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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]

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]

Treatment options for social cognition and negative symptoms in schizophrenia spectrum disorders (SSD) remain limited. Oxytocin could be a promising augmentation approach, but the social context influences the effect in humans. This pilot study hypothesized that oxytocin in a positive social setting through mindfulness-based group therapy (MBGT) would positively affect empathy and negative symptoms as well as affect and stress in an exploratory approach in SSD. An experimental, randomized, double-blinded (participants, psychotherapists), placebo-controlled pilot study with 41 individuals with SSD was conducted at the Charité – Universitätsmedizin Berlin. Oxytocin or placebo (24 I.U.) was administered intranasally 45 min before two sessions of MBGT each. A 2 × 2 mixed model ANCOVA design was calculated to assess empathy by the Interpersonal Reactivity Index and the Multifaceted Empathy Test and negative symptoms by the Self-Evaluation of Negative Symptoms. No benefit of oxytocin compared to placebo on empathy was observed, but significant between-group differences favoring oxytocin were found regarding the negative symptoms Diminished emotional range and Avolition. Negative affect and stress were significantly reduced compared to baseline. Mindfulness increased in both groups. Results indicated protocol adherence and retention rate of 91.1%, a drop-out rate of 8.9 % and a completion of 96 % of all sessions by the participants. No severe adverse events or side effects were reported. Our findings indicate proof-of-concept and suggest a potential role of oxytocin on negative symptoms and related variables in SSD in combination with MBGT. Future research should examine the stability of these effects with larger sample sizes. • Mindfulness-based group therapy works as positive social context for oxytocin. • No additional effect of oxytocin and mindfulness on empathy in schizophrenia. • Positive effect of oxytocin and mindfulness on negative symptoms in schizophrenia. • Decreased negative affect by oxytocin plus mindfulness for schizophrenia. • Stress reduction by oxytocin in combination with mindfulness for schizophrenia. [ABSTRACT FROM AUTHOR]

Negative symptoms of schizophrenia remain clinically and theoretically understudied and represent an unmet psychiatric need. Negative symptoms are assumed to be related to other psychiatric disorders, but their association with dissociative symptoms is yet to be explored, particularly in light of depression and anxiety symptoms. We examined the five domains of negative symptoms (anhedonia, asociality, avolition, blunted affect and alogia) in an Israeli national sample of 1930 participants of whom 645 (33.4%) were with increased risk for dissociative disorder. The results show that anhedonia, blunted affect and alogia significantly associated with risk for dissociative disorder, above and beyond depression and anxiety. When assessing for negative symptoms it may be worth screening for dissociation and vice versa and thus make a more accurate clinical picture of the interplay between them. • Negative symptoms of schizophrenia remain clinically and theoretically understudied. • The association between negative symptoms of schizophrenia and dissociative symptoms is understudied. • We report data collected from 1930 participants in an Israeli national sample. • Anhedonia, blunted affect, and alogia associated with risk for dissociative disorders, considering depression and anxiety. [ABSTRACT FROM AUTHOR]

Non - clinical individuals with higher levels of autistic traits and psychotic experiences also have problems in social relationships. Therefore, this study aimed to model complex associations between autistic and psychotic phenotypes and indicators of social relationships in the general population using a network approach. The sample consisted of 649 participants with a mean age of M = 40.23 and SD = 13.09 sampled from the general population. The sample was representative for the 18–65 years old general population in the Slovak Republic. The following scales were administered: Community Assessment of Psychic Experiences, The Comprehensive Autistic Trait Inventory, and NIH Toolbox Adult Social Relationship Scales. Associations between variables and the presence of communities were identified using Exploratory Graph Analysis. Results revealed four highly stable and densely connected communities within the network: social relationships, autistic traits, positive symptoms, and the last one consisting of all negative symptoms, problems in social interactions, and depression. The most important variables in the network were difficulties in social interaction, perceived rejection, bizarre ideas, depression, and social withdrawal. The psychotic and autistic phenotypes in the general population showed a network of connections with characteristics of social relationships. Community detection revealed that autistic traits and psychotic–like experiences formed relatively independent communities. Further, there was substantial overlap between negative symptoms (e.g., social withdrawal), and core features of the autistic phenotype, especially social interaction difficulties. [ABSTRACT FROM AUTHOR]

Negative symptoms (NS), conceived as Avolition-Apathy (AA) and Expressive Deficit (EXP) domains, and neurocognitive impairments represent unmet therapeutic needs for patients with schizophrenia. The present study investigated if bilateral bipolar-nonbalanced frontal transcranial Direct Current Stimulation (tDCS) could improve these psychopathological dimensions. This randomized, double-blind, sham-controlled study (active-tDCS versus sham-tDCS, both, n = 25) included 50 outpatients diagnosed with schizophrenia clinically stabilized. Patients received 20-min 2 mA active-tDCS or sham-tDCS (anode: left Dorsolateral Prefrontal Cortex; cathode: right orbitofrontal region). Primary outcomes included: PANSS-Negative subscale, Negative Factor (Neg-PANSS), AA and EXP domains; neurocognitive performance at Brief Assessment of Cognition in Schizophrenia. Secondary outcomes included: PANSS subscales and total score, Disorganized/Concrete (DiscC-PANSS) and Positive Factors, Clinical Global Impression (CGI) scores, clinical insight at Scale to Assess Unawareness of Mental Disorder (SUMD). Analysis of covariance (ANCOVA) was performed evaluating between-group changes over time. Significant improvements following active-tDCS were observed for all NS measures (all, p < 0.001; d > 0.8) and for working memory (p = 0.025, d = 0.31). Greater variations following to active treatment emerged also for PANSS-General Psychopathology subscale (p < 0.001; d = 0.54), PANSS total score (p < 0.001; d = 0.69), CGI indexes (all, p < 0.001; d > 0.6), DiscC-PANSS (p < 0.001; d = 0.80) and SUMD-general Unawareness index (p = 0.005; d = 0.15) but not for positive symptoms and others insight measures. Good safety/tolerability profiles were found. Bilateral bipolar-nonbalanced frontal-tDCS is a non-pharmacological approach in schizophrenia effectively improving NS, particularly the AA and EXP domains, probably acting by modulating dysfunctional cortical-subcortical networks. Preliminary results also suggest working memory improvements following tDCS. Further studies are needed to confirm the neurobiological basis of these results. • Negative and cognitive symptoms are unmet therapeutic needs in Schizophrenia. • Avolition-Apathy and Expressive Deficit are subdomains of negative symptoms. • Bilateral prefrontal-tDCS effectively improve negative symptoms and subdomains. • tDCS could improve working memory domain, disorganization and clinical severity. • tDCS is a feasible, safe, and well-tolerated approach in Schizophrenia. [ABSTRACT FROM AUTHOR]

