Assessing the Trajectory of Schizophrenia Effectively in Order to Treat Effectively.

INTRODUCTION: Schizophrenia is a complex psychiatric disorder characterized by heterogeneous symptom trajectories that significantly impact patient outcomes. We believe that the study of the trajectories of Schizophrenia is useful in assessing treatment options and outcomes. While the Positive and Negative Syndrome scale is usually used on one occasion to measure symptoms at a single time, if measured repeatedly , the PANSS is also useful in measuring trajectories. In order to illustrate and promote this serial use, we have reviewed papers which describe the delineation of Trajectories of Symptoms in Schizophrenia based on PANSS scores. This review integrates findings from longitudinal studies focusing on the trajectories of positive symptoms, negative symptoms, the relation between positive and negative symptoms and cognition, soft neurological signs, and treatment response in schizophrenia. METHODS: Studies were identified from the PUBMED database .Studies included in this review employed diverse methodologies such as trajectory analyses, longitudinal assessments, and clinical trials. Data were extracted from a range of patient cohorts, including those with first-episode psychosis and chronic schizophrenia. RESULTS: Longitudinal studies consistently demonstrate variability in the trajectories of positive symptoms, with most patients experiencing early stable remission, though a subgroup exhibits persistent or fluctuating symptomatology. Negative symptoms, on the other hand, often show poor improvement over time, correlating with impaired social and neurocognitive functioning. Cognitive deficits also vary, with some domains showing improvement while others, such as logical memory, deteriorate in certain patient subgroups. The relationship between positive and negative symptom trajectories highlights their complex relationship, influencing overall functioning and treatment outcomes. Antipsychotic medications demonstrate varied responses across patient cohorts, with distinct trajectory patterns observed based on medication type and patient-specific factors such as co-morbid substance abuse and duration of untreated psychosis. CONCLUSION: Understanding the longitudinal trajectories of symptoms in schizophrenia is crucial for optimizing therapeutic strategies and improving patient outcomes. Personalised interventions tailored to individual symptom profiles and early clinical responses are recommended to enhance treatment efficacy and promote recovery. The PANSS scale can be used to delineate Trajectories of various symptom Groups in Schizophrenia.

Obstetric complications and psychopathology in schizophrenia: A systematic review and meta-analysis.

Schizophrenia (SZ) is a severe mental health condition involving gene-environment interactions, with obstetric complications (OCs) conferring an elevated risk for the disease. Current research suggests that OCs may exacerbate SZ symptoms. This study conducted a systematic review and meta-analysis to comprehensively evaluate differences in psychopathology between individuals with and without exposure to OCs in relation to SZ and related disorders. We systematically searched PubMed, PsycINFO, and SCOPUS to identify eligible studies. A total of 4091 records were retrieved through systematic and citation searches. 14 studies were included in the review, and 12 met the criteria for meta-analysis, involving 2992 patients. The analysis revealed that SZ patients who had been exposed to OCs exhibited significantly higher levels of positive symptoms (SMD=0.10, 95 %CI=0.01,0.20; p=0.03), general psychopathology (SMD=0.37, 95 %CI=0.22,0.52; p<0.001), total clinical symptomatology (SMD=0.44, 95 %CI=0.24,0.64; p<0.001) and depressive symptoms (SMD=0.47, 95 %CI=0.09,0.84; p=0.01). No significant differences were found in negative symptomatology and functioning. Our results suggest that OCs are not only associated with an increased risk of developing psychosis but with more severe symptomatology.

Neural Circuitry and Therapeutic Targeting of Depressive Symptoms in Schizophrenia Spectrum Disorders.

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.

Emotion Processing and Its Relationship to Social Functioning and Symptoms in Psychotic Disorder: A Systematic Review and Meta-analysis.

