contribute to social impairment. No research has assessed the unique and combined influence of paranoid ideation, negative symptoms, and sleep problems on social impairment. Therefore, the current study examined how paranoid ideation, negative symptoms, and sleep problems contribute to poorer social skills and social rejection in a transdiagnostic sample of persons with psychosis and community members (N = 112). Assessments included diagnostic and symptom interviews, questionnaires, behavioral ratings of social skill and facial displays of affect, and naive observer reactions utilizing thin-slice methodology. Greater paranoid ideation, negative symptoms, and sleep problems were each related to poorer social skill and more negative reactions from observers. When considered in path analyses, negative symptoms were associated with observer reports of less willingness to interact with participants through poorer social skill. These findings demonstrate the symptom correlates of social rejection and how interpersonal behavior may contribute to social exclusion. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe psychiatric disorder, characterized by positive symptoms, negative symptoms, and cognitive deficits. Elucidating the mechanism of negative symptom and cognitive deficits could contribute to the treatment and prognosis of schizophrenia. We hypothesized that abnormal functional connectivity would be involved in the indirect effects of negative symptoms on cognitive function. A total of 150 schizophrenia male patients and 108 healthy controls matched for age, education and gender were enrolled in the study. The scores of Brief Negative Symptom Scale were divided into two factors: motivation and pleasure deficits (MAP) and diminished expression (EXP). Subsequently, a series of classic neurocognitive tests were used to evaluate cognitive functions. Resting-state fMRI data was collected from all participants. The Anatomical Automatic Labeling template was employed to establish regions of interest, thereby constructing the functional connectivity network across the entire brain. Eventually, scores of patients' negative symptoms scale, cognitive function, and strengths of abnormal functional connectivity were incorporated into a structural equation model to explore the interactions among variables. MAP exhibited a distinctly and significantly negative impact on cognitive function. The functional connectivity between the left insula and left precuneus, along with that between the left precuneus and right angular gyrus, collectively served as intermediaries, contributing to the indirect effects of MAP and EXP on cognitive function. Our findings demonstrated the moderating role of aberrant brain functional connectivity between negative symptoms and cognitive function, providing clues about the neural correlates of negative symptoms and cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Negative symptoms in the context of psychosis are still poorly understood and diagnosed, which impairs the treatment efficacy of current therapies and patient's integration in society. In this study, we aimed to test hypothesis-based and exploratory associations of negative symptom domains, as defined by the Brief Negative Symptom Scale (BNSS), with hormonal and hematological variables, and, complementarily, with standard psychological/cognitive and psychopathological measures. Fifty-one male patients diagnosed with a psychotic disorder underwent a structured interview and blood collection. Standard Spearmen bivariate correlations were used for data analysis. We obtained evidence of hypothesis-based associations between specific negative symptoms and oxytocin, thyroid stimulating hormone levels and neutrophil-to-lymphocyte ratio; as well as novel and hypothesis-free associations with erythrocyte and lymphocyte count, mean corpuscular volume and red cell distribution width. Complementarily, we also obtained some validation of previous associations of negative symptoms with illness resolution, cognitive symptom severity and social performance, and a novel association with anger contagion. We hope our results can generate new hypotheses in psychosis research. Our work suggests further avenues in research on erythrocytic, inflammatory, thyroid and oxytocin-related markers and abnormalities in psychosis, especially in regards to specific negative symptoms, towards more precise and comprehensive etiological, diagnostic and therapeutic models. [ABSTRACT FROM AUTHOR]

Negative symptoms in CHR-P people are generally not responsive to treatments and commonly related to poorer functional outcome. However, less research attention has been dedicated to Persistent Negative Symptoms (PNS), defined as clinically stable negative symptoms of moderate severity evident for at least 6 months. This study aims to (a) determine the prevalence of PNS in a sample of young people at CHR-P; (b) investigate any association of PNS with functioning and clinical features; (c) examine longitudinal course of PNS across 2 years of follow-up and changes in PNS severity levels with specialized treatments. One Hundred Eighty CHR-P participants were recruited and were divided into CHR-P/PNS + and CHR-P/PNS− subgroups. The clinical assessments were based on the PANSS and the GAF and were conducted at baseline and every 12 months during the follow-up. Twenty four participants showed PNS at entry. Of them, 21 concluded the 2-year follow-up period. At baseline, the CHR-P/PNS + participants showed more educational and employment deficits, and more social and functioning impairment. During the follow-up, the CHR-P/PNS + subgroup had a significant longitudinal decrease in negative symptoms, which was specifically related to antidepressant treatment. CHR-P/PNS + subjects also showed a higher incidence of new hospitalization and a lower functional recovery over time. Our findings support that the persistence of negative symptoms in CHR-P people is longitudinally related to worse daily functioning and more severe clinical conditions that are at higher risk of hospitalization and are less responsive to specialized treatments. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets. Study Design Using structural MRI, we compared the brain age gap among CHR-P (n  = 51), ESZ (n  = 78), and unaffected comparison participants (UCP; n  = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n  = 10; CHR-P non-converters; n  = 23) and positive and negative symptoms. Study Results ESZ showed a greater brain age gap relative to UCP and CHR-P (P s < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P  = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P  = .008), but not expressive negative symptom severity. Conclusions Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Disturbances in effort-cost decision-making have been highlighted as a potential transdiagnostic process underpinning negative symptoms in individuals with schizophrenia. However, recent studies using computational phenotyping show that individuals employ a range of strategies to allocate effort, and use of different strategies is associated with unique clinical and cognitive characteristics. Building on prior work in schizophrenia, this study evaluated whether effort allocation strategies differed in individuals with distinct psychotic disorders. Study Design We applied computational modeling to effort-cost decision-making data obtained from individuals with psychotic disorders (n  = 190) who performed the Effort Expenditure for Rewards Task. The sample included 91 individuals with schizophrenia/schizoaffective disorder, 90 individuals with psychotic bipolar disorder, and 52 controls. Study Results Different effort allocation strategies were observed both across and within different disorders. Relative to individuals with psychotic bipolar disorder, a greater proportion of individuals with schizophrenia/schizoaffective disorder did not use reward value or probability information to guide effort allocation. Furthermore, across disorders, different effort allocation strategies were associated with specific clinical and cognitive features. Those who did not use reward value or probability information to guide effort allocation had more severe positive and negative symptoms, and poorer cognitive and community functioning. In contrast, those who only used reward value information showed a trend toward more severe positive symptoms. Conclusions These findings indicate that similar deficits in effort-cost decision-making may arise from different computational mechanisms across the psychosis spectrum. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a chronic mental disorder with a relapsing course with generally incomplete remissions and functional decline with varying positive and negative symptoms along with cognitive impairments. Despite the widespread availability of medications to suppress psychosis and prevent relapse, schizophrenia patients continue to remain disabled in different functional aspects in the community. Disability can hence be termed as one of the consequences of schizophrenia. Aims: The aim of this study was to evaluate the frequency of mental disability among patients with schizophrenia and to evaluate the association between clinical features and disabilities among them. Methods: Fifty-three patients who came to psychiatry outpatients in a government tertiary health care hospital who fulfill diagnostic criteria for schizophrenia with at least 2 years of duration of illness and have been on pharmacotherapy for at least 8 weeks before the day of assessment were considered into the study after obtaining an informed consent. The Mini-international neuropsychiatric interview screening for psychiatric diagnosis was applied. The Positive and Negative Syndrome Scale was applied to know the illness severity of schizophrenia. The Indian Disability Evaluation and Assessment Scale is applied to all to assess the disability among the participants. The Clinician Rating Scale is applied to determine the treatment compliance with psychiatric medications. The Montreal Cognitive Assessment Scale (MoCA) was applied to all participants to assess their cognitive functioning. Results: Mild disability was more prevalent followed by moderate and severe disability. The percentage of disability was found to be positively correlated with negative (r = 0.73) and general psychopathology symptoms (r = 0.67) than with positive symptoms (r = 0.39) and was found to be negatively correlated with total MoCA scores (r = −0.5). All these associations were significant. Conclusions: Disability is found to increase with increase in positive, negative, and general psychopathology symptoms and declining cognitive function. Out of all the symptoms, the negative symptoms are found to strongly influence the severity of disability.