Social functioning is severely affected in psychotic disorders. Negative symptoms and social cognition seem to play an important role in social functioning, although the preponderance and relationship between these three domains is not clear. In this study, we sought to assess the interrelation between social cognition, social functioning, and the expressiveness and experiential factors of negative symptoms in first-episode psychosis (FEP). 216 patients, participants in a multicentre study (AGES-CM), comprised our study sample. The WHO Disability Assessment Schedule (WHODAS 2.0) was used to assess functioning, whereas the Positive and Negative Schizophrenia Syndrome Scale (PANSS) was used to measure the severity of negative symptoms, and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) was applied to assess the emotional processing component of social cognition. Network analyses were conducted with the aim of analysing the patterns of relationships between social cognition, social functioning, and the expressiveness and experiential factors of negative symptoms. Our findings suggest that there is a direct relationship between social cognition and social functioning (weight = -.077), but also an indirect connection between them, mediated by the experiential (but not the expressiveness) factor of negative symptoms (weight = 0.300). The importance of the affectation of subdomains of social cognition, as well as the role of negative symptoms, specifically the experiential factor, in the functioning of patients with FEP seems to be relevant. The inclusion of these factors in prevention and treatment programs would thus allow us to reduce their impact on the social functioning of these patients. [ABSTRACT FROM AUTHOR]

Social cognitive deficits are currently considered as one of the main predictors of clinical symptoms and functional outcome in patients with schizophrenia. Multiple studies have suggested that a two-factor solution (low-level vs. high-level) best describes the structure of social cognitive processes in patients. While higher-order processes have been repeatedly linked to negative symptoms, no such association was found for lower-level processes. Thus, the aim of the current study is to examine whether the association between basic social perception processes and symptoms in patients with schizophrenia is mediated by mentalizing abilities. One hundred thirty-nine patients have completed basic social perception (Communicative Interactions Database task CID-12) and mentalizing (Reading the Mind in the Eyes task) tasks. In line with our hypothesis, we have observed full mediation of the effects of basic social perception abilities on negative symptoms via mentalizing abilities in patients. This effect suggests that, similarly as in the case of positive symptoms, a hierarchical nature of social cognitive processes should be considered while investigating negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Clinical interviews and laboratory-based emotional induction paradigms provide consistent evidence that facial affect is blunted in many individuals with schizophrenia. Although it is clear that blunted facial affect is not a by-product of diminished emotional experience in schizophrenia, factors contributing to blunted affect remain unclear. The current study used a combination of ambulatory video recordings that were evaluated via computerized facial affect analysis and concurrently completed ecological momentary assessment surveys to assess whether blunted affect reflects insufficient reactivity to affective or contextual factors. Specifically, whether individuals with schizophrenia require more intense affective experiences to produce expression, or whether they are less reactive to social factors (i.e. being in the presence of others, social motivation). Participants included outpatients with schizophrenia (n = 33) and healthy controls (n = 31) who completed six days of study procedures. Multilevel linear models were evaluated using both Null-Hypothesis Statistical Testing and Bayesian analyses. Individuals with schizophrenia displayed comparable expression of positive and negative emotion to controls during daily life, and no evidence was found for a different intensity of experience required for expression in either group. However, social factors differentially influenced facial expression in schizophrenia compared to controls, such that individuals with schizophrenia did not modulate their expressions based on social motivation to the same extent as controls. These findings suggest that social motivation may play an important role in determining when blunting occurs. [ABSTRACT FROM AUTHOR]

Avolition defined as a lack of interest or engagement in goal-directed behavior plays a key role in everyday functioning in schizophrenia and is considered as one of the main contributors to the burden of disease. The aim of this study was to 1) validate the self-report BIRT Motivation Questionnaire (BMQ-S) seldom used before in schizophrenia 2) examine the degree of agreement between the BMQ-S and its informant-report version 3) to assess its ability to predict real-world outcome at 12 month follow-up. One hundred and twenty-two (51.9% inpatients) adults with a diagnosis of schizophrenia were included. Exploratory Factor analysis was performed on the BMQ-S to identify the underlying structure. Real life functioning was measured with the Global Assessment of Functioning scale (GAF). Convergent validity was assessed with the Scale for Assessment of Negative Symptom (SANS) and the Lille Apathy Rating Scale (LARS). The main psychometric properties of the BMQ-S (internal consistency, test-retest reliability) were satisfactory. Exploratory factorial analysis revealed a 4-factor model which explained 76% of the overall variance. The BMQ-S correlated significantly with the LARS and the SANS avolition subscore suggesting adequate convergent validity. The correlation between the BMQ-S and the clinician-report version was 0.48. The global score and in particular the Initiation/disorganisation dimension was a significant predictor of global functioning at 12-months even when adjusted for age, chlorpromazine intake and depression. Our findings indicate that the BMQ-S has satisfactory psychometric properties and that schizophrenia patients can reliably assess their lack of motivation. Self-evaluation of avolition should be considered in the overall prediction of real-world functioning in schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r= 0.51; P < 0.001) than positive symptoms (r pb = 0.19; P < 0.001). The associations of CRP with positive and negative symptom dimension scores were similar. At individual symptom level, after adjusting for potential confounders including depressive symptoms, CRP was associated with auditory hallucinations (adjusted OR = 2.22; 95% CI, 1.04–4.76) and anhedonia (adjusted OR = 1.13; 95% CI, 1.02–1.26). Inflammation is associated with sub-clinical psychotic symptoms in young people in general population. Association of CRP with symptoms commonly shared between mood and psychotic disorders, such as auditory hallucinations and anhedonia, could be one explanation for the apparent trans-diagnostic effect of inflammation. • We examined psychotic symptoms in adolescents from a population-based birth cohort. • Common positive symptoms were paranoid ideation, visual and auditory hallucinations. • Negative symptoms were correlated with depressive and positive symptoms. • CRP was similarly associated with positive and negative symptom dimension scores. • CRP was specifically associated with auditory hallucinations and anhedonia. [ABSTRACT FROM AUTHOR]