BACKGROUND: Emotion processing (EP) is impaired in individuals with psychosis and associated with social functioning; however, it is unclear how symptoms fit into this relationship. The aim of this systematic review and meta-analysis was to examine interrelationships between EP, symptoms, and social functioning, test whether different symptom domains mediate the relationship between EP and social functioning, and examine the moderating effects of illness stage and EP task type. STUDY DESIGN: MEDLINE, Embase, and PsycINFO databases were searched for studies that included individuals with psychosis and reported correlations between EP, symptom domains (positive, negative, depressive, and disorganization), and social functioning. Random effects meta-analyses determined the strength of correlations, and subgroup analyses included illness stage and EP task type (lower- vs higher-level processing). Meta-analytic structural equation models tested whether symptom domains mediated the relationship between EP and social functioning. RESULTS: There was a small relationship (r = .18) between EP and social functioning. Positive, negative, and disorganization symptoms mediated this relationship, although indirect effects were small. Higher-level EP tasks were more strongly associated with negative symptoms than lower-level tasks. Relationships between EP and both social functioning and positive symptoms were smaller in the first episode of psychosis than in established illness. CONCLUSIONS: The mediating relationship suggests that EP not only influences social dysfunction directly but contributes to negative and disorganization symptoms, which in turn impair social functioning. This pathway suggests that targeting negative and disorganization symptoms may ultimately improve social outcomes for individuals with psychosis. Future research, particularly in early psychosis, is needed to determine other factors impacting these interrelationships.

Beneficial adjunctive effects of the 5HT3 receptor antagonist ondansetron on symptoms, function and cognition in early phase schizophrenia in a double-blind, 2 × 2 factorial design, randomised controlled comparison with simvastatin.

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.

Pharmacological Treatments of Negative Symptoms in Schizophrenia-An Update.

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.

Dynamics of symptom network in patients with first-episode schizophrenia: Insight from the CNFEST project.

BACKGROUND: Schizophrenia is a heterogeneous psychotic disorder. Recent theories have emphasized the importance of interactions among psychiatric symptoms in understanding the pathological mechanisms of schizophrenia. In the current study, we examined the symptom network in patients with first-episode schizophrenia (FES) at four time points during a six-month follow-up period. METHODS: In total, 565 patients with FES were recruited from the Chinese First-Episode Schizophrenia Trial (CNFEST) project. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up (514 patients at one month, 429 at three months, and 392 at six months). We used a network analysis approach to estimate symptom networks with individual symptoms as nodes and partial correlation coefficients between symptoms as edges. A cross-lagged panel network (CLPN) model was used to identify predictive pathways for clinical symptoms. RESULTS: We found stable and strongly connected edges in patients across the time points, such as links between delusions and suspiciousness/persecution (P1:P6), and emotional withdrawal and passive/apathetic social withdrawal (N2:N4). Emotional withdrawal (N2), poor rapport (N3), and passive/apathetic social withdrawal (N4) had high centrality estimates across all four time points. CLPN analysis showed that negative symptoms, including emotional withdrawal (N2), poor rapport (N3), and passive/apathetic social withdrawal (N4), and stereotyped thinking (N7) may have predictive effects for negative and general symptoms at follow-ups. CONCLUSIONS: The symptom network of schizophrenia may be dynamic as treatment progresses. Negative symptoms remain the central and stable symptoms of schizophrenia. Negative symptoms may be potential therapeutic targets that predict other symptoms.

Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition.

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 symptom factors (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 and World 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.

Development and temporal validation of a clinical prediction model of transition to psychosis in individuals at ultra-high risk in the UHR 1000+ cohort.

The concept of ultra-high risk for psychosis (UHR) has been at the forefront of psychiatric research for several decades, with the ultimate goal of preventing the onset of psychotic disorder in high-risk individuals. Orygen (Melbourne, Australia) has led a range of observational and intervention studies in this clinical population. These datasets have now been integrated into the UHR 1000+ cohort, consisting of a sample of 1,245 UHR individuals with a follow-up period ranging from 1 to 16.7 years. This paper describes the cohort, presents a clinical prediction model of transition to psychosis in this cohort, and examines how predictive performance is affected by changes in UHR samples over time. We analyzed transition to psychosis using a Cox proportional hazards model. Clinical predictors for transition to psychosis were investigated in the entire cohort using multiple imputation and Rubin's rule. To assess performance drift over time, data from 1995-2016 were used for initial model fitting, and models were subsequently validated on data from 2017-2020. Over the follow-up period, 220 cases (17.7%) developed a psychotic disorder. Pooled hazard ratio (HR) estimates showed that the Comprehensive Assessment of At-Risk Mental States (CAARMS) Disorganized Speech subscale severity score (HR=1.12, 95% CI: 1.02-1.24, p=0.024), the CAARMS Unusual Thought Content subscale severity score (HR=1.13, 95% CI: 1.03-1.24, p=0.009), the Scale for the Assessment of Negative Symptoms (SANS) total score (HR=1.02, 95% CI: 1.00-1.03, p=0.022), the Social and Occupational Functioning Assessment Scale (SOFAS) score (HR=0.98, 95% CI: 0.97-1.00, p=0.036), and time between onset of symptoms and entry to UHR service (log transformed) (HR=1.10, 95% CI: 1.02-1.19, p=0.013) were predictive of transition to psychosis. UHR individuals who met the brief limited intermittent psychotic symptoms (BLIPS) criteria had a higher probability of transitioning to psychosis than those who met the attenuated psychotic symptoms (APS) criteria (HR=0.48, 95% CI: 0.32-0.73, p=0.001) and those who met the Trait risk criteria (a first-degree relative with a psychotic disorder or a schizotypal personality disorder plus a significant decrease in functioning during the previous year) (HR=0.43, 95% CI: 0.22-0.83, p=0.013). Models based on data from 1995-2016 displayed good calibration at initial model fitting, but showed a drift of 20.2-35.4% in calibration when validated on data from 2017-2020. Large-scale longitudinal data such as those from the UHR 1000+ cohort are required to develop accurate psychosis prediction models. It is critical to assess existing and future risk calculators for temporal drift, that may reduce their utility in clinical practice over time.