BackgroundSchizophrenia patients are often accompanied by negative symptoms and severe cognitive impairment， but effective interventions intended to alleviate such condition are currently limited. Existing researches on group play therapy for schizophrenia is still in its initial stages， and such therapy has the potential to contribute to symptoms improvement.ObjectiveTo explore the efficacy of group play therapy on improving cognitive function and negative symptoms in hospitalized female patients with schizophrenia， so as to provide references for clinical intervention in such group.MethodsThis study involved 40 female patients with schizophrenia who received inpatient treatment at the Third People's Hospital of Fuyang from April 2022 to May 2023 as well as met the diagnostic criteria of the International Classification of Diseases， tenth edition （ICD-10）. They were divided into study group （n=20） and control group （n=20） according to the random number table method. Both groups received routine treatment， and the study group received 10 sessions of group play therapy for 5 weeks on the basis. At baseline， Scale for Assessment of Positive Symptoms （SAPS）， Scale for Assessment of Negative Symptoms （SANS）， Self-rating Depression Scale （SDS）， Nurses' Observation Scale for Inpatient Evaluation （NOSIE）， and Repeatable Battery for the Assessment of Neuropsychological Status （RBANS） were used for assessment. Post-therapy evaluation was conducted by using SAPS， SANS and RBANS. Patients' baseline SAPS scores， SANS scores， RBANS total scores， and various factor scores of RBANS were used as covariates， and covariance analysis was adopted to compare the scores of each scale between the two groups after treatment.ResultsA total of 39 patients went through the whole study. Results of covariance analysis showed that the SANS score of study group was lower than that of control group， while several scores of RBANS （including total score， immediate memory factor score， speech function factor score and attention factor score） were all higher than those in control group. Significant difference was observed between two groups in scores of both scales above （F=13.408， 10.331， 4.932， 9.967， 10.010， P

Dusica Hadzi Boskovic,1 Jayne Smith-Palmer,2 Johannes Pöhlmann,2 Richard F Pollock,2 Steve Hwang,1 David Bruhn1 1Global Value and Real World Evidence, Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, NJ, USA; 2Covalence Research Ltd, Harpenden, Hertfordshire, UKCorrespondence: Jayne Smith-Palmer, Email smith-palmer@covalence-research.comAim: Negative symptoms of schizophrenia (NSS) have been linked with poor functional outcomes. A literature review was performed to identify instruments used to assess functional outcomes and quality of life in clinical trials and observational studies conducted in groups of people with NSS.Methods: Literature search strings were designed using Medical Subject Headings combined with free-text terms and searches were performed using the PubMed, Embase and the Cochrane Library databases. For inclusion, articles were required to be published as full-text articles, in English, over the period 2011– 2021, include at least one group or treatment arm of people with NSS and report either functional outcomes or quality of life (QoL).Results: Literature searches identified a total of 3,268 unique hits. After two rounds of screening, 37 publications (covering 35 individual studies) were included in the review. A total of fourteen different instruments were used to assess functional outcomes and eleven different instruments were used to assess QoL. In studies in people with NSS, the most frequently used functional outcome measures were the Personal and Social Performance scale and the Global Assessment of Functioning. The most frequently used QoL instruments included the Manchester Short Assessment of Quality of Life, the Heinrich Carpenter Quality of Life Scale, the Schizophrenia Quality of Life Scale and the EQ-5D.Conclusion: A large number of measures have been used to assess functional outcomes and QoL in people with NSS, these include both generic and condition-specific as well as both interviewer-administered and self-reported instruments.Keywords: schizophrenia, quality of life, functional outcomes, negative symptoms

