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Background. The conceptualization of negative symptoms (NS) in schizophrenia is still controversial. Recent confirmatory factor-analytic studies suggested that the bi-dimensional model (motivational deficit [MAP] and expressive deficit [EXP]) may not capture the complexity of NS structure, which could be better defined by a five-factor (five NS domains) or a hierarchical model (five NS domains as first-order factors, and MAP and EXP, as second-order factors). A validation of these models is needed to define the structure of NS. To evaluate the validity and temporal stability of the five-factor or the hierarchical structure of the brief negative symptom scale (BNSS) in individuals with schizophrenia (SCZ), exploring associations between these models with cognition, social cognition, functional capacity, and functioning at baseline and at 4 years follow-up. Methods. Clinical variables were assessed using state-of-the-art tools in 612 SCZ at two-time points. The validity of the five-factor and the hierarchical models was analyzed through structural equation models. Results. The two models had both a good fit and showed a similar pattern of associations with external validators at the two-time points, with minor variations. The five-factor solution had a slightly better fit. The associations with external validators favored the five-factor structure. Conclusions. Our findings suggest that both five-factor and hierarchical models provide a valid conceptualization of NS in relation to external variables and that five-factor solution provides the best balance between parsimony and granularity to summarize the BNSS structure. This finding has important implications for the study of pathophysiological mechanisms and the development of new treatments. [ABSTRACT FROM AUTHOR]

Background: Childhood trauma may impact the course of schizophrenia spectrum disorders (SSD), specifically in relation to the increased severity of depressive or negative symptoms. The type and impact of trauma may differ between sexes. In a large sample of recent-onset patients, we investigated the associations of depressive and negative symptoms with childhood trauma and whether these are sex-specific. Methods: A total of 187 first-episode psychosis patients in remission (Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment study) and 115 recent-onset SSD patients (Simvastatin study) were included in this cross-sectional study (men: n = 218; women: n = 84). Total trauma score and trauma subtypes were assessed using the Childhood Trauma Questionnaire Short Form; depressive and negative symptoms were rated using the Positive And Negative Symptoms Scale. Sex-specific regression analyses were performed. Results: Women reported higher rates of sexual abuse than men (23.5% v. 7.8%). Depressive symptoms were associated with total trauma scores and emotional abuse ratings in men (β : 0.219–0.295; p ≤ 0.001). In women, depressive symptoms were associated with sexual abuse ratings (β : 0.271; p = 0.011). Negative symptoms were associated with total trauma score and emotional neglect ratings in men (β : 0.166–0.232; p ≤ 0.001). Negative symptoms in women were not linked to childhood trauma, potentially due to lack of statistical power. Conclusions: Depressive symptom severity was associated with different types of trauma in men and women with recent-onset SSD. Specifically, in women, depressive symptom severity was associated with childhood sexual abuse, which was reported three times as often as in men. Our results emphasize the importance of sex-specific analyses in SSD research. [ABSTRACT FROM AUTHOR]

Background: A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations. Methods: Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE. Results: In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI. Conclusions: The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex. [ABSTRACT FROM AUTHOR]

Abstract Background The conceptualization of negative symptoms (NS) in schizophrenia is still controversial. Recent confirmatory factor-analytic studies suggested that the bi-dimensional model (motivational deficit [MAP] and expressive deficit [EXP]) may not capture the complexity of NS structure, which could be better defined by a five-factor (five NS domains) or a hierarchical model (five NS domains as first-order factors, and MAP and EXP, as second-order factors). A validation of these models is needed to define the structure of NS. To evaluate the validity and temporal stability of the five-factor or the hierarchical structure of the brief negative symptom scale (BNSS) in individuals with schizophrenia (SCZ), exploring associations between these models with cognition, social cognition, functional capacity, and functioning at baseline and at 4 years follow-up. Methods Clinical variables were assessed using state-of-the-art tools in 612 SCZ at two-time points. The validity of the five-factor and the hierarchical models was analyzed through structural equation models. Results The two models had both a good fit and showed a similar pattern of associations with external validators at the two-time points, with minor variations. The five-factor solution had a slightly better fit. The associations with external validators favored the five-factor structure. Conclusions Our findings suggest that both five-factor and hierarchical models provide a valid conceptualization of NS in relation to external variables and that five-factor solution provides the best balance between parsimony and granularity to summarize the BNSS structure. This finding has important implications for the study of pathophysiological mechanisms and the development of new treatments.

Abstract Background Predominant negative symptoms (PNSs) in schizophrenia can affect the patients’ psychosocial functioning immensely and are less responsive to treatment than positive symptoms. Aims The aim of the study was to observe negative symptoms and psychosocial functioning in PNS schizophrenia patients and to understand whether PNS can be improved and with what treatment strategies. Methods This was a 1-year, prospective, multicentric cohort study conducted in Slovakia. Adult outpatients with diagnosis of schizophrenia according to ICD-10 and PNS evaluated using the criteria by the European Psychiatric Association’s (EPA) guidance were included. Change in negative symptoms, functionality, and treatment patterns were observed. Treatment effectiveness was evaluated using the modified Short Assessment of Negative Domain (m-SAND), the Self-evaluation of Negative Symptoms (SNS) scale, the Personal and Social Performance (PSP) scale, and the Clinical Global Impression – Severity (CGI-S) and the Clinical Global Impression – Improvement (CGI-I) scales. Least-squares (LS) means were calculated for the change from baseline to final visit for the outcomes. Results The study included 188 patients. Functionality improved as, by the end of the study, fewer patients were unemployed (53%) and more worked occasionally (21%). PNS improved significantly according to both physicians and patients (LS mean change from baseline in m-SAND total score: -10.0 (p-value

Background: Negative symptoms of schizophrenia have recently been proposed to result from a decoupling of (intact) hedonic experience and (diminished) approach behavior. The current study challenged this view by exploring the hypothesis that negative symptoms are driven by a specific type of emotional experience abnormality, a reduction in the positivity offset (i.e. the tendency to experience greater levels of positive relative to negative emotion in low-arousal contexts), which limits the production of approach behaviors in neutral environments. Methods: Participants included outpatients with SZ (n = 44) and healthy controls (CN: n = 48) who completed one week of active (ecological momentary assessment surveys of emotional experience and symptoms) and passive (geolocation, accelerometry) digital phenotyping. Mathematical modeling approaches from Cacioppo's Evaluative Space Model were used to quantify the positivity offset in daily life. Negative symptoms were assessed via standard clinical ratings, as well as active (EMA surveys) and passive (geolocation, accelerometry) digital phenotyping measures. Results: Results indicated that the positivity offset was reduced in SZ and associated with more severe anhedonia and avolition measured via clinical interviews and active and passive digital phenotyping. Conclusions: These findings suggest that current conceptual models of negative symptoms, which assume hedonic normality, may need to be revised to account for reductions in the positivity offset and its connection to diminished motivated behavior. Findings identify key real-world contexts where negative symptoms could be targeted using psychosocial treatments. [ABSTRACT FROM AUTHOR]

Background: Negative symptoms such as blunted facial expressivity are characteristic of schizophrenia. However, it is not well-understood if and what abnormalities are present in individuals at clinical high-risk (CHR) for psychosis. Methods: This experimental study employed facial electromyography (left zygomaticus major and left corrugator supercilia) in a sample of CHR individuals (N = 34) and healthy controls (N = 32) to detect alterations in facial expressions in response to emotionally evocative film clips and to determine links with symptoms. Results: Findings revealed that the CHR group showed facial blunting manifested in reduced zygomatic activity in response to an excitement (but not amusement, fear, or sadness) film clip compared to controls. Reductions in zygomatic activity in the CHR group emerged in response to the emotionally evocative peak period of the excitement film clip. Lower zygomaticus activity during the excitement clip was related to anxiety while lower rates of change in zygomatic activity during the excitement video clip were related to higher psychosis risk conversion scores. Conclusions: Together, these findings inform vulnerability/disease driving mechanisms and biomarker and treatment development. [ABSTRACT FROM AUTHOR]