Relationship between the Use of Mobile Applications and Social Functioning in Patients with Schizophrenia. / Sizofreni Hastalarinda Mobil Uygulama Kullanimi ve Sosyal Islevsellik Arasindaki Iliski.

OBJECTIVES: The aim of this study is to examine the prevalence of digital technology tool use in individuals with schizophrenia or schizoaffective disorder in Turkey, as well as evaluating the association between the use and psychosocial functionality and clinical symptoms. METHOD: Data were collected from 100 patients who were diagnosed with schizophrenia or schizoaffective disorder based on the DSM-5 criteria. The use of technology was evaluated with a questionnaire developed for this study. The level of psychosocial functioning was assessed using the Personal and Social Performance Scale (PSP), and the positive and negative symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS). RESULTS: The digital technology users were significantly younger than the non-users. The majority of patients own a mobile phone (86%) and a computer (67%). Furthermore, 61% of patients used mobile applications, with Facebook and WhatsApp being the most popular social media platforms (48%). Patients who used digital technology tools had higher PSP scores. Furthermore, patients who used digital technology tools had significantly lower scores in PANSS negative subscale. There was no difference in PANSS positive subscale scores between digital technology tool users and non-users. CONCLUSION: Patients diagnosed with schizophrenia may benefit from mobile applications and social media tools that can help them participate in daily activities and improve their overall well-being.

Dysconnectivity of the cerebellum and somatomotor network correlates with the severity of alogia in chronic schizophrenia.

Recent fMRI resting-state findings show aberrant functional connectivity within somatomotor network (SMN) in schizophrenia. Moreover, functional connectivity aberrations of the motor system are often reported to be related to the severity of psychotic symptoms. Thus, it is important to validate those findings and confirm their relationship with psychopathology. Therefore, we decided to take an entirely data-driven approach in our fMRI resting-state study of 30 chronic schizophrenia outpatients and 30 matched control subjects. We used independent component analysis (ICA), dual regression, and seed-based connectivity analysis. We found reduced functional connectivity within SMN in schizophrenia patients compared to controls and SMN hypoconnectivity with the cerebellum in schizophrenia patients. The latter was strongly correlated with the severity of alogia, one of the main psychotic symptoms, i.e. poverty of speech and reduction in spontaneous speech,. Our results are consistent with the recent knowledge about the role of the cerebellum in cognitive functioning and its abnormalities in psychiatric disorders, e.g. schizophrenia. In conclusion, the presented results, for the first time clearly showed the involvement of the cerebellum hypoconnectivity with SMN in the persistence and severity of alogia symptoms in schizophrenia.

Effective action of silymarin against ketamine-induced schizophrenia in male mice: Insight into the biochemical and molecular mechanisms of action.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Symptom Dimensions and Cognitive Impairments in Individuals at Clinical High Risk for Psychosis.