Background: The development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain restingstate (rs)-activity with disease-related features. Methods: Sixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables. Results: Attention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity. Conclusion: Neurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes. [ABSTRACT FROM AUTHOR]

Emotional intelligence (EI) and neurocognition (NC) impairments are common in first-episode psychosis (FEP), yet their evolution over time remains unclear. This study identified patient profiles in EI and NC performance in FEP. 98 adult FEP patients and 128 healthy controls (HCs) were tested on clinical, functional, EI, and NC variables at baseline and two-year follow-up (FUP). A repeated-measures ANOVA compared the effects of group (patients and HCs) and time on EI. Significant EI improvements were observed in both groups. Four groups were created based on NC and EI performance at baseline and FUP in patients: impairment in NC and EI, impairment in NC only, impairment in EI only, and no impairment. At FUP, patients impaired in NC and EI showed less cognitive reserve (CR), greater negative and positive symptoms, and poorer functional outcomes. At FUP, three group trajectories were identified: (I) maintain dual impairment (II) maintain no impairment or improve, (III) maintain sole impairment or worsen. The maintain dual impairment group had the lowest levels of CR. EI and NC impairments progress differently in FEP. Greater CR may protect against comorbid EI/NC impairment. Identifying these patient characteristics could contribute to the development of personalised interventions. [ABSTRACT FROM AUTHOR]

• Inflammation is a pathological characteristic in some first-episode psychosis cohorts. • Negative symptoms have been consistently linked with inflammatory abnormalities. • 6-weeks of exercise significantly reduced IL-6 and Th-cell ratio in psychosis. • Regular exercise training caused a reduction in negative symptomology. • Exercise may be useful as adjunct therapy for individuals experiencing psychosis. First-Episode Psychosis (FEP) is a devastating mental health condition that commonly emerges during early adulthood, and is characterised by a disconnect in perceptions of reality. Current evidence suggests that inflammation and perturbed immune responses are involved in the pathology of FEP and may be associated specifically with negative symptoms. Exercise training is a potent anti-inflammatory stimulus that can reduce persistent inflammation, and can improve mood profiles in general populations. Therefore, exercise may represent a novel adjunct therapy for FEP. The aim of this study was to assess the effect of exercise on biomarkers of inflammation, negative symptoms of psychosis, and physiological health markers in FEP. Seventeen young males (26.67 ± 6.64 years) were recruited from Birmingham Early Intervention in Psychosis Services and randomised to a 6-week exercise programme consisting of two-to-three sessions per week that targeted 60–70 % heart-rate max (HRMax), or a treatment as usual (TAU) condition. Immune T-helper (Th-) cell phenotypes and cytokines, symptom severity, functional wellbeing, and cognition were assessed before and after 6-weeks of regular exercise. Participants in the exercise group (n = 10) achieved 81.11 % attendance to the intervention, with an average exercise intensity of 67.54 % ± 7.75 % HRMax. This led to favourable changes in immune cell phenotypes, and a significant reduction in the Th1:Th2 ratio (−3.86 %) compared to the TAU group (p = 0.014). After the exercise intervention, there was also a significant reduction in plasma IL-6 concentration (–22.17 %) when compared to the TAU group (p = 0.006). IL-8, and IL-10 did not show statistically significant differences between the groups after exercise. Symptomatically, there was a significant reduction in negative symptoms after exercise (−13.54 %, Positive and Negative Syndrome Scale, (PANSS) Negative) when compared to the TAU group (p = 0.008). There were no significant change in positive or general symptoms, functional outcomes, or cognition (all p > 0.05). Regular moderate-to-vigorous physical activity is feasible and attainable in clinical populations. Exercise represents a physiological tool that is capable of causing significant inflammatory biomarker change and concomitant symptom improvements in FEP cohorts, and may be useful for treatment of symptom profiles that are not targeted by currently prescribed antipsychotic medication. [ABSTRACT FROM AUTHOR]

Objectives: Emerging evidence indicates a connection between oxidative stress, immune-inflammatory processes, and the negative symptoms of schizophrenia. In addition to possessing potent antioxidant and anti-inflammatory properties, sulforaphane (SFN) has shown promise in enhancing cognitive function among individuals with schizophrenia. This study aims to investigate the efficacy of combined treatment with SFN in patients with schizophrenia who experience negative symptoms and its effect on the levels of superoxide dismutase (SOD) and the inflammatory marker, high-sensitivity C-reactive protein (HsCRP). Design: Forty-five patients with schizophrenia were recruited, who mainly experienced negative symptoms during a stable period. In addition to the original treatments, the patients received SFN tablets at a daily dose of 90 mg for 24 weeks. At baseline, 12 weeks, and 24 weeks, the participants were interviewed and evaluated. The reduction rate of the Positive and Negative Syndrome Scale (PANSS) was used to assess each participant. The side effects scale of Treatment Emergent Symptom Scale (TESS) was applied to assess the adverse reactions. Additionally, the levels of the SOD, HsCRP, and other indicators were examined. Results: The study findings revealed a significant decrease in PANSS negative subscale scores (P < 0.001). Furthermore, there was a significant increase in SOD activity and HsCRP levels (P < 0.001 and P < 0.05). Notably, the group of participants who exhibited a reduction in PANSS negative subscale scores demonstrated a significant improvement in HsCRP levels (P < 0.05). Conclusions: Our study suggests that SFN may potentially serve as a safe adjunctive intervention to improve the negative symptoms of schizophrenia. The potential mechanism by which SFN improves negative symptoms in schizophrenia patients may involve its anti-inflammatory properties, specifically its ability to reduce HsCRP levels. Trial registration ClinicalTrial.gov (ID: NCT03451734). [ABSTRACT FROM AUTHOR]