Background: Psychotic experiences and negative symptoms (PENS) are common in non-clinical populations. PENS are associated with adverse outcomes, particularly when they persist. Little is known about the trajectories of PENS dimensions in young people, nor about the precursory factors associated with these trajectories. Methods: We conducted growth mixture modelling of paranoia, hallucinations, and negative symptoms across ages 16, 17, and 22 in a community sample (N = 12 049–12 652). We then described the emergent trajectory classes through their associations with genome-wide polygenic scores (GPS) for psychiatric and educational phenotypes, and earlier childhood characteristics. Results: Three trajectory classes emerged for paranoia, two for hallucinations, and two for negative symptoms. Across PENS, GPS for clinical help-seeking, major depressive disorder, and attention deficit hyperactivity disorder were associated with increased odds of being in the most elevated trajectory class (OR 1.07–1.23). Lower education GPS was associated with the most elevated trajectory class for hallucinations and negative symptoms (OR 0.77–0.91). Conversely for paranoia, higher education GPS was associated with the most elevated trajectory class (OR 1.25). Trajectory class associations were not significant for schizophrenia, obsessive-compulsive disorder, bipolar disorder, or anorexia GPS. Emotional/behaviour problems and life events in childhood were associated with increased odds of being in the most elevated trajectory class across PENS. Conclusions: Our results suggest latent heterogeneity in the development of paranoia, hallucinations, and negative symptoms in young people that is associated with specific polygenic scores and childhood characteristics. [ABSTRACT FROM AUTHOR]

Background: Currently there is no first-line treatment recommended for the negative symptoms of schizophrenia. Psychosocial and behavioural interventions are widely used to reduce the burden of negative symptoms. Meta-analytic studies have summarised the evidence for specific approaches but not compared evidence quality and benefit. Aim: To review and evaluate the evidence from meta-analytic studies of psychosocial and behavioural interventions for the negative symptoms of schizophrenia. Method: A systematic literature search was undertaken to identify all meta-analyses evaluating psychosocial and behavioural interventions reporting on negative symptom outcomes in people with schizophrenia. Data on intervention, study characteristics, acceptability and outcome were extracted. Risk of bias was evaluated. Results were summarised descriptively, and evidence ranked on methodological quality. Results: In total, 31 systematic reviews met the inclusion criteria evaluating the efficacy of negative symptom interventions on 33 141 participants. Exercise interventions showed effect sizes (reduction in negative symptoms) ranging from −0.59 to −0.24 and psychological interventions ranging from −0.65 to −0.04. Attrition ranged between 12% to 32%. Across the studies considered heterogeneity varied substantially (range 0–100). Most of the reviews were of very low to low methodological quality. Methodological quality ranking suggested that the effect size for cognitive remediation and exercise therapy may be more robust compared with other approaches. Conclusions: Most of the interventions considered had a small-to-moderate effect size, good acceptability levels but very few had negative symptoms as the primary intervention target. To improve the confidence of these effect sizes being replicated in clinical settings future studies should minimise risk of bias. [ABSTRACT FROM AUTHOR]

Background: Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes. Aims: To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories. Method: We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases. Results: Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F -statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data. Conclusions: Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension. [ABSTRACT FROM AUTHOR]

Background: Psychotic disorders and schizotypal traits aggregate in the relatives of probands with schizophrenia. It is currently unclear how variability in symptom dimensions in schizophrenia probands and their relatives is associated with polygenic liability to psychiatric disorders. Aims: To investigate whether polygenic risk scores (PRSs) can predict symptom dimensions in members of multiplex families with schizophrenia. Method: The largest genome-wide data-sets for schizophrenia, bipolar disorder and major depressive disorder were used to construct PRSs in 861 participants from the Irish Study of High-Density Multiplex Schizophrenia Families. Symptom dimensions were derived using the Operational Criteria Checklist for Psychotic Disorders in participants with a history of a psychotic episode, and the Structured Interview for Schizotypy in participants without a history of a psychotic episode. Mixed-effects linear regression models were used to assess the relationship between PRS and symptom dimensions across the psychosis spectrum. Results: Schizophrenia PRS is significantly associated with the negative/disorganised symptom dimension in participants with a history of a psychotic episode (P = 2.31 × 10−4) and negative dimension in participants without a history of a psychotic episode (P = 1.42 × 10−3). Bipolar disorder PRS is significantly associated with the manic symptom dimension in participants with a history of a psychotic episode (P = 3.70 × 10−4). No association with major depressive disorder PRS was observed. Conclusions: Polygenic liability to schizophrenia is associated with higher negative/disorganised symptoms in participants with a history of a psychotic episode and negative symptoms in participants without a history of a psychotic episode in multiplex families with schizophrenia. These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Negative symptoms are one of the most incapacitating features of Schizophrenia but their pathophysiology remains unclear. They have been linked to alterations in grey matter in several brain regions, but findings have been inconsistent. This may reflect the investigation of relatively small patient samples, and the confounding effects of chronic illness and exposure to antipsychotic medication. We sought to address these issues by investigating concurrently grey matter volumes (GMV) and cortical thickness (CTh) in a large sample of antipsychotic-naïve or minimally treated patients with First-Episode Schizophrenia (FES). Methods: T1-weighted structural MRI brain scans were acquired from 180 antipsychotic-naïve or minimally treated patients recruited as part of the OPTiMiSE study. The sample was stratified into subgroups with (N = 88) or without (N = 92) Prominent Negative Symptoms (PMN), based on PANSS ratings at presentation. Regional GMV and CTh in the two groups were compared using Voxel-Based Morphometry (VBM) and FreeSurfer (FS). Between-group differences were corrected for multiple comparisons via Family-Wise Error (FWE) and Monte Carlo z-field simulation respectively at p < 0.05 (2-tailed). Results: The presence of PMN symptoms was associated with larger left inferior orbitofrontal volume (p = 0.03) and greater CTh in the left lateral orbitofrontal gyrus (p = 0.007), but reduced CTh in the left superior temporal gyrus (p = 0.009). Conclusions: The findings highlight the role of orbitofrontal and temporal cortices in the pathogenesis of negative symptoms of Schizophrenia. As they were evident in generally untreated FEP patients, the results are unlikely to be related to effects of previous treatment or illness chronicity. [ABSTRACT FROM AUTHOR]

Background The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations. Aims To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis. Method Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points. Results The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016). Conclusions The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.