Individuals with schizophrenia show difficulties in achieving vital objectives. Abnormal behavioral and emotional responses to environmental feedback may be some of the psychological mechanisms underlying this lack of goal attainment in schizophrenia. The present study aims to assess how different types of feedback may affect performance in a computerized affective Posner task (non-monetary vs. monetary rewards; contingent vs. non-contingent feedback). The sample was composed of 32 patients with schizophrenia and 35 controls. Reaction times and error rates were the behavioral measurements. The emotional experience was assessed through self-reported affective scales. The results indicated that: ii) the performance with monetary rewards was better than with non-monetary ones in all participants, especially in patients with schizophrenia when higher attentional resources are required (invalid trials). Second, all participants demonstrated faster reaction times, but higher error rates, with non-contingent feedback (frustration condition). Significantly, the schizophrenia group only equaled the controls performance in the non-contingent condition with monetary rewards. Additionally, the higher the negative symptoms were in patients, the worse performance they had under frustration. Third, discrepancies between performance and self-report affect were found in patients. Specifically, after the induction of frustration, the patients reported feeling better and having no arousal changes. Therefore, the findings suggest that, in schizophrenia: i) non-monetary rewards are relatively less important; ii) monetary rewards lessen the negative effects of frustration, iii) discrepancies in self-reported affective scales suggest an unrealistic self-evaluation made under frustration. These findings shed light on the underlying mechanisms of the lack of goal attainment in schizophrenia. • Monetary rewards highly improved cognitive performance in the schizophrenia group. • Non-monetary rewards have scarce benefits for individuals with schizophrenia, compared to controls. • The schizophrenia group showed discrepancies between performance and affective experience under frustration. • The results of this experiment reveal an abnormal emotional and behavioral response to feedback in schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia Spectrum Disorder (SSD) is a chronic psychiatric disorder with modest treatment outcomes. Changes in neuronal morphology may be associated with the symptomatology of SSD. In the present study, we compared the retinal nerve fibre layer thickness (RNFLT) of typically developed adults with that of individuals with SSD in both acute and chronic stages. Fifteen healthy adult males (mean age: 36.40 years) and 30 individuals with SSD (mean age: 37.9 years) took part in the study. Among the latter, 15 had a chronic mean SSD for 15.33 years, while 15 were in an acute psychotic phase with a mean illness duration of 12.20 years. Experts rated positive and negative symptoms of SSD. Retinal nerve fibre layer thickness (RNFLT) of all participants was measured with optical coherence tomography (OCT). Compared to healthy controls, individuals with acute SSD had the lowest macula thickness in the right eye. For nerve fiber layer atrophy, participants with acute SSD showed the largest atrophy (right eye, inferior quadrant). For retinal thickness and macular volume cube, compared to healthy controls, participants with acute SSD had the lowest thickness in the subfield of the right eye. Non-linear associations were observed between RNFL and positive and negative symptoms: e.g., for macula central and subfoveal thickness (left and right eye) and for participants with both acute and chronic SSD, exclusively positive and exclusively negative symptoms (as opposed to prevalently negative with some positive symptoms or prevalently positive with some negative symptoms) were associated with lower volumes. In participants with acute SSD, a longer disease duration was associated with thicker RNFL, while in participants with a chronic SSD a longer disease duration was associated with a thinner RNFL. The present results confirm previous findings that specific neuronal morphological abnormalities can be observed among individuals with SSD. The non-linear associations between neuronal alterations and positive and negative symptomatology suggested that higher pronounced SSD severity appears to be particularly related to morphological changes. Disease duration and RNFL thickness were linearly associated, though, in opposite directions depending on the chronic or acute state. [ABSTRACT FROM AUTHOR]

In patients with schizophrenia, clinical symptoms and cognitive impairment are its core features, both of which have a significant impact on the prognosis and functional outcome. Empathy, as an important social cognition, has been found to be associated with the clinical symptoms in schizophrenia, but the conclusions on this issue are inconsistent. Therefore, this study will continue to explore it through a large sample of inpatients with chronic schizophrenia in the Chinese Han population. We obtained the sociodemographic characteristics of 987 inpatients, measured their clinical symptoms using the Positive and Negative Syndrome Scale (PANSS), and assessed their self-reported empathy using the Interpersonal Reactivity Index (IRI). The factor score for negative symptoms (FSNS) of PANSS was additionally calculated. Correlation and linear regression analysis showed that patients' PANSS scores were widely correlated with their IRI scores. In particular, the negative symptoms of patients were significantly correlated to IRI total score (r = −0.131, p <.001) and subscales such as Perspective Taking (PT) (r = −0.233, p <.001). FSNS had close relationships with empathy as well. There are also many significant associations between other dimensions, such as general psychopathology and Perspective Taking (PT) or Fantasy (FS) (all p <.05). Our results indicated that clinical symptoms, especially negative symptoms, were closely related to their current empathy in patients with schizophrenia, suggesting that the severity of clinical symptoms may be a powerful factor in predicting social cognition such as empathy of schizophrenia. [ABSTRACT FROM AUTHOR]

High-frequency transcranial random noise stimulation (hf-tRNS) is a non-invasive neuromodulatory technique capable of increasing human cortex excitability. There were only published case reports on the use of hf-tRNS targeting the lateral prefrontal cortex in treating negative symptoms of schizophrenia, thus necessitating systematic investigation. We designed a randomized, double-blind, sham-controlled trial in a cohort of stabilized schizophrenia patients to examine the efficacy of add-on hf-tRNS (100–640 Hz; 2 mA; 20 min) using a high definition 4 × 1 electrode montage (anode AF3, cathodes AF4, F2, F6, and FC4) in treating negative symptoms (ClinicalTrials.gov ID: NCT04038788). Participants received either active hf-tRNS or sham twice daily for 5 consecutive weekdays. Primary outcome measure was the change over time in the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), which was measured at baseline, after 10-session stimulation, and at one-week and one-month follow-ups. Among 36 randomized patients, 35 (97.2%) completed the trial. Intention-to-treat analysis showed a significantly greater decrease in PANSS-FSNS score after active (−17.11%) than after sham stimulation (−1.68%), with a large effect size (Cohen's d = 2.16, p < 0.001). The beneficial effect lasted for up to one month. In secondary-outcome analyses, the authors observed improvements with hf-tRNS of disorganization symptoms, unawareness of negative symptoms, subjective response to taking antipsychotics, and antipsychotic-induced extrapyramidal symptoms. No effects were observed on the neurocognitive performance and other outcome measures. Overall, hf-tRNS was safe and efficacious in improving negative symptoms. Our promising findings should be confirmed in a larger sample of patients with predominant negative symptoms. [ABSTRACT FROM AUTHOR]

The resistance of negative symptoms to pharmacologic treatment has spurred interest in understanding the psychological factors that contribute to their formation and persistence. However, little is understood about the psychological processes that reinforce and sustain the negative symptoms domain of diminished expression. Prior research has shown that higher levels of diminished expression relate to deficits in metacognitive capacity. We propose a more complex model in which diminished expression occurs when impairments in metacognitive self-reflectivity, alterations in higher-order language structure, and cognitive symptoms interact and thus interfere with persons' ability to understand and express emotions in ways others can recognize. Individuals with schizophrenia-spectrum disorders (N = 201) provided personal narratives detailing their life story and reflections about their mental illness. Self-reflectivity was measured with the Metacognition Assessment Scale-Abbreviated, and situation models were extracted from participants' personal narratives via Coh-Metrix 3.0, an automated program that calculates language indices. Diminished expression and cognitive symptoms were measured with the Positive and Negative Syndrome Scale. Structural equation models (SEM) examined whether self-reflectivity mediated the impact of cognitive symptoms and situation models on diminished expression. Results of the SEM revealed that self-reflectivity partially mediated the impact of situation models on diminished expression (β = −.073, p =.008, ±95% CI [-0.126, −0.019]). and fully mediated the influence of cognitive symptoms in diminished expression (β = 0.099, p =.001, ±95% CI [0.038, 0.160]). In conclusion, results suggest that self-reflectivity, linguistic cohesion, and cognitive symptoms may be useful targets for intervention in efforts to treat diminished expression in psychosis. [ABSTRACT FROM AUTHOR]