Previous studies reported that peripheral inflammation was associated with cognitive performance and brain structure in schizophrenia. However, the moderating effect of inflammation has not been extensively studied. This study investigated whether inflammation markers moderated the association between negative symptoms and neurocognition in schizophrenia. This cross-sectional study included 137 drug-naïve schizophrenia patients (DNS) and 67 healthy controls (HC). We performed the Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for cognitive assessment and the Positive and Negative Syndrome Scale (PANSS) for psychiatric symptoms. Plasma concentrations of interferon-gamma (IFN-γ), neutrophil gelatinase-associated lipocalin (NGAL), and nuclear factor kappa B (NF-κB) were measured. The MCCB neurocognition score, social cognition score, and total score; the plasma concentrations of NGAL, IFN-γ, and NF-κB were significantly decreased in DNS than in HC (all P's < 0.001). PANSS negative subscale (PNS), PANSS reduced expressive subdomain (RES) negatively correlated with neurocognition score (P = 0.007; P = 0.011, respectively). Plasma concentrations of IFN-γ and NGAL positively correlated with neurocognition score (P = 0.043; P = 0.008, relatively). The interactions of PNS × NGAL; PNS × IFN-γ; RES × IFN-γ accounted for significant neurocognition variance (P = 0.025; P = 0.029, P = 0.007, respectively). Simple slope analysis showed that all the above moderating effects only occurred in patients with near normal IFN-γ and NGAL levels. Plasma concentrations of IFN-γ and NGAL moderated the relationship between negative symptoms (especially RES) and neurocognition in schizophrenia. Treatment targeting inflammation may contribute to neurocognition improvement in schizophrenia. [ABSTRACT FROM AUTHOR]

Recent operational criteria for treatment-resistant schizophrenia (TRS) recognized positive and negative symptoms. TRS patients may have heterogeneity in negative symptoms, but empirical data were lacking. We aimed to characterize TRS patients based on negative symptoms using cluster analysis, and to examine between-cluster differences in social functioning. We administered the Clinical Assessment Interview of Negative symptoms (CAINS), Brief Negative Symptom Scale (BNSS), the Positive and Negative Syndrome Scale (PANSS) and the Social and Occupational Functional Assessment (SOFAS to 126 TRS outpatients. All patients also completed the Temporal Experience of Pleasure Scale (TEPS), the Emotion Expressivity Scale (EES), and the Social Functional Scale (SFS). A two-stage hierarchical cluster analysis was performed with the CAINS, TEPS and EES as clustering variables. We validated the clusters using ANOVAs to compare group differences in the BNSS, PANSS, SOFAS and SFS. Clustering indices supported a 3-cluster solution. Clusters 1 (n = 46) and 3 (n = 16) exhibited higher CAINS scores than Cluster 2 (n = 64), and were negative-symptom TRS subtypes. Cluster 1 reported lower TEPS than Cluster 3; but Cluster 3 reported lower EES than Cluster 1. Upon validation, Clusters 1 and 3 exhibited higher BNSS scores than Cluster 2, but only Cluster 1 exhibited lower SOFAS and higher PANSS general symptoms than Cluster 2. Both Clusters 1 and 3 had higher self-report functioning than Cluster 2. We provided evidence for heterogeneity of negative symptoms in TRS. Negative symptoms can characterize TRS patients and predict functional outcome. • This empirical study characterized TRS patients using the CAINS, self-rated experiential pleasure and emotion expressivity. • Hierarchical cluster analysis categorized 126 TRS patients into three clusters. • The cluster with the highest CAINS-negative symptoms and lowest experiential pleasure exhibited poor social functioning. • Our findings encouraged operational criteria for TRS to incorporate BNSS and CAINS-measured negative symptoms. [ABSTRACT FROM AUTHOR]

Suicidal ideation is common among individuals with first episode psychosis (FEP), with prevalence estimates up to 56.5 %. Despite its high prevalence, relatively little is known about how sociodemographic, clinical and/or developmental characteristics contribute to the experience of suicidal ideation in individuals with FEP. In this cross-sectional study (FEP n = 551 and controls n = 857), univariate logistic regression analyses were performed to study the associations of sociodemographic, clinical, and developmental factors with suicidal ideation in individuals with FEP as well as controls. Suicidal ideation was assessed using the Community Assessment of Psychic Experiences (CAPE). In addition, multivariate logistic regression analyses were conducted based on a stepwise approach. In FEP, only depressive symptoms remained significantly associated with suicidal ideation when all correlates were integrated into one model. In the multivariate model in controls, depressive symptoms, positive symptoms, and traumatic childhood experiences were significantly associated with suicidal ideation. This study showed that depressive symptoms are an important factor relating to suicidal ideation in individuals with FEP, over and above other clinical, sociodemographic, and developmental factors. This underscores the relevance of screening for suicidal ideation in individuals with FEP, and highlights the need for a better understanding of the diagnostic uncertainty and course of mood symptoms in early psychosis. Cross-sectional study design, self-reported questionnaires. [ABSTRACT FROM AUTHOR]

The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one's performance, are an intermediary variable along the pathway from impaired neurocognitive performance to negative symptoms and functioning in daily life. Although reliable associations between these variables have been established in chronic schizophrenia, less is known about the nature of these relationships in recent-onset schizophrenia (ROSz). This current study tested the associations between DPB and variables in the cognitive model (neurocognitive performance, negative symptoms, functioning) as well as mediation by DPB of the association between neurocognitive performance and negative symptoms in ROSz. A total of 52 participants (32 adults with ROSz and 20 non-psychiatric healthy comparators; HC) completed in-lab measures of neurocognitive performance, self-reported defeatist performance beliefs, and clinician administered measures of negative symptoms and functional outcome. Bivariate relationships among these variables were tested with Pearson correlations. Bootstrapped regression analyses were conducted to test the strength of the indirect effect of neurocognitive performance on negative symptoms through DPB. Defeatist performance beliefs were significantly elevated in ROSz, and were associated with neurocognitive performance, negative symptoms, and functional outcome as predicted by the cognitive model. There was a significant indirect effect of neurocognition on experiential negative symptoms through DPB, indicating DPB are a partial mediator of the relationship between neurocognitive performance and negative symptoms. These findings are consistent with the cognitive model of negative symptoms and extend previous findings in both ROSz and established schizophrenia. Specifically, these data demonstrate that DPB are elevated among ROSz and the associations with neurocognition and clinical outcomes (e.g., negative symptoms and functioning) are of similar magnitude to those reported in chronic schizophrenia. DPB may therefore be a viable treatment target in the early course of illness. [ABSTRACT FROM AUTHOR]