Background: Deficits in goal-directed behavior (i.e. behavior conducted to achieve a specific goal or outcome) are core to schizophrenia, difficult to treat, and associated with poor functional outcomes. Factors such as negative symptoms, effort-cost decision-making, cognition, and functional skills have all been associated with goal-directed behavior in schizophrenia as indexed by clinical interviews or laboratory-based tasks. However, little work has examined whether these factors relate to the real-world pursuit of goal-directed activities in this population. Methods: This study aimed to fill this gap by using Ecological Momentary Assessment (four survey prompts per day for 1 week) to test hypotheses about symptom, effort allocation, cognitive, and functional measures associated with planned and completed goal-directed behavior in the daily lives of 63 individuals with schizophrenia. Results: Individuals with schizophrenia completed more goal-directed activities than they planned [ t (62) = −4.01, p < 0.001]. Motivation and pleasure (i.e. experiential) negative symptoms, controlling for depressive symptoms, negatively related to planned goal-directed behavior [odds ratio (OR) 0.92, p = 0.005]. Increased effort expenditure for high probability rewards (planned: OR 1.01, p = 0.034, completed: OR 1.01, p = 0.034) along with performance on a daily functional skills task (planned: OR 1.04, p = 0.002, completed: OR 1.03, p = 0.047) negatively related to both planned and completed goal-directed activity. Conclusions: Our results present correlates of real-world goal-directed behavior that largely align with impaired ability to make future estimations in schizophrenia. This insight could help identify targeted treatments for the elusive motivated behavior deficits in this population. [ABSTRACT FROM AUTHOR]

Background: People with psychosis experience cardiometabolic comorbidities, including metabolic syndrome, coronary heart disease and diabetes. These physical comorbidities have been linked to diet, inactivity and the effects of the illness itself, including disorganisation, impairments in global function and amotivation associated with negative symptoms of schizophrenia or co-morbid depression. Methods: We aimed to describe the dietary intake, physical activity (PA) and sedentary behaviour patterns of a sample of patients with established psychosis participating in the Improving Physical Health and Reducing Substance Use in Severe Mental Illness (IMPaCT) randomised controlled trial, and to explore the relationship between these lifestyle factors and mental health symptomatology. Results: A majority of participants had poor dietary quality, low in fruit and vegetables and high in discretionary foods. Only 29.3% completed ⩾150 min of moderate and/or vigorous activity per week and 72.2% spent ⩾6 h per day sitting. Cross-sectional associations between negative symptoms, global function, and PA and sedentary behaviour were observed. Additionally, those with more negative symptoms receiving IMPaCT therapy had fewer positive changes in PA from baseline to 12-month follow-up than those with fewer negative symptoms at baseline. Conclusion: These results highlight the need for the development of multidisciplinary lifestyle and exercise interventions to target eating habits, PA and sedentary behaviour, and the need for further research on how to adapt lifestyle interventions to baseline mental status. Negative symptoms in particular may reduce patient's responses to lifestyle interventions. [ABSTRACT FROM AUTHOR]

Background: Recent network models propose that mutual interaction between symptoms has an important bearing on the onset of schizophrenic disorder. In particular, cross-sectional studies suggest that affective symptoms may influence the emergence of psychotic symptoms. However, longitudinal analysis offers a more compelling test for causation: the European Schizophrenia Cohort (EuroSC) provides data suitable for this purpose. We predicted that the persistence of psychotic symptoms would be driven by the continuing presence of affective disturbance. Methods: EuroSC included 1208 patients randomly sampled from outpatient services in France, Germany and the UK. Initial measures of psychotic and affective symptoms were repeated four times at 6-month intervals, thereby furnishing five time-points. To examine interactions between symptoms both within and between time-slices, we adopted a novel technique for modelling longitudinal data in psychiatry. This was a form of Bayesian network analysis that involved learning dynamic directed acyclic graphs (DAGs). Results: Our DAG analysis suggests that the main drivers of symptoms in this long-term sample were delusions and paranoid thinking. These led to affective disturbance, not vice versa as we initially predicted. The enduring relationship between symptoms was unaffected by whether patients were receiving first- or second-generation antipsychotic medication. Conclusions: In this cohort of people with chronic schizophrenia treated with medication, symptoms were essentially stable over long periods. However, affective symptoms appeared driven by the persistence of delusions and persecutory thinking, a finding not previously reported. Although our findings as ever remain hostage to unmeasured confounders, these enduring psychotic symptoms might nevertheless be appropriate candidates for directly targeted psychological interventions. [ABSTRACT FROM AUTHOR]

Background: Residual negative symptoms and cognitive impairment are common for chronic schizophrenia patients. The aim of this study was to investigate the efficacy of a mindfulness-based intervention (MBI) on negative and cognitive symptoms of schizophrenia patients with residual negative symptoms. Methods: In this 6-week, randomized, single-blind, controlled study, a total of 100 schizophrenia patients with residual negative symptoms were randomly assigned to the MBI or control group. The 6-week MBI group and the control group with general rehabilitation programs maintained their original antipsychotic treatments. The scores for the Positive and Negative Syndrome Scale (PANSS), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Symptom Checklist 90 (SCL-90) were recorded at baseline and week 6 to assess psychotic symptoms, cognitive performance, and emotional state, respectively. Results: Compared with general rehabilitation programs, MBI alleviated the PANSS-negative subscore, general psychopathology subscore, and PANSS total score in schizophrenia patients with residual negative symptoms (F = 33.77, p Bonferroni < 0.001; F = 42.01, p Bonferroni < 0.001; F = 52.41, p Bonferroni < 0.001, respectively). Furthermore, MBI improved RBANS total score and immediate memory subscore (F = 8.80, p Bonferroni = 0.024; F = 11.37, p Bonferroni = 0.006), as well as SCL-90 total score in schizophrenia patients with residual negative symptoms (F = 18.39, p Bonferroni < 0.001). Conclusions: Our results demonstrate that MBI helps schizophrenia patients with residual negative symptoms improve clinical symptoms including negative symptom, general psychopathology symptom, and cognitive impairment. Trial registration: ChiCTR2100043803. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia (SZ) is typically preceded by a prodromal (i.e. pre-illness) period characterized by attenuated positive symptoms and declining functional outcome. Negative symptoms are prominent among individuals at clinical high-risk (CHR) for psychosis (i.e. those with prodromal syndromes) and predictive of conversion to illness. Mechanisms underlying negative symptoms are unclear in the CHR population. Methods: The current study evaluated whether CHR participants demonstrated deficits in the willingness to expend effort for rewards and whether these impairments are associated with negative symptoms and greater risk for conversion. Participants included 44 CHR participants and 32 healthy controls (CN) who completed the Effort Expenditure for Reward Task (EEfRT). Results: Compared to CN, CHR participants displayed reduced likelihood of exerting high effort for high probability and magnitude rewards. Among CHR participants, reduced effort expenditure was associated with greater negative symptom severity and greater probability of conversion to a psychotic disorder on a cross-sectional risk calculator. Conclusions: Findings suggest that effort-cost computation is a marker of illness liability and a transphasic mechanism underlying negative symptoms in the SZ spectrum. [ABSTRACT FROM AUTHOR]

Background: Recent stressful life events (SLE) are a risk factor for psychosis, but limited research has explored how SLEs affect individuals at clinical high risk (CHR) for psychosis. The current study investigated the longitudinal effects of SLEs on functioning and symptom severity in CHR individuals, where we hypothesized CHR would report more SLEs than healthy controls (HC), and SLEs would be associated with poorer outcomes., Methods: The study used longitudinal data from the EU-GEI High Risk study. Data from 331 CHR participants were analyzed to examine the effects of SLEs on changes in functioning, positive and negative symptoms over a 2-year follow-up. We compared the prevalence of SLEs between CHR and HCs, and between CHR who did (CHR-T) and did not (CHR-NT) transition to psychosis., Results: CHR reported 1.44 more SLEs than HC ( p < 0.001), but there was no difference in SLEs between CHR-T and CHR-NT at baseline. Recent SLEs were associated with poorer functioning and more severe positive and negative symptoms in CHR individuals (all p < 0.01) but did not reveal a significant interaction with time., Conclusions: CHR individuals who had experienced recent SLEs exhibited poorer functioning and more severe symptoms. However, as the interaction between SLEs and time was not significant, this suggests SLEs did not contribute to a worsening of symptoms and functioning over the study period. SLEs could be a key risk factor to becoming CHR for psychosis, however further work is required to inform when early intervention strategies mitigating against the effects of stress are most effective.