Creativity is considered an essential human accomplishment and a key component for daily life problem solving. It has been suggested that impairment in working memory, cognitive flexibility, and theory of mind could lead to lower creativity in schizophrenia. Additionally, other neurocognitive and social cognitive domains, as well as clinical symptoms could play a role in this relationship. However, the extent to which each of these domains influences creativity in schizophrenia remains unknown. Therefore, the aim of this study was to simultaneously investigate the specific contribution of neurocognitive, social cognitive, and clinical variables to creativity in schizophrenia. One hundred and one patients with schizophrenia were assessed in terms of sociodemographic, clinical, neurocognitive, social cognitive, and creativity variables. After controlling for sociodemographic variables, regression analyses showed that higher social perception (β = 0.286, p =.004) and processing speed (β = 0.219, p =.023) predicted creativity total score. Higher social perception (β = 0.298, p =.002) and processing speed (β = 0.277, p =.004) explained figural creativity. Finally, lower negative symptoms (β = −0.302, p =.002) and higher social perception (β = 0.210, p =.029) predicted verbal creativity. Results suggest that neurocognitive, social cognitive, as well as clinical symptoms influence creativity of patients with schizophrenia. Moreover, these findings point out the prominent role of social cognition in creativity in schizophrenia. [ABSTRACT FROM AUTHOR]

Some patients with schizophrenia have impaired hypothalamic-pituitary-adrenal axis function. However, there is a dearth of studies focusing on corticotropin-releasing hormone (CRH) levels in the brains of schizophrenia patients, which motivated us to examine whether cerebrospinal fluid (CSF) CRH concentrations are altered in these patients. We also examined the possible correlation of CSF CRH level with clinical variables such as schizophrenia symptoms and antipsychotic medication. The study population comprised 20 patients with a diagnosis of schizophrenia according to DSM-5 criteria and 25 healthy controls, who underwent lumbar puncture. Most of the patients were treated with antipsychotic drugs and their doses were converted to chlorpromazine (CP) equivalent values. CSF CRH concentrations were measured by an enzyme immunoassay. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS). There was a significantly lower CSF CRH concentration in the patients than in the controls (Mann-Whitney U test: p = 0.014). A significantly negative correlation of CSF CRH levels with PANSS negative scores was found in the patients (Spearman's: ρ = −0.58, p = 0.007). However, CSF CRH concentrations were not significantly correlated with the PANSS total (ρ = −0.035, p = 0.89), positive (ρ = 0.25, p = 0.30), or general psychopathology (ρ = 0.13, p = 0.59) scores. No significant correlation was found with CP equivalent values (ρ = 0.00, p = 1.00). In conclusion, we found that the patients with schizophrenia had lower CSF CRH concentrations compared to the controls and that the lower CSF CRH was associated with negative symptoms of the illness. Further studies in a larger sample and in drug-free patients are warranted. • Cerebrospinal fluid (CSF) CRH levels were measured. • CRH levels were lower in patients with schizophrenia. • CRH levels were significantly correlated with severity of negative symptoms. [ABSTRACT FROM AUTHOR]

The present study explored an efficient new therapy that combined repetitive transcranial magnetic stimulation (rTMS) and family intervention in addition to risperidone to improve schizophrenia. A randomized controlled trial (January 2016–September 2017) involving 200 patients, of which 188 patients completed the 12-week study, and 50 controls were conducted in the research. The patients were randomly assigned to 12 weeks of treatment with risperidone alone (risperidone group), rTMS and risperidone (rTMS group), family intervention and risperidone (family intervention group), rTMS and risperidone plus family intervention (combined group). MATRICS Consensus Cognitive Battery (MCCB) and the Positive and Negative Symptoms Scale (PANSS) were used to evaluate treatment efficacy. Repeated measures analysis of variance (RMANOVA) were performed to evaluate different treatment efficacy between four groups after 12 weeks of treatment. (1) There were no significant differences in sex, age, education, cognitive function, or PANSS scores between the four groups at baseline (p's > 0.05). (2) There was a significant decrease in the PANSS scores and an increase in the MCCB scores after 12 weeks of treatment in all groups (time effect p's < 0.001). (3) The improvements in positive symptoms and negative symptoms were more obvious in the combined group than in other groups (p's < 0.05). (4) The combined group showed the superior effect in cognition function after 12 weeks. (5) And, interestingly, a remarkable synergistic effect between rTMS and family intervention therapy was observed. There was a synergistic effect between rTMS and the family intervention as an effective combined therapy in improving schizophrenia. This study is registered with Chictr.org , number ChiCTR1900024422 (http://www.chictr.org.cn/edit.aspx?pid=34285&htm=4). [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection. [ABSTRACT FROM AUTHOR]

Animal-assisted therapy (AAT) is increasingly researched as a potential treatment for physical and mental illness, including schizophrenia. The aim of the current paper is to systematically review randomised controlled trials (RCTs) to assess the effectiveness of AAT for schizophrenia and related disorders. We searched PubMed, PsycINFO, CINAHL, EMBASE, The Cochrane Library, CAB Abstracts, and Web of Science for RCTs of AAT for schizophrenia and related disorders. Primary outcomes were mental state and behaviour, clinical global response, and quality of life and wellbeing. Studies were eligible if they were RCTs that had compared AAT, or other animal-assisted intervention, to any control group using any participants with a clinical diagnosis of schizophrenia (or related disorder), regardless of age, gender, setting, or severity and duration of illness. Seven studies were identified for the review. Meta-analysis was not possible due to heterogeneity of studies, including marked differences in outcome measures and interventions. Five out of seven studies included symptoms as an outcome measure, with one reporting improvements in negative symptoms and one study reporting improvements in positive and emotional symptoms. The remaining studies reported no significant effects of AAT. Three studies included quality of life as an outcome measure but did not find any significant effects. Two studies did, however, report improvements in various measures of self-view. The use of AAT for schizophrenia remains inconclusive and there is currently not enough evidence to draw any firm conclusions due to heterogeneity of studies, risk of bias, and small samples. Rigorous, large-scale RCTs are needed to assess the true impact of AAT on schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract The serotonin 5-hydroxytryptamine type 3 (5-HT3) receptor has been implicated in the pathogenesis of schizophrenia. This meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of adjunctive ondansetron, a potent 5-HT3 receptor antagonist, in the treatment of schizophrenia. Only RCTs examining adjunctive ondansetron for schizophrenia were included. Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were analyzed using RevMan, Version 5.3. Study quality was evaluated with the Cochrane risk of bias and the Jadad scale. Data of 5 RCTs (n = 304) covering 149 patients on ondansetron (4-8 mg/day) and 155 patients on placebo were analyzed. Three RCTs reported "randomized allocation" with a specific description; the weighted Jadad score was 3.8. Adjunctive ondansetron outperformed placebo in the reduction of Positive and Negative Syndrome Scale (PANSS) total score [3 RCTs, n = 171; SMD: −1.06 (95%CI: −2.10, −0.02), p = 0.04, I2 = 85%], the negative [4 RCTs, n = 209; SMD: −0.96 (95%CI: −1.71, −0.22), p = 0.01, I2 = 80%], and general psychopathology symptom scores [3 RCTs, n = 171; SMD: −0.97 (95%CI: −1.91, −0.02), p = 0.04, I2 = 82%], but not in the positive (p = 0.05) and depressive symptom scores (p = 0.91). The difference in PANSS total score remained significant after excluding one outlying RCT [2 RCTs, n = 141; SMD: −0.50 (95%CI: −0.84, −0.16), P = 0.004, I2 = 0%]. Four RCTs examined the effect of ondansetron on cognition applying different instruments yielding conflicting findings. Ondansetron was superior over placebo in improving extrapyramidal symptoms, but no group differences were found in overall discontinuation rate and adverse drug reactions. In conclusion, adjunctive ondansetron appears to be efficacious and safe in improving negative symptoms and general psychopathology. The effect of ondansetron on cognitive impairment in schizophrenia needs to be further explored in large-scale RCTs. Highlights • Ondansetron, a potent 5-HT3 receptor antagonist, has been used in treating schizophrenia, with conflicting results. • Adjunctive ondansetron appears to be efficacious and safety in improving negative symptoms and general psychopathology. • The effect of ondansetron on cognitive impairment in schizophrenia needs to be further examined in large-scale prospective studies. [ABSTRACT FROM AUTHOR]