OBJECTIVE: Understanding the intricate relationship between symptom dimensions, clusters, and cognitive impairments is crucial for early detection and intervention in individuals at clinical high-risk(CHR) for psychosis. This study delves into this complex interplay within a CHR sample and aims to predict the conversion to psychosis. METHODS: A comprehensive cognitive assessment was performed among 744 CHR individuals. The study included a three-year follow-up period to assess conversion to psychosis. Symptom profiles were determined using the Structured Interview for Prodromal Syndromes. By applying factor analysis, symptom dimensions were categorized as dominant negative symptoms(NS), positive symptoms-stressful(PS-S), and positive symptoms-odd(PS-O). The factor scores were used to define three dominant symptom groups. Latent class analysis(LCA) and factor mixture model(FMM) were employed to identify discrete clusters based on symptom patterns. The three-class solution was chosen for the LCA and FMM analysis. RESULTS: Individuals in the dominant NS group exhibited significantly higher conversion rates to psychosis than those in the other groups. Specific cognitive variables, including performance in the Brief Visuospatial Memory Test-Revised(Odd ratio, OR=0.702, p=0.001) and Neuropsychological Assessment Battery mazes(OR=0.776, p=0.024), significantly predicted conversion to psychosis. Notably, cognitive impairments associated with NS and PS-S affected different cognitive domains. LCA- and FMM-Cluster 1, characterized by severe NS and PS-O, exhibited more impairments in cognitive domains than other clusters. No significant difference in the conversion rate was observed among LCA and FMM clusters. CONCLUSIONS: These findings highlight the importance of NS in the development of psychosis and suggest specific cognitive domains that are affected by symptom dimensions.

Interview Versus Performance Assessment of Cognition as Predictors of Real-World Outcomes in a Large-Scale Cross-Sectional Study in Schizophrenia.

The Cognitive Assessment Interview (CAI) is an interview-based scale measuring cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). It is approved as a coprimary measure of performance-based instruments, such as the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Recent research highlights negative symptoms, social cognition, and functional capacity as mediators of cognitive impairment's impact on functioning. This study compared mediation analysis outcomes using CAI or MCCB scores, providing insights into the utility of interview-based tools in research and clinical practice. The study included 618 individuals diagnosed with schizophrenia, recruited from 24 Italian psychiatric clinics. Neurocognitive assessments utilized both CAI and MCCB. Mediation analyses explored negative symptoms, social cognition, and functional capacity as mediators of the impact of neurocognition on real-life functioning domains. The study's results extend the validation of the CAI as a coprimary measure that provides valid information on the impact of cognitive impairment on real-life functioning and its possible mediators, complementing the information obtained using the MCCB. Interview-based cognitive assessment might be essential for understanding schizophrenia complexity and its impact on various cognitive and functional domains for clinicians, patients, and caregivers.

Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials.

BACKGROUND: Currently approved antipsychotics do not adequately treat negative symptoms (NS), which are a major determinant of functional disability in schizophrenia. KarXT, an M1 /M4 preferring muscarinic receptor agonist, has shown efficacy as a broad-spectrum monotherapy for the treatment of schizophrenia in participants with acute psychosis. Post hoc analyses evaluated the possibility that NS improve independently of positive symptoms with KarXT in a subgroup of participants with moderate-to-severe NS and no predominance of positive symptoms. METHODS: Data were pooled from the three pivotal trials of KarXT monotherapy in people with schizophrenia with an acute exacerbation of psychosis. All 3 studies used similar 5-week randomized, double-blind, placebo-controlled designs (modified intention-to-treat sample N = 640). PANSS criteria proposed in the literature identified a subset of study participants (n = 64) with prominent NS. RESULTS: KarXT was significantly better than placebo on PANSS Marder Negative Factor Scores in the full sample (p < .001; Cohen's d = 0.42) and more so in the prominent NS subgroup (p < .001; Cohen's d = 1.18). Further, the KarXT effect in the NS subgroup remained significant after accounting for changes in positive symptoms, depression/anxiety, disorganization, and hostility. CONCLUSIONS: Participants with prominent NS revealed greater improvement of NS following KarXT therapy than the full sample that persisted after accounting for positive and other symptoms. While these findings must be interpreted with caution, they are consistent with the possibility that NS improvements associated with KarXT are not secondary to improvements in other symptom domains and support further investigation in larger, stable outpatient studies.

Increased Sensitivity to Effort and Perception of Effort in People with Schizophrenia.