Schizophrenia is a highly heterogenous disorder with substantial interindividual variation in how the illness is experienced and how it presents clinically. The disorder is composed of primary symptom clusters-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. These, along with duration, severity, and excluding other possible etiologies, comprise the diagnostic criteria for the disorder outlined in the two commonly used diagnostic classification systems-the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition, Text Revision and the International Classification of Diseases, 11 th Revision. These primary symptoms as well as accessory symptoms (mood disturbances, anxiety, violence) and comorbidities (substance use, suicidality) bear upon each other to varying degrees and impact functional outcomes. The following review presents two patient cases illustrating the clinical heterogeneity of schizophrenia, the natural history of the illness and diagnosis, followed by the current understanding of the primary symptom clusters, accessory symptoms, and comorbidities. In addition to noting symptom prevalence, onset, and change over time, attention is paid to the impact of symptoms on functional outcome.

Background: Executive control over low-level information processing is impaired proximal to psychosis onset with evidence of recovery over the first year of illness. However, previous studies demonstrating diminished perceptual modulation via attention are complicated by simultaneously impaired perceptual responses. The present study examined the early auditory gamma-band response (EAGBR), a marker of early cortical processing that appears preserved in first-episode psychosis (FEP), and its modulation by attention in a longitudinal FEP sample., Methods: Magnetoencephalography was recorded from 25 FEP and 32 healthy controls (HC) during active and passive listening conditions in an auditory oddball task at baseline and follow-up (4-12 months) sessions. EAGBR inter-trial phase coherence (ITPC) and evoked power were measured from responses to standard tones. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS)., Results: There was no group difference in EAGBR power or ITPC. While EAGBR ITPC increased with attention in HC, this modulation was impaired among FEP. Diminished EAGBR modulation in FEP persisted at longitudinal follow-up. However, among FEP, recovery of EAGBR modulation was associated with reduced PANSS negative scores., Conclusion: FEP exhibit impaired executive control over the flow of information at the earliest stages of sensory processing within auditory cortex. In contrast to previous work, this deficit was observed despite an intact measure of sensory processing, mitigating potential confounds. Recovery of sensory gain modulation over time was associated with reductions in negative symptoms, highlighting a source of potential resiliency against some of the most debilitating and treatment refractory symptoms in early psychosis.

Antipsychotics effective for schizophrenia approved prior to 2024 shared the common mechanism of postsynaptic dopamine D 2 receptor antagonism or partial agonism. Positive psychosis symptoms correlate with excessive presynaptic dopamine turnover and release, yet this postsynaptic mechanism improved positive symptoms only in some patients, and with concomitant risk for off-target motor and endocrine adverse effects; moreover, these agents showed no benefit for negative symptoms and cognitive dysfunction. The sole exception was data supporting cariprazine's superiority to risperidone for negative symptoms. The muscarinic M 1 /M 4 agonist xanomeline was approved in September 2024 and represents the first of a new antipsychotic class. This novel mechanism improves positive symptoms by reducing presynaptic dopamine release. Xanomeline also lacks any D 2 receptor affinity and is not associated with motor or endocrine side effects. Of importance, xanomeline treated patients with higher baseline levels of cognitive dysfunction in clinical trials data saw cognitive improvement, a finding likely related to stimulation of muscarinic M 1 receptors. Treatment resistance is seen in one-third of schizophrenia patients. These individuals do not have dopamine dysfunction underlying their positive symptoms, and therefore show limited response to antipsychotics that target dopamine neurotransmission. Clozapine remains the only medication with proven efficacy for resistant schizophrenia, and with unique benefits for persistent impulsive aggression and suicidality. New molecules are being studied to address the array of positive, negative and cognitive symptoms of schizophrenia; however, until their approval, clinicians must be familiar with currently available agents and be adept at prescribing clozapine.

Summary: Important developments in the conceptualisation and classification of negative symptoms have contributed to refining hypotheses on their pathophysiology. The uptake of recent progress is still only partial and the whole field might make a leap forward once relevant studies fully make use of assessment tools based on current conceptualisations. [ABSTRACT FROM AUTHOR]

Summary: Negative symptoms of schizophrenia manifest as reduced motivation and pleasure (MAP) and impaired emotional expressivity (EXP). These can occur as primary phenomena, but have also been suggested to occur secondary to other clinical factors, including antipsychotic-induced sedation. However, this relationship has not been established formally. Here, we examined the effect of antipsychotic-induced sedation (assessed via the proxy of total daily sleep duration) on MAP and EXP in a cohort of 187 clozapine-treated patients with schizophrenia followed for over 2 years on average, using multilevel regression and mediation models. MAP, but not EXP, was adversely influenced by sedation, independently of the severity of psychosis or depression. Moreover, clozapine impaired MAP indirectly by worsening sedation, but after accounting for clozapine-induced sedation, clozapine improved MAP. Our results highlight the importance of addressing sedative side-effects of antipsychotics to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Investigations into possible mechanisms that may contribute to the development, maintenance, and exacerbation of negative symptoms are needed. Defeatist beliefs, self-efficacy, and early maladaptive schemas have been shown to contribute to negative symptoms in schizophrenia. Likewise, negative symptoms occur in those at clinical high-risk (CHR) for psychosis. Aims: The aim of this study was to determine if negative symptoms were associated with defeatist beliefs, self-efficacy, and early maladaptive schemas in CHR participants of a group therapy intervention study. Method: All CHR participants (n = 203; 99 males, 104 females) were recruited as part of a three-site randomized control trial: Recovery through Group Study (ReGroup). Negative symptoms, defeatist beliefs, self-efficacy and early maladaptive schemas were assessed by trained clinical raters. Mediation analyses were conducted to examine the relationship between defeatist beliefs, self-efficacy, functioning, and negative symptoms. Results: The majority of CHR youth (72.9%) had at least one negative symptom of moderate to above moderate severity at baseline. In multiple mediation analyses, both asocial beliefs and social self-efficacy mediated the effects of social functioning on negative symptoms. Finally, defeatist performance attitudes significantly mediated the effects of role functioning on negative symptoms. Conclusions: These results highlight the importance of considering beliefs and attitudes in relation to functioning and severity of negative symptoms. Psychosocial interventions may wish to target beliefs and attitudes in effort to reduce negative symptoms and improve functioning in CHR youth. [ABSTRACT FROM AUTHOR]

Introduction Research indicates improvements in negative symptoms and empathy for schizophrenia spectrum disorders (SSD) after mindfulness-based interventions (MBI). Current treatment approaches for SSD remain limited regarding their effectiveness on negative symptoms and sociocognitive deficits. After oxytocin (OXT) administration, especially in a positive social context, an increase in empathy could be shown. The effect of mindfulness in combination with OXT has not yet been examined. Objectives This study investigates the additional effect of OXT administration combined with MBI on empathy and negative symptoms in patients with SSD. Methods An experimental, randomised, triple-blinded, placebo-controlled study is proposed. Based on power calculations, 140 participants with SSD will be recruited at Charité – Universitätsmedizin Berlin. A dose of intranasal oxytocin with 24 I.U. or placebo will be administered 45 minutes before each session. Following each administration, a total of four MBI interventions will take place for two weeks. Empathy as primary outcome will be measured using validated psychometric questionnaires. Outcomes, including negative symptoms and OXT plasma levels, will be measured at baseline and post-intervention. A 2x2 mixed-model ANCOVA design with time as within- and group as between-subject factor will be calculated to assess empathy and negative symptom changes. Results The study hypothesises that applying intranasal oxytocin in combination with MBI will increase empathy and reduce negative symptoms in patients with SSD. Conclusions Findings could provide insight into enhancing therapies like MBI by utilising OXT as a possible supplementary treatment option. Findings could therefore pave the way for a personalised psychiatric medicine treatment for individuals with SSD. Disclosure No significant relationships.