Abstract Transcranial direct current stimulation (tDCS) has generated interest in recent years as a potential adjunctive treatment for patients with schizophrenia. The primary objective of this meta-analysis was to evaluate the efficacy of tDCS on positive symptoms, particularly auditory hallucinations, and negative symptoms. A literature search of randomized sham-controlled trials was conducted using the OVID database on October 9, 2018. The standardized mean differences (SMDs) were calculated to examine changes in symptom severity between active and sham groups for the following symptom domains: auditory hallucinations, positive symptoms (including auditory hallucinations), and negative symptoms. Moderator analyses were performed to examine the effects of study design and participant demographics. We identified 10 eligible studies. Main-analyses showed no effects of tDCS on auditory hallucinations (7 studies, n = 242), positive symptoms (9 studies, n = 313), or negative symptoms (9 studies, n = 313). Subgroup analyses of studies that applied twice-daily stimulation showed a significant reduction in the severity of auditory hallucinations (4 studies, n = 138, SMD = 1.04, p = 0.02). Studies that applied ≥10 stimulation sessions showed a reduction in both auditory hallucination (5 studies, n = 186, SMD = 0.86, p = 0.009) and negative symptom severity (7 studies, n = 257, SMD = 0.41, p = 0.04). Meta-regression analyses revealed a negative association between mean age and the SMDs for auditory hallucinations and negative symptoms, and a positive association between baseline negative symptom severity and the SMDs for negative symptoms. Our findings highlight the need to optimize tDCS parameters and suggest twice-daily or 10 or more stimulation sessions may be needed to improve clinical outcomes in patients with schizophrenia. Highlights • Our primary analyses showed no effects of tDCS on positive or negative symptoms. • Twice-daily tDCS was associated with reduced severity of auditory hallucinations. • More than 10 tDCS sessions was associated with reduced auditory hallucination and negative symptom severity. • Effects of tDCS on symptom severity were negatively associated with age. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) has been shown to be effective in treating some of the symptoms of schizophrenia. In the current study, we sought to determine whether oxy-hemoglobin ([oxy-Hb]), measured by near-infrared spectroscopy (NIRS), is associated with effects of transcranial direct current stimulation (tDCS) on psychotic symptoms of schizophrenia. Twenty-six patients underwent tDCS (2 mA × 20 min) two times per day for five consecutive days. The anodal electrode was placed over the left dorsolateral prefrontal cortex while the cathodal electrode was placed over the right supraorbital region. One month after the last administration of tDCS, positive, but not negative symptoms, evaluated by the Positive and Negative Syndrome Scale (PANSS), were significantly improved. At baseline, regional [oxy-Hb] concentrations in the brain were measured by a 52-channel NIRS instrument. Significant negative correlation was demonstrated between [oxy-Hb] concentrations of left temporoparietal regions throughout verbal fluency tasks vs. changes of PANSS Positive and Negative subscale scores. This is the first study to demonstrate the correlation between the response of neural activity to cognitive tasks at baseline and the ability of tDCS to improve positive and negative psychotic symptoms. Our observations suggest that NIRS provides a marker to predict the response to treatment with tDCS in schizophrenia. [ABSTRACT FROM AUTHOR]

Traditional efforts to delineate the clinical heterogeneity of schizophrenia have been unsuccessful because of the absence of a valid, stable, and meaningful subtyping scheme. A clinically-informed nosology supported by multivariate statistical classification methods may provide a better approach for classifying schizophrenia. The goals of the current study were to 1) use multivariate classification methods to validate a clinical subtyping scheme based on the profile of negative symptoms; and 2) following validation to contrast the statistically-derived subgroups to ascertain distinguishing demographic, clinical, cognitive, and functional characteristics. In the current study, 706 people with schizophrenia completed measures of positive and negative symptoms, premorbid adjustment, cognition, and psychosocial functioning. Latent class analysis served to identify the number of negative symptom subgroups in schizophrenia. Next, statistical classification methods—Bayes Theorem and the Base Rate Classification Technique—were used to assign participants into the identified subgroups. Subgroups were compared on external validation variables not used in the classification process via logistic regression and discriminant function analysis. Latent class analysis supported a three-class model of schizophrenia that included deficit, persistent, and transient negative symptom subgroups. Posthoc comparisons showed that demographic characteristics, positive symptoms, premorbid adjustment, and cognitive profiles can distinguish the schizophrenia subgroups with moderate accuracy. The deficit subgroup had the greatest impairments in psychosocial functioning and quality of life variables. Findings suggest that schizophrenia encapsulates qualitatively distinct negative symptom subgroups that differ in their demographic, symptomatic, neuropsychological, and functional profiles. Schizophrenia heterogeneity reflects a combination of non-arbitrary subgroups and severity-based differences in negative symptoms. [ABSTRACT FROM AUTHOR]

Crack cocaine (crack) addiction represents a major social and health burden, especially seeing as users are more prone to engage in criminal and violent acts. Crack users show a higher prevalence of psychiatric comorbidities – particularly antisocial personality disorders – when compared to powder cocaine users. They also develop cognitive deficits related mainly to executive functions, including working memory. It is noteworthy that stimulant drugs can induce psychotic states, which appear to mimic some symptoms of schizophrenia among users. Social withdraw and executive function deficits are, respectively, negative and cognitive symptoms of schizophrenia mediated by reduced dopamine (DA) tone in the prefrontal cortex (PFC) of patients. That could be explained by an increased expression of D2R short isoform (D2S) in the PFC of such patients and/or by hypofunctioning NMDA receptors in this region. Reduced DA tone has already been described in the PFC of mice exposed to crack smoke. Therefore, it is possible that behavioral alterations presented by crack users result from molecular and biochemical neuronal alterations akin to schizophrenia. Accordingly, we found that upon crack inhalation mice have shown decreased social interaction and working memory deficits analogous to schizophrenia's symptoms, along with increased D2S/D2L expression ratio and decreased expression of NR1, NR2A and NR2B NMDA receptor subunits in the PFC. Herein we propose two possible mechanisms to explain the reduced DA tone in the PFC elicited by crack consumption in mice, bringing also the first direct evidence that crack use may result in schizophrenia-like neurochemical, molecular and behavioral alterations. [ABSTRACT FROM AUTHOR]

Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants ( N = 124) were genotyped for DA-related polymorphisms in genes for DRD4 , DRD2/ANKK1 , DAT1 , and COMT , which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants ( N = 23) using PET scans with the D2R-selective, non-displaceable radioligand ( N -[ 11 C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status. [ABSTRACT FROM AUTHOR]

Research in individuals at clinical high-risk (CHR) for psychosis has focused on subjects with no more than 12 months of present or worsened attenuated positive symptoms. However, the impact of long duration attenuated positive and/or negative prodromal symptoms on outcomes is unclear. Seventy-six CHR subjects with attenuated positive symptoms and at least moderate severity level negative symptoms rated on the Scale of Prodromal Symptoms (SOPS) were prospectively followed for a mean of 3.0 ± 1.6 years. Social and Role functioning was assessed with the Global Functioning: Social and Role scales. Correlations between attenuated positive and negative symptom duration and severity and conversion to psychosis and functional outcomes were analyzed. The average onset of SOPS rated negative symptoms (M = 53.24 months, SD = 48.90, median = 37.27) was approximately twelve months prior to the emergence of attenuated positive symptom (M = 40.15 months, SD = 40.33, median = 24.77, P < 0.05). More severe positive symptoms ( P = 0.004), but not longer duration of positive ( P = 0.412) or negative ( P = 0.754) symptoms, predicted conversion to psychosis. Neither positive symptom duration ( P = 0.181) nor severity ( P = 0.469) predicted role or social functioning at study endpoint. Conversely, longer negative symptom duration predicted poor social functioning ( P = 0.004). Overall, our findings suggest that the severity of attenuated positive symptoms at baseline may be more important than symptom duration for determining individuals at increased risk of developing psychosis. In contrast, long-standing negative symptoms may be associated with persistent social difficulties and therefore have an important position in the treatment of disability. [ABSTRACT FROM AUTHOR]

Cognitive remediation has proven efficacy for improving neurocognition in people with schizophrenia. The current study evaluated the benefits of cognitive remediation on neurocognition, functioning, psychotic symptoms, and aggression in a sample of forensic and mental health patients. Care recipients with schizophrenia or schizoaffective disorder (N = 78) receiving services in the forensic and mental health units of a state hospital were randomized to participate in cognitive remediation versus computer games control activities. Participants' neurocognition, functional capacity, experiential recovery, psychotic symptoms, and aggression incidents were assessed at baseline and posttreatment. Cognitive remediation was associated with improvements in several neurocognitive domains and circumscribed domains of functional capacity. People assigned to cognitive remediation experiences greater reductions in negative symptoms, agitation/excitement, and verbal and physical aggression. In addition to improving neurocognition in long-term hospitalized forensic and mental health patients, cognitive remediation may enhance efforts at reducing negative symptoms, emotion dysregulation, and aggression incidents. Forensic settings may represent a new frontier for the clinical dissemination of cognitive remediation. [ABSTRACT FROM AUTHOR]

Social deficits are common in people with schizophrenia and the treatment of deficits in social competence has been a long-time treatment strategy. However, negative symptoms and social cognitive deficits also contribute to social dysfunction. In this study, we examined the correlations between everyday social outcomes, a performance based measure of social competence, and performance on 8 different social cognition tests in 179 patients with schizophrenia. Social cognition, social competence, and motivation-related negative symptoms accounted for 32% of the variance in real-world social outcomes. In addition, two different social cognition tests, along with expression-related negative symptoms accounted for 32% of the variance in performance-based assessments of social competence. These data suggest that negative symptoms exert an important influence on social outcomes and social competence, but not social cognition, and that social cognition and social competence exert separable influences on real-world social outcomes. Improving social outcomes seems to require a multi-faceted approach which considers social cognition, social competence, and negative symptoms. [ABSTRACT FROM AUTHOR]

Low IQ has recently been shown to predict neuropsychological effort test failure in healthy and neurological populations. Although low IQ is common in schizophrenia (SZ), its effect on effort test performance remains unclear in this population. The current study examined the role of IQ in effort test performance in a sample of 60 outpatients with SZ and 30 demographically matched healthy controls (CN). Participants were administered a battery of neuropsychological tests, and insufficient effort was calculated using two embedded effort indices: the Reliable Digit Span Effort Index and the Finger Tapping Effort Index. Results indicated that 16.1% of SZ patients and 0% CN failed both effort measures and that 32.1% of SZ and 3.3% of CN failed one measure. In SZ, IQ in the <70 or 70–79 range was associated with the highest rates of falling below the effort cut-off scores; however, patients with IQs in the low-average or higher range (>80) did not fall below effort cut-offs. Findings suggest that low IQ is a significant predictor of insufficient effort during neuropsychological test performance in schizophrenia, calling into question the validity of neuropsychological effort testing in SZ patients with low IQ. [ABSTRACT FROM AUTHOR]

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched PubMed, clinical trial registries, reference lists, and other sources for parallel group, placebo-controlled RCTs. Our primary outcome variable was the effect of ar/mod on negative symptom outcomes. Eight RCTs (pooled N = 372; median duration, 8 weeks) met our selection criteria. Ar/mod (200 mg/day) significantly attenuated negative symptom ratings (6 RCTs; N = 322; standardized mean difference [SMD], −0.26; 95% CI, −0.48 to −0.04). This finding remained similar in all but one sensitivity analysis - when the only RCT in acutely ill patients was excluded, the outcome was no longer statistically significant (SMD, −0.17; 95% CI, −0.51 to 0.06). The absolute advantage for ar/mod was small: just 0.27 points on the PANSS-N (6 RCTs). Ar/mod attenuated total psychopathology ratings (7 RCTs; N = 342; SMD, −0.23; 95% CI, −0.45 to −0.02) but did not influence positive symptom ratings (5 RCTs; N = 302; mean difference, −0.58; 95% CI, −1.71 to 0.55). Although data were limited, cognition, fatigue, daytime drowsiness, adverse events, and drop out rates did not differ significantly between ar/mod and placebo groups. Fixed and random effects models yielded similar results. There was no heterogeneity in all but one analysis. Publication bias could not be tested. We conclude that ar/mod (200 mg/day) is safe and well tolerated in the short-term treatment of schizophrenia. Ar/mod reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: The negative symptoms of schizophrenia are a major source of impairment and distress but both pharmacological and psychological treatment options provide only modest benefit. Developing more effective psychological treatments for negative symptoms will require a more sophisticated understanding of the psychological processes that are implicated in their development and maintenance. We extended previous work by demonstrating that metacognitive functioning is related to negative symptom expression across the first 12 months of first episode psychosis (FEP). Previous studies in this area have either been cross-sectional or have used much older participants with long-standing symptoms. In this study, forty-five FEP participants were assessed three times over 12 months and provided data on PANSS rated symptoms, premorbid adjustment, metacognitive functioning, and DUP. Step-wise linear regression showed that adding metacognition scores to known predictors of negative symptoms (baseline symptom severity, gender, DUP, and premorbid academic and social adjustment) accounted for 62% of the variance in PANSS negative symptom scores at six months and 38% at 12 months. The same predictors also explained 47% of the variance in positive symptoms at both six and 12 months. However, exploration of the simple correlations between PANSS symptom scores and metacognition suggests a stronger univariate relationship between metacognition and negative symptoms. Overall, the results indicate that problems with mental state processing may be important determinants of negative symptom expression from the very early stages of psychosis. These results provide further evidence that metacognitive functioning is a potentially relevant target for psychological interventions. [Copyright &y& Elsevier]