OBJECTIVE: Motivational deficits in schizophrenia are proposed to be attributable in part to abnormal effort-cost computations, calculations weighing the costs vs. the benefits of actions. Several reports have shown that people with schizophrenia display a reduced willingness to exert effort for monetary rewards when compared to controls. The primary goal of the current study was to further characterize reduced willingness to exert effort in schizophrenia by determining whether reduced willingness reflects (1) reduced sensitivity to reward, (2) increased sensitivity to effort, or (3) a combination of both. DESIGN: We assessed effort-cost decision-making in 30 controls and 30 people with schizophrenia, using 2 separate experimental tasks. Critically, one paradigm allowed for independent estimation of effects of reward and effort sensitivity on choice behavior. The other task isolated effort sensitivity by measuring effort in the absence of reward. Clinical interviews and self-report questionnaires were administered to people with schizophrenia to determine negative symptom severity. RESULTS: Across both tasks, we found evidence for reduced willingness to exert effort in people with schizophrenia compared to controls. Further, in both paradigms reduced willingness to exert effort was driven by increased sensitivity to effort in people with schizophrenia compared to controls. In contrast, measures of reward sensitivity did not significantly differ between groups. Surprisingly, we did not find correlations between task variables and measures of negative symptom severity. CONCLUSIONS AND RELEVANCE: These findings further specify prior work by identifying a specific contributory role for increased effort sensitivity in effort-cost decision-making deficits in schizophrenia.

Abnormal hedonic process in patients with stable schizophrenia: Relationships to negative symptoms and social functioning.

Background: Anhedonia is a deficit of dynamic reward process, and a large proportion of schizophrenia patients continue to experience anhedonia even during the stable phase. However, few studies have examined the multiple aspects of performance in reward processing in patients with stable schizophrenia and evidence suggests that physical and cognitive effort may involve different neural mechanisms. Methods: Parallel measures of effort-based expenditure for reward tasks (EEfRT) and self-report questionnaires of pleasure were applied in 61 patients with stable schizophrenia (SSZ) and 46 healthy controls (HCs), and percentages of hard task choices (HTC%) were used to assess motivation in reward processing. Negative symptoms, neurocognitive and social function were evaluated in SSZ patients, and associations with performance in reward tasks were explored. Results: SSZ patients reported more severe consummatory and anticipatory anhedonia and social anhedonia. HTC% in reward tasks of SSZ patients were significantly lower than that of HCs, especially in cognitive-effort tasks. HTC% in cognitive tasks were correlated with motivation and pleasure dimension of negative symptoms, whereas HTC% in physical tasks were associated with expression dimension. Anticipatory anhedonia and negative symptoms were correlated with Personal and Social Performance Scale (PSP) scores. Conclusion: Patients with stable schizophrenia have social anhedonia, physically consummatory and anticipatory anhedonia and reduced reward motivation. They are less willing to make cognitive effort than physical effort for reward. The different associations of physical and cognitive effort with negative symptoms indicate physical and cognitive effort may represent disparate neuropsychological processes. Anticipatory anhedonia is closely related to social functioning.

Sex differences in prolactin levels and clinical outcomes in patients with a first psychotic episode.

AIM: To analyze the clinical, neurocognitive, and functional impact of prolactin levels according to sex in patients with a First Episode Psychosis (FEP). METHODS: We measured prolactin levels in 221 non-affective FEP patients treated with antipsychotics (AP) and 224 healthy controls, at baseline and 2-year follow-up. We examined whether the relationships between clinical and functional variables were mediated by prolactin, controlling for antipsychotic use, according to sex. RESULTS: Prolactin levels were higher in patients when compared to controls at both time points. Baseline factors associated with prolactin were chlorpromazine equivalents, attention, and executive functioning. In the FEP group, prolactin levels were associated with functioning and diminished expression in males, and with working memory in females. Prolactin levels (p=0.0134) played a role as a mediator between negative symptomatology (p=0.086) and functional outcome (p=0.008) only in FEP male patients at baseline. CONCLUSIONS: Prolactin plays a role in the functionality and clinical symptomatology of FEP patients. Our results suggest that pharmacological counselling in patients with hyperprolactinemia at baseline and negative symptomatology might improve their functional and clinical outcomes.

Illness-related variables and abnormalities of resting-state brain activity in schizophrenia.

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 resting-state (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.

Use of video-recordings of site-based interviews for quality assurance in a study of subjects with schizophrenia and persistent negative symptoms.

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.