Deficits in N -methyl- d -aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d -amino acid oxidase (DAAO) inhibitor that increases d -serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d -serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale—Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov : NCT03382639 [ABSTRACT FROM AUTHOR]

Deficits in executive functions (EF) are strongly related to real-life functioning and negative symptoms (NS) in schizophrenia. Recently, virtual reality has enabled more ecologically valid approaches to assess EF in simulated "real-life" scenarios among which the virtual cooking task (VCT) has gained attention. However, the clinical implications of the VCT in schizophrenia have not been investigated exhaustively. In this study, clinically stable individuals with schizophrenia (n = 38) and healthy controls (n = 42) completed a novel VCT and a set of computerized standard EF tools (CST) to primarily investigate concurrent and discriminant validity. In addition, the study explored links between EF assessments, functioning, and NS while controlling for antipsychotic intake, clinical stability, and age. This VCT consisted of four tasks with increasing difficulty and time constraints. The most relevant findings indicate that (1) the VCT showed moderate to strong correlations with CST, (2) the VCT discriminated EF performance between both the groups, (3) the VCT predicted interpersonal functioning, and (4) the VCT predicted NS in greater extent than CST. Accordingly, the findings give support to the concurrent and discriminant validity of the VCT to assess EF and indicate its value to deepen the study of collateral functional deficits and NS in schizophrenia. [ABSTRACT FROM AUTHOR]

Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu 3) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu 3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear. We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu 3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits. We first established that PCP treatment augmented excitatory transmission onto dopamine D 1 receptor–expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu 3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu 3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell. These data demonstrate that activation of mGlu 3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]

The onset of psychotic symptoms occurs prior to age 19 in 39% of the patients with schizophrenia. There are limited approved treatment options for adolescents with schizophrenia. Brexpiprazole was approved by the United States Food and Drug Administration (FDA) for treatment of schizophrenia in adolescents in 2022. Extrapolation of adult data to youth and use of pharmacologic modeling coupled with open long-term safety data were used by the FDA to approve brexpiprazole for adolescent schizophrenia. They were all reviewed herein. D2 receptor partial agonist antipsychotic agents are preferred in the early phase of treatment of psychotic disorders. Approval of brexpiprazole in adolescent schizophrenia provides an additional option. Brexpiprazole was approved by the FDA on the basis of extrapolation of adult data without controlled trials in adolescents. This reduces placebo exposure in young people. Two previous agents (asenapine and ziprasidone) approved for adult schizophrenia failed to separate from placebo in adolescent schizophrenia studies; this partially undermines the process of extrapolation. For brexpiprazole, the paucity of data in adolescents relegates it to a second-line agent. More research on brexpiprazole is needed to delineate its relative role in the management of adolescent schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is associated with changes in white matter (WM) integrity and with reduced life expectancy, in part because of the cardiometabolic side effects of antipsychotics. Physical activity (PA) has emerged as a candidate lifestyle intervention that is safe and effective. The study aimed to assess how an adapted PA program delivered remotely by web (e-APA) improved WM integrity in patients with schizophrenia (SZPs) and healthy controls (HCs) and to evaluate associations among WM integrity, cardiorespiratory fitness, and symptom severity. This longitudinal study was conducted over 16 weeks with 31 participants (18 SZPs and 13 HCs). Diffusion tensor imaging and tract-based spatial statistics were employed to assess WM integrity. Cardiorespiratory fitness was measured by maximal oxygen uptake (VO2max), and assessments for clinical symptoms included the Positive and Negative Syndrome Scale, Self-evaluation of Negative Symptoms and the Brief Negative Syndrome Scale (BNSS). Only the SZPs had significantly increased WM integrity after the e-APA program, with increased fractional anisotropy and decreased radial diffusivity in fasciculi involved in motor functions and language process. Furthermore, decreased negative symptoms assessed with BNSS were associated with greater WM integrity following the program. These findings suggest that e-APA may improve WM integrity abnormalities and support e-APA as a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic psychiatric disorder severely affecting patients' functioning and quality of life. Unlike positive symptoms, cognitive impairment and negative symptoms cannot be treated pharmacologically and represent consistent predictors of the illness's prognosis. Cognitive remediation (CR) interventions have been applied to target these symptoms. Brain stimulation also provides promising yet preliminary results in reducing negative symptoms, whereas its effect on cognitive impairment remains heterogeneous. Here, we combined intermittent theta burst stimulation (iTBS) with CR to improve negative symptoms and cognitive impairment in schizophrenia spectrum patients. One hundred eligible patients were invited, and twenty-one participated. We randomized them into four groups, manipulating the stimulation condition (real vs. sham) and CR (no training vs. training). We delivered fifteen iTBS sessions over the left dorsolateral prefrontal cortex for three weeks, followed (or not) by 50 min of training. Consensus-based clinical and cognitive assessment was administered at baseline and after the treatment, plus at three follow-ups occurring one, three, and six months after the intervention. Mixed-model analyses were run on cognitive and negative symptom scores. The preliminary findings highlighted a marginal modulation of iTBS on negative symptoms, whereas CR improved isolated cognitive functions. We herein discuss the limitations and strengths of the methodological approach. [ABSTRACT FROM AUTHOR]