Introduction Negative symptoms (NS) are a core feature of schizophrenia. NS show heterogeneity proven by factor analysis, which revealed two distinct negative symptoms subdomains: diminished expression (DE) and avolition/apathy (AA) (Marder et al. 2017, Fleischhacker et al. 2019). Some studies showed the different effects of these subdomains on clinical features of schizophrenia that suggest different pathophysiological mechanisms for their development (Stanculete 2021). It has been also shown that the levels of peripheral interleukins (IL) specifically correlate with NS (Enache et al. 2021), in particular, increased IL levels were determined in patients with deficit syndrome compared to non-deficit schizophrenia (Goldsmith et al. 2018). Objectives To search for the association of genes for IL-4, IL-6, IL-10 and C-reactive protein (CRP) with NS subdomains. Methods The total sample included 551 patients (women 51,4%, aged 18-72 years) with ICD-10 diagnosis of schizophrenia. NS were assessed by PANSS. PANSS-derived factors include AA (items N2, N4, G16) and DE (N1, N3, N6, G5, G7, G13). Genotyping was performed for the following polymorphisms: C-589T IL-4, C-174G IL-6, C-592A IL-10, G-1082A IL-10, CRP (rs2794521). Results There are effects of C-592A IL-10 (p=0.017) and G-1082A IL-10 (p=0.012) on AA subdomain. Post-hoc Bonferroni corrected comparisons show that carriers of the haplotype AA (C-592A)- AA (G-1082A) have the highest AA score. A significant effect of CRP (rs2794521) on AA is identified (p=0.007). There is a trend towards the association of C-589T IL-4 and C-174G IL-6 with AA. No association of these polymorphisms with DE was found. Conclusions AA and DE may have different genetic background. Disclosure No significant relationships.

Introduction Schizophrenia is frequently a chronic and disabling disorder, characterized by heterogeneous positive and negative symptoms. Negative symptoms are a major health concern and a core component of schizophrenia that account for a large part of the long-term disability and poor functional outcomes in patients with the disorder. Adequate treatment would mean important progress and Distinguishing primary from secondary negative symptoms may inform about treatment options. Objectives Objective: to provide information that may be useful for clinicians treating patients with negative symptoms of schizophrenia. Methods We searched Pubmed and Cochrane Library database for english language articles. Results Negative symptoms are a core component of schizophrenia that account for a large part of the long-term disability and poor functional outcomes. Negative symptoms are common in schizophrenia; up to 60% of patients may have prominent clinically relevant negative symptoms that require treatment. Negative symptoms can occur at any point in the course of illness, although they are reported as the most common first symptom of schizophrenia. Negative symptoms can be primary symptoms, which are intrinsic to the underlying pathophysiology of schizophrenia, or secondary symptoms that are related to psychiatric or medical comorbidities, adverse effects of treatment, or environmental factors. Negative symptoms clearly constitute an unmet medical need in schizophrenia, and new and effective treatments are urgently needed. Conclusions Clinically relevant negative symptoms of schizophrenia need to be recognized, assessed, and as well managed as possible in order to achieve improved outcomes for patients. More studies are needed to establish the better approach to negative symptoms. Disclosure No significant relationships.

Introduction Current research suggests emotion recognition to be significantly impaired in individuals with schizophrenia spectrum disorders (SSD), whereby negative symptoms are theorised to play a crucial role. Emotion recognition deficits are assumed to be predictors of transition from clinical high risk to schizophrenia. So far, little attention has been given hereby to the subdomains of negative symptoms and recognizing the individual basic emotions. Objectives Our study aimed to explore the relationship between the recognition of the basic emotions and each negative symptom domain. Methods 66 patients with a SSD diagnosis were recruited at the Charité – Universitätsmedizin Berlin. Correlational and regression analyses to control for the covariates (age, education, sex) were conducted between the recognition of the six basic emotions (anger, disgust, fear, happiness, sadness, surprise) using the Emotion Recognition Task of the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the seven different subdomains of negative symptoms of the Positive and Negative Syndrome Scale (PANSS). Results revealed significantly negative correlations of blunted affect with the recognition of happiness, fear, and disgust. Difficulties in abstract thinking, also correlated positively with the recognition of fear. Additionally, we found a significant positive correlation between stereotyped thinking and difficulties in abstract thinking with the response latency in emotion recognition. Conclusions Individuals with SSD and domains of negative symptoms showed specific impairments in recognizing the representation of basic emotions. A longitudinal design to make causality statements would be useful for future research. Moreover, emotion recognition should be considered for early detection and individualized treatment. Disclosure No significant relationships.

Introduction Schizophrenia is often accompanied by functional deterioration which can impede a person‛s everyday activities. Families are an important part in providing care for their ailed member‚ but often lack resources to deal with different challenges included in such care. Mental health professionals treating such patients sometimes neglect the importance of including their families‚ or primary caretaker in the treatment plan. Objectives We will present two cases of patients diagnosed with schizophrenia with prominently negative symptoms and the challenges met by their caretakers and mental health professionals in the treatment. Methods Patient history‚ psychiatric evaluation, psychiatric treatment‚ and the role of the family will be presented. Results 21 years old patient came with his mother after years of not meeting the expected level of functioning. He was misdiagnosed for a couple of years. His treatment was impeded by loss in the family‚ which also affected both him and his mother. Inability to include her earlier in his treatment became a challenge. Second patient has been treated for schizophrenia with dominant negative symptoms‚ inconsistently‚ for ten years. Her family became more involved in her treatment only after she presented with positive symptoms. Their involvement was important as it resulted in patient‛s better compliance. Conclusions Supporting a family member diagnosed with schizophrenia can be overwhelming for the families. Including family members in the treatment early on, can be beneficial both for the patient and the family. Disclosure No significant relationships.

Introduction The world literature presents ambiguous results regarding the conjugation of negative and depressive syndromes, due to an incomplete understanding of the main symptoms of depression in schizophrenia. Objectives To analyze the variants of the conjugation of depressive and negative symptoms at different stages of schizophrenia. Methods We used the data of our own observations (238 patients with a diagnosis of schizophrenia and no more than 5 years of experience of the disease) and compared them with the previously published results of studies. As a hypothesis, we analyze the variants of the conjugacy of affect and the negative domain within the framework of a single discrete field of schizophrenia. Results The analysis shows that with the apparent heterogeneity of the psychopathological structure, some depressive features, such as apathy, anhedonia and social autism (characteristic of negative symptoms), tend to the abulia factor, whereas low mood, suicidal thoughts, pessimism, show affinity for the cluster of impoverishment of expression, that is, they represent an attenuated type of negative symptoms tending to the affective spectrum. Conclusions The conjugacy of depressive and negative disorders in schizophrenia, taking into account their phenomenological similarity, allows us to formulate a hypothesis about their existence within the framework of a single continuum model. The proposed continuum model can be used to understand the processes underlying pathogenesis and formulate the principles of personalized treatment and can be used as a starting point for research on the underlying biological processes and personalized treatment. Disclosure No significant relationships.

Introduction The discovery of second-generation antipsychotics represented an authentic breakthrough for the management of psychotic disorders. Nevertheless, they still don’t adequately manage some aspects of these disorders, such as negative symptoms (NS), cognitive impairment, or extra-pyramidal symptoms (EPS). New-generation antipsychotics present different pharmacological mechanisms and have been reported to ameliorate these aspects. Among them, cariprazine acts as a D2/D3 partial agonist with variable affinity with serotoninergic receptors, and many studies show its efficacy for preventing and treating positive symptoms as well as for the management of NS and EPS. Objectives To report a case of a patient diagnosed with schizophrenia with highly invalidating antipsychotic-induced EPS that remitted after switching to cariprazine, while maintaining clinical stability. To review literature about cariprazine and its relationship with NS and EPS. Methods We describe the case of a 66-year-old woman diagnosed with schizophrenia and under treatment with three-month injectable paliperidone 175mg. During her follow-up at outpatient clinic, she presented a progressively highly invalidating non-trembling parkinsonian syndrome attributable to medication. Paliperidone plasmatic levels were within therapeutic range. An antipsychotic switch was agreed, and cariprazine was started. Results The switch from a second-generation antipsychotic to cariprazine entailed the remission of a highly invalidating EPS while improving some of the NS and maintaining psychopathological stability. Conclusions Assessing and differentiating NS and EPS is of an utmost importance during the follow-up of patients under antipsychotic treatment. Cariprazine is an interesting alternative when treating patients diagnosed with psychotic disorders that present mostly NS and antipsychotic-induced EPS. Disclosure No significant relationships.