Abstract: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic condition associated with increased risk for schizophrenia. No study do date has explored how positive and negative symptoms of psychosis are distributed among individual patients with 22q11.2DS and if distinct patterns of symptoms can be identified. Negative symptoms being more frequent than positive symptoms in 22q11.2DS, we expected that a high number of patients would display predominant negative symptoms (PNS), whereas predominant positive symptoms would be less frequently reported. The present study aims at investigating the cognitive deficits and functional outcome associated with distinct patterns of psychotic symptoms in 22q11.2DS. 63 adolescents and young adults with 22q11.2DS participated in this study. Each participant underwent a clinical and a cognitive evaluation. A cluster analysis was used to identify groups of individuals with distinct patterns of symptoms. Individuals from the different clusters were then compared on a series of cognitive measures and on functional outcome. Three clusters of individuals were identified: low levels of symptoms, PNS, and high levels of symptoms. Individuals with PNS had significantly lower visual memory scores and decreased processing speed compared to participants with low levels of symptoms. They were also rated as having lower functional and occupational outcome. The present results indicate that one third of adolescents and young adults with 22q11.2DS display PNS. This pattern of symptoms was associated with specific cognitive deficits and decreased functional outcome. Future studies are needed to examine the developmental trajectories of these individuals and assess their risk of conversion to full-blown psychosis. [Copyright &y& Elsevier]

Abstract: Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamine and glutamate pathways has been proposed for the emergence of these symptoms. SP1, SP3 and SP4 transcription factors regulate genes in these pathways, suggesting a possible involvement in negative symptoms. In this study, we characterized Sp factors in the brains of subjects with schizophrenia and explored a possible association with negative symptoms. We also included analysis of NR1, NR2A and DRD2 as Sp target genes. Postmortem cerebellum and prefrontal cortex from an antemortem clinically well-characterized and controlled collection of elderly subjects with chronic schizophrenia (n = 16) and control individuals (n = 14) were examined. We used the Positive and Negative Syndrome and the Clinical Global Impression Schizophrenia scales, quantitative PCR and immunoblot. SP1 protein and mRNA were reduced in the prefrontal cortex in schizophrenia whereas none of Sp factors were altered in the cerebellum. However, we found that SP1, SP3 and SP4 protein levels inversely correlated with negative symptoms in the cerebellum. Furthermore, NR2A and DRD2 mRNA levels correlated with negative symptoms in the cerebellum. In the prefrontal cortex, SP1 mRNA and NR1 and DRD2 inversely correlated with these symptoms while Sp protein levels did not. This pilot study not only reinforces the involvement of SP1 in schizophrenia, but also suggests that reduced levels or function of SP1, SP4 and SP3 may participate in negative symptoms, in part through the regulation of NMDA receptor subunits and/or Dopamine D2 receptor, providing novel information about the complex negative symptoms in this disorder. [Copyright &y& Elsevier]

Abstract: Negative symptoms of schizophrenia are normally grouped into a single category. However, the diversity of such symptoms suggests that they are actually made up of more than one dimension. The DSM-V proposes two negative symptom domains, namely expressive deficits and avolition/asociality. We investigated whether the negative symptoms do indeed have two dimensions. An exploratory factor analysis was carried out based on interviews with the PANSS (664 patients). We restricted our analysis to items that had been described as negative symptoms in previous factor analyses. The symptom structure was then tested for stability by performing a confirmatory factor analysis on PANSS interviews from a separate cohort (2172 patients). Exploratory factor analysis yielded a two-factor structure of negative symptoms. The first factor consisted of PANSS items Flat affect, Poor rapport, Lack of spontaneity, Mannerisms and posturing, Motor retardation, and Avolition. The second factor consisted of Emotional withdrawal, Passive/apathetic social withdrawal, and Active social avoidance. The first factor could be related to expressive deficits, reflecting a loss of initiative, and the second factor to social amotivation, related to community interaction. This factor structure supports the DSM-V classification and may be relevant for pathophysiology and treatment of schizophrenia and other psychotic disorders. [Copyright &y& Elsevier]

Abstract: Background: Previous studies indicate that negative symptoms reflect a separable domain of pathology from other symptoms of schizophrenia. However, it is currently unclear whether negative symptoms themselves are multi-faceted, and whether sub-groups of patients who display unique negative symptom profiles can be identified. Methods: A data-driven approach was used to examine the heterogeneity of negative symptom presentations in two samples: Study 1 included 199 individuals with schizophrenia assessed with a standard measure of negative symptoms and Study 2 included 169 individuals meeting criteria for deficit schizophrenia (i.e., primary and enduring negative symptoms) assessed with a specialized measure of deficit symptoms. Cluster analysis was used to determine whether different groups of patients with distinct negative symptoms profiles could be identified. Results: Across both studies, we found evidence for two distinctive negative symptom sub-groups: one group with predominantly Avolition–Apathy (AA) symptoms and another with a predominantly Diminished Expression (DE) profile. Follow-up discriminant function analyses confirmed the validity of these groups. AA and DE negative symptom sub-groups significantly differed on clinically relevant external validators, including measures of functional outcome, premorbid adjustment, clinical course, disorganized symptoms, social cognition, sex, and ethnicity. Conclusions: These results suggest that distinct subgroups of patients with elevated AA or DE can be identified within the broader diagnosis of schizophrenia and that these subgroups show clinically meaningful differences in presentation. Additionally, AA tends to be associated with poorer outcomes than DE, suggesting that it may be a more severe aspect of psychopathology. [Copyright &y& Elsevier]

Abstract: Some 5-HT3 antagonists such as ondansetron have shown beneficial effects on negative symptoms of patients with schizophrenia. We aimed to evaluate the efficacy of granisetron (another 5-HT3 antagonist) add-on therapy in the treatment of negative symptoms of patients with stable schizophrenia. In a randomized, double-blind, and placebo-controlled study, forty stable patients with schizophrenia (DSM-IV-TR), were randomized to either granisetron (1 mg twice daily) or placebo (twice daily) in addition to risperidone up to 6 mg/day for eight weeks. The patients were assessed using positive and negative syndrome scale (PANSS) and extrapyramidal symptom rating scale (ESRS) at baseline, week 4 and 8. Hamilton depression rating scale (HDRS) was used to assess depression at baseline and week 8. Thirty-eight patients completed the trial. Granisetron group showed a significantly greater improvement on negative subscale than the placebo group at endpoint [t(38) = 6.046, mean difference (±95% CI) = 3.2(1.8–3.7), P < 0.001]. The same effect was observed for total score [t(38) = 4.168, mean difference (95% CI) = 3.2(1.6–4.7), P < 0.001]. However the placebo and granisetron groups did not differ in their reduction of positive and general psychopathology symptoms scores. HDRS scores and its changes did not differ between the two groups. The ESRS score at week 4 was significantly lower in the granisetron than the placebo group while the two groups showed similar ESRS score at week 8. Frequency of other side effects was similar between the two groups. In summary, granisetron add-on can safely and effectively reduce the primary negative symptoms of patients with schizophrenia. [Copyright &y& Elsevier]