• People with schizophrenia spectrum disorders report normal quantity of mental imagery. • Mental imagery vividness is reduced in people with schizophrenia spectrum disorders. • Reduced vividness is related to low anticipatory pleasure, motivation, and activity. • Reduced vividness may cause a lack of incentive to seek pleasurable experiences. Many people with schizophrenia spectrum disorders (SSDs) experience profound amotivation, which is strongly related to anticipatory anhedonia. Yet, the neuropsychological fundamentals of anticipatory anhedonia and amotivation are barely understood, resulting in a lack of effective treatments for these patients. Aberrancies in positive mental imagery may interfere with the anticipation of pleasure and could thus explain anticipatory anhedonia and amotivation. However, the nature of mental imagery and its relationship with amotivational psychopathology in SSD is largely unknown. In this preregistered study, we therefore examined mental imagery characteristics and their relation to anticipatory anhedonia, amotivation, and daily life activity in SSD. The N = 86 participants included individuals with SSD (n = 43) and demographically matched healthy controls (n = 43). Mental imagery, anticipatory pleasure, amotivation, and activity engagement were assessed with structured interviews and self-report questionnaires. Ecological momentary assessment was used to measure state anticipatory pleasure and activity engagement in daily life (n = 81). Compared to the control group, the SSD group showed comparable quantity, but less vividness of mental imagery. Reduced vividness of mental imagery in SSD was significantly associated with higher anticipatory anhedonia, amotivation, and low activity engagement in cross-sectional and prospective analyses. Reduced mental imagery vividness may cause a lack of internal incentive to seek pleasurable experiences and could explain amotivation. Interventions aiming to improve mental imagery vividness and related anticipatory pleasure responses in SSD may be effective in targeting amotivation. [ABSTRACT FROM AUTHOR]

• Negative symptoms impact quality of life and functioning. • Complement regulators and coagulation regulators are prognostic factors of negative symptoms. • Their prognostic value is independent of clinical and demographic prognostic factors. • These results may aid early intervention for negative symptoms of psychosis. Negative symptoms impact the quality of life of individuals with psychosis and current treatment options for negative symptoms have limited effectiveness. Previous studies have demonstrated that complement and coagulation pathway protein levels are related to later psychotic experiences, psychotic disorder, and functioning. However, the prognostic relationship between complement and coagulation proteins and negative symptoms is poorly characterised. In the North American Prodrome Longitudinal Studies 2 and 3, negative symptoms in 431 individuals at clinical high-risk for psychosis (mean age: 18.2, SD 3.6; 42.5 % female) were measured at multiple visits over 2 years using the Scale of Psychosis-Risk Symptoms. Plasma proteins were quantified at baseline using mass spectrometry. Four factors were derived to represent levels of proteins involved in the activation or regulation of the complement or coagulation systems. The relationships between standardised protein group factors and serial measurements of negative symptoms over time were modelled using generalised least squares regression. Analyses were adjusted for baseline candidate prognostic factors: negative symptoms, positive symptoms, functioning, depressive symptoms, suicidal ideation, cannabis use, tobacco use, antipsychotic use, antidepressant use, age, and sex. Clinical and demographic prognostic factors of follow-up negative symptoms included negative, positive, and depressive symptoms, functioning, and age. Adjusting for all candidate prognostic factors, the complement regulators group and the coagulation regulators group were identified as prognostic factors of follow-up negative symptoms (β: 0.501, 95 % CI: 0.160, 0.842; β: 0.430, 95 % CI: 0.080, 0.780 respectively. The relationship between complement regulator levels and negative symptoms was also observed in NAPLS2 alone (β: 0.501, 95 % CI: −0.037, 1.039) and NAPLS3 alone, additionally adjusting for BMI (β: 0.442, 95 % CI: 0.127, 0.757). The results indicate that plasma complement and coagulation regulator levels are prognostic factors of negative symptoms, independent of clinical and demographic prognostic factors. These results suggest complement and coagulation regulator levels could have potential utility in informing treatment decisions for negative symptoms in individuals at risk. [ABSTRACT FROM AUTHOR]

Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears to be affected in different domains, especially in the reward domain. Here, we tested adaptive coding of reward in a large group of patients with schizophrenia (n = 86) and control subjects (n = 66). We assessed: (i) the association between adaptive coding deficits and symptoms; (ii) the longitudinal stability of deficits (the same task was performed 3 months apart); and (iii) the stability of results between two experimental sites. We used functional MRI and the monetary incentive delay task to assess adaptation of participants to two different reward ranges: a narrow range and a wide range. We used a region-of-interest analysis to evaluate adaptation within striatal and visual regions. Patients and control subjects underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, with a decreased slope in the narrow reward range with respect to that of control participants, in striatal but not visual regions. This pattern was observed at both research sites. Upon retesting, patients increased their narrow-range slopes, showing improved adaptive coding, whereas control subjects slightly reduced them. At retesting, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal an effect of practice in patients, leading to improvement, with steeper slopes upon retesting. However, in some patients, an excessively steep slope may result in poor discriminability of larger rewards, owing to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (retest, overadaptation) situations might contribute to the multiple motivational symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]

Yoga has shown promise as an add-on therapy for patients with schizophrenia. However, most studies have been short-term, with methodological limitations. We conducted a six-month parallel-group randomized-controlled trial (with rater blinding) to evaluate the effectiveness of a yoga-based intervention in improving symptoms and quality of life in patients with schizophrenia. We recruited 110 patients from an urban tertiary hospital and a semi-urban community centre who met DSM 5 criteria for schizophrenia and were on stable medication for at least six weeks. Participants were randomly assigned to either yoga add-on therapy (YT) or treatment-as-usual (TAU) groups. Clinical assessments were conducted at baseline and at one, three and six months. The primary outcome was changes in positive/negative symptom scores and secondary outcomes included changes in quality of life, perceived stress and socio-occupational functioning. Intention to treat analysis with a longitudinal mixed model approach revealed a significant group-by-time interaction with the YT group showing medium effect improvements in negative symptoms (η2 p = 0.06) and small effect improvements in positive symptoms (η2 p = 0.012), WHOQOL-BREF quality of life [psychological well-being (η2 p = 0.015) and environmental health (η2 p = 0.048)] when compared to TAU. The patients successfully learned and performed yoga practices without reporting any significant adverse effects. Our findings suggest that yoga-based intervention may be a valuable adjuvant therapy for medication-stabilized patients with schizophrenia, especially in ameliorating negative symptoms and enhancing quality of life. Future controlled trials, including active physical interventions, are crucial to validate yoga's efficacy, optimize clinical use, and elucidate underlying mechanisms. • First six-month RCT of yoga as add-on therapy in schizophrenia. • Significant improvement in negative symptoms after yoga intervention (medium effect size). • Improvements in positive symptoms and quality of life (small effect size). • Yoga safely implemented, with no significant adverse effects. • Study supports yoga as a beneficial adjunct therapy for stabilized schizophrenia patients. [ABSTRACT FROM AUTHOR]