Introduction The ongoing debate regarding the treatment efficacy for negative and cognitive symptoms in schizophrenia is a subject of continuous frustration among psychiatrists. These symptoms are reputedly hard to tackle therapeutically and their impact on long-term functional prognosis made them an important target for the maintenance treatment. Objectives To review the literature in order to find the most adequate treatment options for negative and cognitive symptoms of schizophrenia. Methods A literature review was performed through the main electronic databases (PubMed, CINAHL, SCOPUS, EMBASE, www.clinicaltrials.gov) using the search paradigm “schizophrenia” AND “negative symptoms” AND “cognitive symptoms” AND “pharmacological treatment”. All papers published between January 2000 and August 2021 were included. Results The efficacy of atypical antipsychotics over cognitive dysfunctions in schizophrenia decreases with time, without significant differences between the agents. Clozapine, amisulpride, olanzapine, and risperidone have superior efficacy over positive and negative symptoms, with small to moderate effect sizes. Meta-analyses show decreased severity of negative symptoms during treatment with atypical antipsychotics, especially with clozapine, amisulpride, olanzapine, zotepine, and risperidone. Atypical antipsychotics had a superior effect over neurocognitive domains when compared to the typical antipsychotics. Newer atypical antipsychotics, with partial D2/D3 agonism, are preferred to other atypical agents, although based on a low level of evidence. Antidepressants, especially mirtazapine, may be a solution for negative symptoms, while modafinil/armodafinil is also useful as an add-on. Conclusions Although new therapeutic options are explored, there is a paucity of encouraging results from the pipeline regarding the treatment efficacy over negative/cognitive symptoms. Disclosure No significant relationships.

Introduction Social connectedness might positively influence the course of clinical symptoms in people with psychotic disorders. Objectives This study examines satisfaction with social connectedness (SSC) as predictor of positive and negative symptoms in people with a psychotic disorder. Methods Data from the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS, 2014-2019) was used from patients diagnosed with a psychotic disorder (N=2109). Items about social connectedness of the Manchester short assessment of Quality of Life (ManSA) were used to measure SSC. Linear mixed models were used to estimate the association of SSC with the Positive and Negative Syndrome Scale (PANSS) after one and two years against α=0.01. Analyses were adjusted for symptoms, time since onset, gender and age. Additionally, fluctuation of positive and negative symptom scores over time was estimated. Results Mean duration of illness of the sample was 18.8 years (SD 10.7) with >65% showing only small variation in positive and negative symptoms over a two to five-year time period. After adjustment for covariates, SSC showed to be negatively associated with positive symptoms after one year (β=-0.47, p

Introduction The relevance of this study is determined by the need to search for biological markers of schizophrenia. The detection and validation of such molecules can become the basis for the creation of additional paraclinical diagnostic methods or contribute to the creation of targets for individual pharmacotherapy, which is an important task of modern fundamental medicine. Objectives Comparative proteomic analysis of serum in schizophrenic patients with positive and negative symptoms. Methods The study includes 10 healthy donors and 27 patients with schizophrenia. Samples preparation included: serum purification from major proteins via affinity chromatography, 1D-PAGE proteins separation, in-gel tryptic hydrolysis, LC-MS/MS mass-spectrometry (Orbitrap Q-exactive HF mass spectrometer, Agilent Technologies). Identification of proteins was carried out using Mascot software Ver. 2.1 («Matrix Science», USA). Proteins for quantitative analysis were selected in view of the DISGENET database. Quantitative LC-MS-SRM analysis of selected protein was performed on QQQ TSQ Vantage (Thermo Scientific) with labeled peptide standards. Results Receptor-interacting serine/threonine-protein kinase 1 was selected for quantitative assessment. Significant differences were revealed in the RIPK1 concentrations in the serum of schizophrenic patients with negative and positive symptoms (p=0.02). The serum concentration of RIPK1 in patients with negative symptoms is tenfold in patients with positive symptoms. Conclusions Receptor-interacting serine/threonine-protein kinase 1 can be considered a biomarker of negative symptoms of schizophrenia based on a significant increase in serum concentration. Mass spectrometric analysis was carried out of the “Human Proteome” Core Facility of the Institute of Biomedical Chemistry Moscow. Support by Grant of RSF № 18-15-00053P. Disclosure No significant relationships.

Introduction The appearance of inhibitory symptoms encompassed in what are known as negative symptoms is part of the usual symptoms of schizophrenia. Sometimes this inhibition reaches a significant severity, so it is essential to know its approach. Objectives Case report and literature review regarding the treatment of resistant schizophrenia with a predominance of negative symptoms Methods We present the clinical case of a 28-year-old man diagnosed with schizophrenia at 23 years old, whose onset was characterized by delusional ideas of harm (poisoning) and delusions with a mystic-religious theme that lead him to reduce his intake until requiring a first admission for severe desnutrition. Subsequently, after two more admissions, the patient presents selective reduction in food intake, decrease in daily activity and apathy without positive symptoms. Results Throughout the treatment, several lines of antipsychotic treatments have been tried at the maximum tolerated dose (haloperidol, oral paliperidone and depot, aripiprazole and clozapine up to a dose of 600 mg). Clozapine resistance required testing various augmentation strategies (Venlafaxine, Lamotrigine and Electroconvulsive therapy) with low results. Finally, to complement the treatment, the patient was transferred to a mid-stay unit where psychosocial treatment with a multidisciplinary approach was started. This has allowed more continuous follow-up and thus a partial improvement of the clinic. Conclusions Numerous studies describe numerous augmentation strategies for clozapine-resistant schizophrenia with negative symptoms. However, the results are still inconclusive, needing more research. Meanwhile, we want to highlight the importance of complementing the treatment with psychosocial approaches. Disclosure No significant relationships.

Negative psychotic symptoms are among the most disabling features of schizophrenia, and are strongly associated with relatively poor clinical and functional outcomes. However, there are no effective treatments for negative symptoms, and this represents a major unmet clinical need. Recent research has shown that negative symptoms are already present in many patients at illness onset. There is evidence that cariprazine may improve negative symptoms in patients with chronic schizophrenia. However, its utility in treating negative symptoms in the early stage of the disorder is unclear. Here, we report six cases of patients with first-episode psychosis who were treated with cariprazine.

Abstract Background The Positive and Negative Syndrome Scale (PANSS) is widely used in schizophrenia and has been divided into distinct factors (5-factor models) and subfactors. Network analyses are newer in psychiatry and can help to better understand the relationships and interactions between the symptoms of a psychiatric disorder. The aim of this study was threefold: (a) to evaluate connections between schizophrenia symptoms in two populations of patients (patients in the acutely exacerbated phase of schizophrenia and patients with predominant negative symptoms [PNS]), (b) to test whether network analyses support the Mohr 5 factor model of the PANSS and the Kahn 2 factor model of negative symptoms, and finally (c) to identify the most central symptoms in the two populations. Methods Using pooled baseline data from four cariprazine clinical trials in patients with acute exacerbation of schizophrenia (n = 2193) and the cariprazine–risperidone study in patients with PNS (n = 460), separate network analyses were performed. Network structures were estimated for all 30 items of the PANSS. Results While negative symptoms in patients with an acute exacerbation of schizophrenia are correlated with other PANSS symptoms, these negative symptoms are not correlated with other PANSS symptoms in patients with PNS. The Mohr factors were partially reflected in the network analyses. The two most central symptoms (largest node strength) were delusions and uncooperativeness in acute phase patients and hostility and delusions in patients with PNS. Conclusions This network analysis suggests that symptoms of schizophrenia are differently structured in acute and PNS patients. While in the former, negative symptoms are mainly secondary, in patients with PNS, they are mainly primary. Further, primary negative symptoms are better conceptualized as distinct negative symptom dimensions of the PANSS.