Abstract: Background: There is evidence that alogia and formal thought disorder (FTD), two prominent speech symptoms in schizophrenia, are associated with different patterns of verbal fluency task deficits. Verbal fluency is thought to involve several cognitive mechanisms, including controlled retrieval, semantic memory, and context processing. Methods: The current research examined whether alogia and FTD were associated with different patterns of verbal fluency performance and whether these patterns of verbal fluency performance would implicate deficits in controlled retrieval, semantic memory, or context processing. In the current research, 34 people with schizophrenia completed letter and category fluency tasks and detailed ratings of alogia and FTD symptoms were made from typed transcripts. Results: Overall, alogia was associated with increased response latency between each word on the category fluency task, suggesting an association between alogia and poor controlled retrieval. In contrast, FTD was associated with a decreased proportion of semantically-related words on letter fluency, suggesting an association between FTD and poor context processing. Conclusions: Alogia and FTD appear to be associated with unique patterns of fluency performance, implicating separate cognitive mechanisms. [Copyright &y& Elsevier]

Abstract: According to A.T. Beck and colleagues’ cognitive formulation of poor functioning in schizophrenia, maladaptive cognitive appraisals play a key role in the expression and persistence of negative symptoms and associated real-world functioning deficits. They provided initial support for this model by showing that dysfunctional attitudes are elevated in schizophrenia and account for significant variance in negative symptoms and subjective quality of life. The current study used structural equation modeling to further evaluate the contribution of dysfunctional attitudes to outcome in schizophrenia. One hundred eleven outpatients and 67 healthy controls completed a Dysfunctional Attitudes Scale, and patients completed a competence measure of functional capacity, clinical ratings of negative symptoms, and interview-based ratings of real-world functioning. Patients reported higher defeatist performance beliefs than controls and these were significantly related to lower functional capacity, higher negative symptoms, and worse community functioning. Consistent with Beck and colleagues’ formulation, modeling analyses indicated a significant indirect pathway from functional capacity→dysfunctional attitudes→negative symptoms→real-world functioning. These findings support the value of dysfunctional attitudes for understanding the determinants of outcome in schizophrenia and suggest that therapeutic interventions targeting these attitudes may facilitate functional recovery. [Copyright &y& Elsevier]

Abstract: Objective: The emerging field of psychiatric epigenetics is constrained by the dearth of research methods feasible in living patients. With this focus, we report on two separate approaches, one in vitro and one in vivo, developed in our laboratory. Method: In the first approach, we isolated lymphocytes from 12 subjects and cultured their cells with either 0.7mM valproic acid (VPA), 100nM Trichostatin A (TSA), or DMSO (control) for 24h based upon previous dose response experiments. We then measured GAD67 mRNA expression using realtime RT-PCR, total acetylated histone 3 (H3K9,K14ac) levels using Western blot analysis, and attachment of H3K9,K14ac to the GAD67 promoter using ChIP. In the second approach, we measured GAD67 mRNA and total H3K9,K14ac levels in lymphocytes from 11 schizophrenia and 7 bipolar patients before and after 4 weeks of clinical treatment with Depakote ER® (VPA). Results: In the first approach, VPA induced a 383% increase in GAD67 mRNA, an 89% increase in total H3K9,K14ac levels, and a 482% increase in H3K9,K14ac attachment to the GAD67 promoter. TSA induced comparable changes on all measures. In the second approach, bipolar subjects had significantly higher baseline levels of H3K9,K14ac compared to subjects with schizophrenia. Subjects with clinically relevant serum levels of VPA (⩾65μg/mL) showed a significant increase in GAD67 mRNA expression. Conclusions: Our results utilizing two separate approaches for examining chromatin remodeling in real clinical time provide possible means to investigate epigenetic events in living patients. [Copyright &y& Elsevier]

Abstract: Background: Pain is a dynamic phenomenon resulting from the activity of both excitatory (e.g. sensitization) and inhibitory endogenous modulation systems. Preliminary experimental studies have shown diminished pain sensitivity in schizophrenia patients. The objective of the study was to investigate the role of excitatory and inhibitory systems on pain perception in schizophrenia. Methods: Participants were 23 patients with a schizophrenia-spectrum disorder (DSM-IV criteria) and 29 healthy volunteers, who did not differ in age, sex or ethnicity. Excitatory and inhibitory systems were elicited using a temporal summation test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory control (DNIC) by means of a cold-pressor test. Results: Time was a significant predictor of pain scores in controls, but not in patients. That is, pain ratings increased during the tonic thermal stimulation among controls but not in schizophrenia patients. When correlation coefficients (between time and pain ratings) for patients and controls were compared, the correlation coefficient emerged as significantly weaker in the schizophrenia group (Z =12.04; p =0.0001), suggesting a lack of sensitization in schizophrenia. DNIC was similar in magnitude in both patients and controls. Conclusions: Diminished pain sensitivity in schizophrenia may be related to abnormal excitatory mechanisms, but not to DNIC. More studies are needed to better characterize the neurophysiological and neurochemical mechanisms involved in the lack of sensitization in schizophrenia. [Copyright &y& Elsevier]

Impaired insight is an important contributing factor to poor treatment response and outcome in schizophrenia. Prior studies have attempted to identify the illness characteristics that underlie these deficits, with conflicting results regarding associations with symptoms and neurocognitive deficits. These inconsistencies may be a function of a number of methodological issues, which were addressed in this study. In a prospective, longitudinal study, 50 individuals with schizophrenia or schizoaffective disorder underwent baseline assessments upon discharge from an acute inpatient unit, and again at a 6-month follow-up. Unawareness of positive and negative symptoms were studied separately, with analyses focusing on changes in insight over time as well as associations with disorganized symptoms, depression, and card sorting deficits. Subjects showed greater insight for negative symptoms than for positive symptoms. Insight for positive symptoms improved only slightly over the follow-up period, while negative symptom awareness did not change. Insight for negative symptoms showed modest associations with card sorting deficits, while awareness for positive symptoms showed stronger associations with thought disorder, depression, and card sorting deficits. Awareness for positive symptoms in schizophrenia may be distinct from awareness of negative symptoms. Clinicians should also be aware of the multidetermined nature of impaired insight, and future research should aim to isolate distinct mechanisms that give rise to these deficits. [Copyright &y& Elsevier]