One-third of people with schizophrenia have elevated levels of anti-gliadin antibodies (AGA IgG). A 5-week randomized double-blind pilot study was performed in 2014–2017 in an inpatient setting to test the effect of a gluten-free diet (GFD) on participants with schizophrenia or schizoaffective disorder who also had elevated AGA IgG (≥ 20 U) but were negative for celiac disease. This earlier pilot study reported that the GFD-group showed improved gastrointestinal and psychiatric symptoms, and also improvements in TNF-α and the inflammatory cytokine IL-23. Here, we performed measurements of these banked plasma samples to detect levels of oxidative stress (OxSt) using a recently developed iridium (Ir)-reducing capacity assay. Triplicate measurements of these samples showed an Intraclass Correlation Coefficient of 0.84 which indicates good reproducibility. Further, a comparison of the OxSt measurements at the baseline and 5-week end-point for this small sample size shows that the GFD-group (N = 7) had lowered OxSt levels compared to the gluten-containing diet group (GCD; N = 9; p = 0.05). Finally, we showed that improvements in OxSt over these 5 weeks were correlated to improvements in gastrointestinal (r = +0.64, p = 0.0073) and psychiatric (r = +0.52, p = 0.039) symptoms. Also, we showed a possible association between the decrease in OxSt and the lowered levels of IL-23 (r = +0.44, p = 0.087), although without statistical significance. Thus, the Ir-reducing capacity assay provides a simple, objective measure of OxSt with the results providing further evidence that inflammation, redox dysregulation and OxSt may mediate interactions between the gut and brain. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Negative symptoms and cognitive impairments are highly frequent in schizophrenia spectrum disorders (SSD), associated with adverse functional outcomes and quality of life. Repetitive transcranial magnetic stimulation (rTMS) has been considered a promising therapeutic option in SSD. However, placebo effects of rTMS on these symptoms remained unclear. Objective: To investigate placebo effects of rTMS on alleviating negative symptoms and cognitive impairment in patients with SSD and to explore potential moderators. Methods: We systematically searched five electronic databases up to 15 July 2023. Randomized, double-blind, sham-controlled trials investigating effects of rTMS on negative symptoms or cognition in patients with SSD were included. The pooled placebo effect sizes, represented by Hedges' g, were estimated using the random-effects model. Potential moderators were explored through subgroup analysis and meta-regression. Results: Forty-four randomized controlled trials with 961 patients (mean age 37.53 years; 28.1% female) in the sham group were included. Significant low-tomoderate pooled placebo effect sizes were observed for negative symptoms (g=0.44, p<0.001), memory (g=0.31, p=0.010), executive function (g=0.35, p<0.001), working memory (g=0.26, p=0.004), and processing speed (g=0.36, p=0.004). Subgroup analysis indicated that placebo effects were affected by sham stimulation methods, rTMS targeting approaches, and stimulation frequency. Conclusions: Placebo effects of rTMS on negative symptoms and cognition in patients with SSD are significant in a small-to-moderate magnitude, which might be mediated by rTMS parameters. Our findings will provide new insights for practitioners to further optimize and establish standardized rTMS protocols for future RCTs tackling cardinal symptoms in SSD. [ABSTRACT FROM AUTHOR]

Early initiation of antipsychotic treatment plays a crucial role in the management of first-episode schizophrenia (FES) patients, significantly improving their prognosis. However, limited attention has been given to the long-term effects of antipsychotic drug therapy on FES patients. In this research, we examined the changes in abnormal brain regions among FES patients undergoing long-term treatment using a dynamic perspective. A total of 98 participants were included in the data analysis, comprising 48 FES patients, 50 healthy controls, 22 patients completed a follow-up period of more than 6 months with qualified data. We processed resting-state fMRI data to calculate coefficient of variation of fractional amplitude of low-frequency fluctuations (CVfALFF), which reflects the brain regional activity stability. Data analysis was performed at baseline and after long-term treatment. We observed that compared with HCs, patients at baseline showed an elevated CVfALFF in the supramarginal gyrus (SMG), parahippocampal gyrus (PHG), caudate, orbital part of inferior frontal gyrus (IOG), insula, and inferior frontal gyrus (IFG). After long-term treatment, the instability in SMG, PHG, caudate, IOG, insula and inferior IFG have ameliorated. Additionally, there was a positive correlation between the decrease in dfALFF in the SMG and the reduction in the SANS total score following long-term treatment. In conclusion, FES patients exhibit unstable regional activity in widespread brain regions at baseline, which can be ameliorated with long-term treatment. Moreover, the extent of amelioration in SMG instability is associated with the amelioration of negative symptoms. [ABSTRACT FROM AUTHOR]