Background. The Positive and Negative Syndrome Scale (PANSS) is widely used in schizophrenia and has been divided into distinct factors (5-factor models) and subfactors. Network analyses are newer in psychiatry and can help to better understand the relationships and interactions between the symptoms of a psychiatric disorder. The aim of this study was threefold: (a) to evaluate connections between schizophrenia symptoms in two populations of patients (patients in the acutely exacerbated phase of schizophrenia and patients with predominant negative symptoms [PNS]), (b) to test whether network analyses support the Mohr 5 factor model of the PANSS and the Kahn 2 factor model of negative symptoms, and finally (c) to identify the most central symptoms in the two populations. Methods. Using pooled baseline data from four cariprazine clinical trials in patients with acute exacerbation of schizophrenia (n = 2193) and the cariprazine–risperidone study in patients with PNS (n = 460), separate network analyses were performed. Network structures were estimated for all 30 items of the PANSS. Results. While negative symptoms in patients with an acute exacerbation of schizophrenia are correlated with other PANSS symptoms, these negative symptoms are not correlated with other PANSS symptoms in patients with PNS. The Mohr factors were partially reflected in the network analyses. The two most central symptoms (largest node strength) were delusions and unco-operativeness in acute phase patients and hostility and delusions in patients with PNS. Conclusions. This network analysis suggests that symptoms of schizophrenia are differently structured in acute and PNS patients. While in the former, negative symptoms are mainly secondary, in patients with PNS, they are mainly primary. Further, primary negative symptoms are better conceptualized as distinct negative symptom dimensions of the PANSS. [ABSTRACT FROM AUTHOR]

Objective: There is ongoing debate regarding the relationship between clinical symptoms and cognition in schizophrenia spectrum disorders (SSD). The present study aimed to explore the potential relationships between symptoms, with an emphasis on negative symptoms, and social and non-social cognition. Method: Hierarchical cluster analysis with k-means optimisation was conducted to characterise clinical subgroups using the Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms in n = 130 SSD participants. Emergent clusters were compared on the MATRICS Consensus Cognitive Battery, which measures non-social cognition and emotion management as well as demographic and clinical variables. Spearman's correlations were then used to investigate potential relationships between specific negative symptoms and emotion management and non-social cognition. Results: Four distinct clinical subgroups were identified: 1. high hallucinations, 2. mixed symptoms, 3. high negative symptoms, and 4. relatively asymptomatic. The high negative symptom subgroup was found to have significantly poorer emotion management than the high hallucination and relatively asymptomatic subgroups. No further differences between subgroups were observed. Correlation analyses revealed avolition-apathy and anhedonia-asociality were negatively correlated with emotion management, but not non-social cognition. Affective flattening and alogia were not associated with either emotion management or non-social cognition. Conclusions: The present study identified associations between negative symptoms and emotion management within social cognition, but no domains of non-social cognition. This relationship may be specific to motivation, anhedonia and apathy, but not expressive deficits. This suggests that targeted interventions for social cognition may also result in parallel improvement in some specific negative symptoms. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia (SZ) is typically preceded by a prodromal (i.e. pre-illness) period characterized by attenuated positive symptoms and declining functional outcome. Negative symptoms are prominent among individuals at clinical high-risk (CHR) for psychosis (i.e. those with prodromal syndromes) and highly predictive of conversion to illness. Mechanisms underlying negative symptoms in the CHR population are unclear. Two studies were conducted to evaluate whether abnormalities in a reward processing mechanism thought to be core to negative symptoms in SZ, value representation, also exist in CHR individuals and whether they are associated with negative symptoms transphasically. Methods: Study 1 included 33 individuals in the chronic phase of illness who have been diagnosed with schizophrenia or schizoaffective disorder (SZ) and 40 healthy controls (CN). Study 2 included 37 CHR participants and 45 CN. In both studies, participants completed the delay discounting (DD) task as a measure of value representation and the Brief Negative Symptom Scale was rated to measure negative symptoms. Results: Results indicated that patients with SZ had steeper discounting rates than CN, indicating impairments in value representation. However, CHR participants were unimpaired on the DD task. In both studies, steeper discounting was associated with greater severity of negative symptoms. Conclusions: These findings suggest that deficits in value representation are associated with negative symptoms transphasically. [ABSTRACT FROM AUTHOR]

Introduction Motivation deficit is a significant aspect of lack of improvement in patients with schizophrenia especially with predominant negative symptoms (PNS). Therefore, improvement depends not only on symptoms reduction and better social functioning but also on patient engagement which is a key but less investigated aspect of successful treatment. Objectives To investigate and compare patient engagement in PNS patients after cariprazine and risperidone treatment characterized by the 11 items of the Positive and Negative Syndrome Scale (PANSS-11). Methods In this phase 3 study patients suffering from PNS of schizophrenia (PANSS-FSNS≥24) were randomized to 26 weeks of treatment with either cariprazine or risperidone (target dose 4.5 and 4 mg/day, respectively). To compare the effects of the two drugs on patient engagement the PANSS-11 scale was used. Change from baseline (CfB) on the selected items and PANSS-11 total score were analyzed using mixed model of repeated measures approach without correction for multiplicity. Results PANSS-11 total score mean CfB were -11.20 (SD=0.43) for cariprazine-, and -9.44 (SD=0.45) for risperidone-treated patients with a -1.79 (95% CI=-3.01, -0.56) mean difference (p=0.004) in favor of cariprazine. Most item differences were statistically significant (N1, N2, N3, N4, N5, G16) or numerically higher (N6, G7, G13) for cariprazine versus risperidone. Conclusions Cariprazine significantly improved patient engagement in patients with PNS of schizophrenia compared to risperidone based on the PANSS-11 post-hoc analysis. These results suggest that cariprazine treatment may improve not only the symptoms and everyday functioning of PNS patients but their engagement with life. Conflict of interest Studies were funded by Gedeon Richter Plc. and Allergan Plc (prior to its acquisition by AbbVie). Dr. Laszlovszky, Dombi, Balogh, Dr Barabassy, Dr Vass, Dr. Szatmári and Dr. Németh are employees of Gedeon Richter Plc.

Introduction Different electrophysiological indices have been investigated to identify diagnostic and prognostic markers of schizophrenia (SCZ). However, these indices have limited use in clinical practice, since both specificity and association with illness outcome remain unclear. In recent years, machine learning techniques, through the combination of multidimensional data, have been used to better characterize SCZ and to predict illness course. Objectives The aim of the present study is to identify multimodal electrophysiological biomarkers that could be used in clinical practice in order to improve precision in diagnosis and prognosis of SCZ. Methods Illness-related and functioning-related variables were measured at baseline in 113 subjects with SCZ and 57 healthy controls (HC), and after four-year follow-up in 61 SCZ. EEGs were recorded at baseline in resting-state condition and during two auditory tasks (MMN-P3a and N100-P3b). Through a Linear Support Vector Machine, using EEG data as predictors, four models were generated in order to classify SCZ and HC. Then, we combined unimodal classifiers’ scores through a stacking procedure. Pearson’s correlations between classifiers score with illness-related and functioning-related variables, at baseline and follow-up, were performed. Results Each EEG model produced significant classification (p < 0.05). Global classifier discriminated SCZ from HC with accuracy of 75.4% (p < 0.01). A significant correlation (r=0.40, p=0.002) between the global classifier scores with negative symptoms at follow-up was found. Within negative symptoms, blunted affect showed the strongest correlation. Conclusions Abnormalities in electrophysiological indices might be considered trait markers of schizophrenia. Our results suggest that multimodal electrophysiological markers might have prognostic value for negative symptoms.