Objective: Promoting leisure participation requires a collaborative approach that emphasizes personal interests, strengths, and motivations. The purpose of this article was to test the effectiveness of the Independence through Community Access and Navigation (ICAN) intervention on community participation, recreation participation, and positive emotions among individuals with schizophrenia spectrum disorders. Using motivational interviewing and an individualized placements and support framework, the ICAN intervention focuses on working with participants to identify and participate in personally meaningful leisure activities by connecting with personal motivations and mainstream community opportunities. Method: This randomized controlled trial was conducted with 74 participants diagnosed with schizophrenia with assessments conducted at baseline and posttreatment. Intervention effects were examined with repeated-measures analysis of variance (ANOVA). Multiple regression analysis was also performed using a change score as an outcome variable and baseline negative symptoms score, condition, and interaction as predictors. Results: There was no significant main effect of ICAN on positive emotions, recreation participation, or community participation; however, among those in the experimental group, those with impairments in motivation and pleasure experienced improvements in community participation. Conclusions and Implications for Practice: For individuals experiencing greater negative symptoms, a supported leisure intervention may be an effective strategy to explore personal motivations and increase leisure participation. Future research should test the intervention effectiveness specifically targeting a larger sample of individuals with more severe negative symptoms. Impact and Implications: Individuals with greater negative symptoms experienced a significant increase in recreation and community participation. Supported leisure interventions inherently draw upon principles of shared decision making and may meet the specific needs of individuals who experience negative symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Our object is to examine the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on the symptoms, cognitive functions and subjective experiences in patients with chronic schizophrenia and to enhance the overall understanding of the TMS method. Methods: Thirty three patients who had chronic schizophrenia were included in the study. Seventeen patients received rTMS and 16 received sham. The Positive and Negative Syndrome Scale, Repeatable Battery for the Assessment of Neuropsychological Status Scale, Insight and Treatment Attitudes Questionnaire and a self-experience checklist developed by the researchers to evaluate post-TMS experiences were applied to all patients. Results: There were no statistical differences between the groups with regard to symptoms, cognitive functions and insight. However rTMS group reported overall better treatment experience and more positive subjective experiences. Conclusion: rTMS treatment did not cause any improvement in symptoms, cognitive functions and insight but provided a better selfexperience, which might improve treatment compliance. [ABSTRACT FROM AUTHOR]

This study investigates whether early clozapine use is associated with improved responses in different clinical domains, including positive and negative symptoms, functioning, and well-being. Data from 254 clozapine-treated patients at Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) were analysed. Among them, 231 (90.9 %) had a diagnosis of schizophrenia, 21 (8.3 %) schizoaffective disorder, and 2 (0.8 %) had other diagnoses. The International Classification of Diseases-Mortality and Morbidity Statistics criteria (ICD-10) were employed (World Health Organization, 1992). The cohort was assessed using the positive and negative syndrome scale (PANSS), the Brief Negative Symptom Scale (BNSS), Global Assessment of Functioning Scale (GAF), and the short version of Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). Logistic regression models (for positive and negative symptom remission) and linear regression (for functioning and well-being) were utilized to assess the influence of time to clozapine initiation (TCI), age at the first episode of psychosis (AFE), duration of clozapine treatment (DCT), and gender. Early clozapine treatment (within the first three years after the first episode of psychosis) was associated with increased negative symptom remission (exp (B) = 0.38; p = 0.02) and higher functioning scores (β = −0.12, p = 0.046). However, no effect of time to clozapine initiation was found on positive symptom remission rates or well-being scores. Initiating clozapine treatment within the first 3 years of the first episode of psychosis may lead to reduced severity of negative symptoms and improved functioning in clozapine-treated patients. The time to clozapine initiation did not influence its effect on positive symptom remission rates. [ABSTRACT FROM AUTHOR]

Sandplay therapy (SPT) is a promising approach to the treatment of negative psychosis symptoms, due to the psychodynamic lens it brings to both the underlying trauma and the attachment insecurity commonly associated with psychotic episodes. Additionally, SPT and other psychodynamic interventions offer a strengths-based alternative to a cognitive approach to the treatment of psychosis symptoms. Given the evidence that increasing social cognition, attachment security, and engagement with the imagination may all be associated with decreasing negative symptoms of psychosis, it is surprising that SPT, an expressive play therapy with Jungian origins, has not been tested for treatment of psychosis, even for negative symptoms, in any randomised clinical trials. Psychodynamic and cognitive perspectives on psychosis treatment are reviewed, exploring their different assumptions, and implications for direct social work practice as illustrated by a case example, are discussed. [ABSTRACT FROM AUTHOR]

Background: Gut dysbiosis has been established as a characteristic of schizophrenia (SCH). However, the signatures regarding SCH patients with prominent negative symptoms (SCH‐N) in young adults have been poorly elucidated. Methods: Stool samples were obtained from 30 young adults with SCH‐N, 32 SCH patients with prominent positive symptoms (SCH‐P) along with 36 healthy controls (HCs). Microbial diversity and composition were analyzed by 16S rRNA gene sequencing. Meanwhile, psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Results: There is a significant difference in β‐diversity but not α‐diversity indexes among the three groups. Moreover, we found a higher abundance of Fusobacteria and Proteobacteria phyla and a lower abundance of Firmicutes phyla in SCH‐N when compared with HC. Besides, we identified a diagnostic potential panel comprising six genera (Coprococcus, Monoglobus, Prevotellaceae_NK3B31_group, Escherichia‐Shigella, Dorea, and Butyricicoccus) that can distinguish SCH‐N from HC (area under the curve = 0.939). However, the difference in microbial composition between the SCH‐N and SCH‐P is much less than that between SCH‐N and the HC, and SCH‐N and SCH‐P cannot be effectively distinguished by gut microbiota. Conclusion: The composition of gut microbiota was changed in the patients with SCH‐N, which may help in further understanding of pathogenesis in young adults with SCH‐N. [ABSTRACT FROM AUTHOR]

This study examined associations between resting-state amplitude of low frequency fluctuations (ALFF) and negative symptoms represented by total scores, second-order dimension (motivation and pleasure, expressivity), and first-order domain (anhedonia, avolition, asociality, alogia, blunted affect) factor scores in schizophrenia (n = 57). Total negative symptom scores showed positive associations with ALFF in temporal and frontal brain regions. Negative symptom domain scores showed predominantly stronger associations with regional ALFF compared to total scores, suggesting domain scores may better map to neural signatures than total scores. Improving our understanding of the neuropathology underlying negative symptoms may aid in addressing this unmet therapeutic need in schizophrenia.