Introduction General-population studies investigating the biological correlates of anhedonia/amotivation might be informative for treatment breakthroughs for a number of clinical conditions. Reduced gut-microbial diversity might lead to an anhedonic/amotivational syndrome (“sickness behaviour”). However, how gut-microbial diversity contribute to this clinical phenotype is a key gap in knowledge. We hypothesised the endocannabinoid system would be at play. Objectives We tested the hypothesis that the endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation Methods Secondary data analysis on 786 volunteer twins (TwinsUK). Measures of gut-microbiome, faecal endocannabinoid metabolites, and anhedonia/amotivation were collected over five years. To test our hypothesis we used a multilevel mediation model using alpha diversity as predictor, faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. Analyses were adjusted for obesity, diet, antidepressants, and sociodemographic covariates. Results Mean age was 65.2±7.6; 27% were obese and 4.7% were on antidepressants. Alpha diversity was significantly associated with anhedonia/amotivation (β=-0.37; 95%CI: -0.71 to -0.03; P=0.03). Faecal PEA levels mediated this association: the indirect effect was significant (β=-0.13; 95%CI: -0.24 to -0.01; P=0.03), as was the total effect (β=-0.38; 95%CI: -0.72 to -0.04; P=0.03). The direct effect of alpha diversity on anhedonia/amotivation was attenuated fully Conclusions We provided the first evidence showing that the association between gut-microbial features and anhedonia/amotivation is mediated by the endocannabinoid system. These findings shed light on a new therapeutic target in an area of unmet clinical need. Disclosure No significant relationships.

Introduction Negative symptoms (NS) represent a core aspect of schizophrenia with a huge impact on real life functioning. Dysfunctions within the dopaminergic cortico-striatal circuits have been documented in subjects with schizophrenia (SCZ) and hypothesized as possible neurobiological mechanisms underlying some domains of NS. Objectives We investigated relationships between the resting-state functional connectivity (RS-FC) of the ventro-tegmental area (VTA) and NS. Methods Resting-state fMRI data were recorded in 35 SCZ, recruited within the Italian Network for Research on Psychoses. We performed partial correlations between RS-FC and NS (evaluated with the Brief Negative Symptom Scale) controlling for possible sources of secondary negative symptoms. Results We found that the experiential domain correlated with the RS-FC of the VTA with the left ventro-lateral prefrontal cortex (lVLPFC) (r=0.372, p=0.039), while the Expressive deficit domain correlated with the RS-FC of the VTA with the left dorso-lateral prefrontal cortex (lDLPFC) (r= 0.470, p .008). Looking at subdomains, only the avolition (r= 0.418, p=0.019) and the blunted affect (r= 0.465, p=.008) showed the same correlations of the domains to which they belong. Conclusions According to our findings, separate dysfunctional neuronal circuits could underpin distinct negative symptom subdomains. A better understanding of neurobiological dysfunctions underlying NS could help to design new treatments, targeting different NS subdomains.

Negative symptoms are considered a core feature of schizophrenia. They are present since the prodromal phase and tend to persist more than other psychopathological dimensions in the chronic stages. The domain of apathy has attracted research efforts for the strong association with poor functional outcome. This negative symptom domain is observed in a number of neuropsychiatric disorders and might have both overlapping and distinct pathophysiological mechanisms. In schizophrenia it can be secondary to other aspects of the disorder, such as positive symptoms and depression, to drug side effects and/or social isolation, often observed in affected subjects. When primary to schizophrenia, apathy is conceptualized in terms of a reduction of the voluntary activity due to a lack of interest and motivation for goal-directed behavior initiation and persistence. In a percentage of subjects, apathy tend to persist and do not respond to available pharmacological and psychosocial treatments. The assessment of this domain in patients with schizophrenia using internationally recognized criteria for its definition, as were recently developed in other neuropsychiatric disorders, might help disentangle the different pathophysiological mechanisms. In the presentation, studies of apathy in schizophrenia will be illustrated to highlight the relationships with cognitive dysfunction, other psychopathological dimensions and functional outcome using state of the art instruments to assess the construct in schizophrenia.

Apathy is a quantitive reduction of goal-directed activity either in behavioural, cognitive, emotional or social dimension in comparison to the person’s previous level of functioning in these areas. Apathy is prevalent across many neurodegenerative, neurological, and psychiatric disorders. It represents the most common behavioural and psychological symptom in people with Alzheimer’s Disease and is often observed in Parkinson’s disease, vascular dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis/motor neuron disease, frontotemporal dementia, progressive supranuclear palsy, major depression, and schizophrenia. However, the definition and terminology employed to refer to apathy can vary in the context of different conditions and specialities and the diagnostic criteria have evolved. Additionally, the term apathy is employed to describe both a symptom and a syndrome. Indeed, little progress has been achieved in assessing the validity of the same construct across different disorders (eg. neurodegenerative disorders, schizophrenia or affective disorders). In 2018, a new version of the diagnostic criteria for apathy (DCA) in neuropsychiatric disorders was published. The validity of this new consensus has yet to be assessed among all relevant populations, including schizophrenia. Six European centres (Naples, Geneve, Nice, Rennes, Barcelona, Cambridge) aimed to test the prevalence of apathy, measured with the 2018 DCA, in patients diagnosed with schizophrenia. As a second aim, we focused on the relationship between DCA and other measures of apathy and negative symptoms in schizophrenia (BNSS and PANSS). In this talk, we will compare the preliminary findings of this pan-European study in schizophrenia patients with previous studies on neurodegenerative disorders.

Introduction Increasing evidence shows that impaired neuroplasticity and high inflammation play a crucial role in the pathophysiology of schizophrenia. Prospective studies demonstrated that patients with high inflammation usually have a poor treatment response and clinical practice learns that negative symptoms are challenging to treat. The predictive value of biomarkers for negative symptoms in patients with schizophrenia has sparsely been explored. Objectives Here, we investigated whether biomarkers are associated with negative symptoms at baseline, and whether biomarkers could predict negative symptoms after six years in patients with schizophrenia. Methods We investigated serum biomarkers in an epidemiological study on schizophrenia (N, baseline=110; N, follow-up=65). Negative symptoms were measured using the Positive and Negative Syndrome Scale. Biomarkers (N=189) were measured with a multi-analyte profiling platform and analysed using linear regression models, adjusted for site, age, gender, ethnicity, anti-inflammatory agents, smoking, cardiovascular disease and diabetes, and adjusted for multiple comparisons (q, Benjamini-Hochberg procedure). Results In particular, decreased platelet-derived growth factor (PDGF) (responsible for proliferation of oligodendrocytes) was associated with more negative symptoms at baseline and follow-up (figure). Several other biomarkers associated with inflammation, neuroplasticity and metabolism correlated with the severity of negative symptoms cross-sectionally and/or prospectively. Figure. Biomarkers for Negative Symptoms in Schizophrenia. Conclusions Although our sample size at follow-up was limited, we feel that these analyses contribute to further research of possible predictive biomarkers for negative symptoms in schizophrenia. During the conference we will elaborate our findings with applied machine learning techniques which might shed more light on the predictive value of biomarkers for negative symptoms in schizophrenia. Disclosure No significant relationships.