Metabolic shift toward ketosis in asocial cavefish increases social-like affinity.

BACKGROUND: Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic shifts regulate social affinity is not well investigated. RESULTS: In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No major behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not largely regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with exogenous ketone bodies, revealing that ketone bodies are pivotal molecules positively associated with social affinity. CONCLUSIONS: Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis, possibly linking the seasonal food availability and sociality.

Environmental context predicts state fluctuations in negative symptoms in youth at clinical high risk for psychosis.

BACKGROUND: Negative symptoms (avolition, anhedonia, asociality) are a prevalent symptom in those across the psychosis-spectrum and also occur at subclinical levels in the general population. Recent work has begun to examine how environmental contexts (e.g. locations) influence negative symptoms. However, limited work has evaluated how environments may contribute to negative symptoms among youth at clinical high risk for psychosis (CHR). The current study uses Ecological Momentary Assessment to assess how four environmental contexts (locations, activities, social interactions, social interaction method) impact state fluctuations in negative symptoms in CHR and healthy control (CN) participants. METHODS: CHR youth (n = 116) and CN (n = 61) completed 8 daily surveys for 6 days assessing negative symptoms and contexts. RESULTS: Mixed-effects modeling demonstrated that negative symptoms largely varied across contexts in both groups. CHR participants had higher negative symptoms than CN participants in most contexts, but groups had similar symptom reductions during recreational activities and phone call interactions. Among CHR participants, negative symptoms were elevated in several contexts, including studying/working, commuting, eating, running errands, and being at home. CONCLUSIONS: Results demonstrate that negative symptoms dynamically change across some contexts in CHR participants. Negative symptoms were more intact in some contexts, while other contexts, notably some used to promote functional recovery, may exacerbate negative symptoms in CHR. Findings suggest that environmental factors should be considered when understanding state fluctuations in negative symptoms among those at CHR participants.

Two and five-factor models of negative symptoms in schizophrenia are differentially associated with trait affect, defeatist performance beliefs, and psychosocial functioning.

Recent factor analytic evidence supports both two-factor (motivation and pleasure, MAP; diminished expression, EXP) and five-factor (anhedonia, asociality, avolition, blunted affect, alogia) conceptualizations of negative symptoms. However, it is unclear whether these two conceptualizations of the latent structure of negative symptoms have differential associations with external correlates. The current study evaluated external correlates of the two- and five-factor structures by examining associations with variables known to have critical relations with negative symptoms: trait affect, defeatist performance beliefs, neurocognition, and community-based psychosocial functioning. Participants included a total of 245 outpatients diagnosed with schizophrenia who were rated on the Brief Negative Symptom Scale and completed a battery of additional measures during periods of clinical stability. These additional measures included the Positive and Negative Affect Schedule, Defeatist Performance Beliefs scale, MATRICS Consensus Cognitive Battery, and Level of Function Scale. Pearson correlations indicated differential patterns of associations between the BNSS scores and the external correlates. Support for the two-factor model was indicated by a stronger association of MAP with positive affect and psychosocial functioning, compared to EXP with neurocognition. Significance tests examining a differential magnitude of associations showed that the two-dimension negative symptom structure masked unique correlational relationships among the five negative symptom domains with neurocognition and social/vocational community functioning and captured unique patterns of correlation with trait affect. Support for the five-factor model was shown by a stronger association between Blunted Affect with Attention/Vigilance, and stronger associations between Avolition, Anhedonia, and Asociality with psychosocial functioning. Results offer support for both the two-dimension and five-domain model of negative symptoms as well as a hierarchical two-dimensions-five-domains model of negative symptoms. Findings may have implications for diagnostic criteria and descriptions of the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5), as well as possible treatment targets of negative symptoms.

Environmental factors contributing to negative symptoms in youth at clinical high risk for psychosis and outpatients with schizophrenia.

BACKGROUND: A bioecosystem theory was recently proposed positing that negative symptoms of schizophrenia (SZ) are influenced by environmental factors. These environmental processes reflect sources of resource deprivation that manifest across multiple systems that impact individuals directly through microsystems and indirectly through the exosystem and macrosystem. As an initial test of this theory, the current study examined whether self-reported environmental resource deprivation was associated with anhedonia, avolition, and asociality. METHOD: Two samples were collected: (1) outpatients with schizophrenia or schizoaffective disorder (SZ: n = 38) and matched psychiatrically heathy controls (CN: n = 31); (2) youth at clinical high risk for psychosis (CHR: n = 34) and matched CN (n = 30). Measures of negative symptoms and environmental factors influencing the frequency of recreational, goal-directed, and social activities were collected. RESULTS: Negative symptoms were associated with environmental deprivation factors in the microsystem (number of social and activity settings) and exosystem (economy, mass media, politics/laws, neighborhood crime). These associations did not appear due to depression and were greater among those with SZ than CHR. CONCLUSIONS: These findings provide preliminary support for the bioecosystem theory and highlight an under-recognized role for environmental factors underlying negative symptoms across phases of psychotic illness. Environmental systems-focused treatment approaches may offer a novel means of treating negative symptoms, which could be promising when coupled with person-level pharmacological and psychosocial treatments.

Intranasal Oxytocin for Negative Symptoms of Schizophrenia: Systematic Review, Meta-Analysis, and Dose-Response Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Negative symptoms are a core aspect of psychopathology in schizophrenia. Currently available pharmacological agents have proven minimally efficacious for remediating negative symptoms. A promising treatment avenue is the intranasal administration of the neuropeptide oxytocin. However, there have been inconsistencies in effects of oxytocin on negative symptoms throughout the literature, and factors leading to inconsistent effects are unclear. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials to compare the effectiveness of oxytocin with placebo for the treatment of negative symptoms and determine moderators of treatment effect. Random effects meta-analyses and dose-response meta-analysis were performed on mean changes in negative symptoms. RESULTS: In an initial analysis of all 9 identified randomized clinical trials, intranasal oxytocin showed no significant effect on negative symptoms. For higher doses (>40-80 IU), a beneficial effect on negative symptoms was found with a moderate effect size, but this effect disappeared after exclusion of 1 outlier study. The dose-response meta-analysis predicted that higher doses of oxytocin may be more efficacious for negative symptoms. For positive symptoms, no beneficial effect of oxytocin was found in the main meta-analysis, but the dose-response meta-analysis suggested a potential advantage of higher doses. CONCLUSIONS: The present results show no consistent beneficial effect of intranasal oxytocin for the treatment of negative and positive symptoms. The dose-response meta-analysis does not allow drawing any firm conclusions but suggests that high doses of intranasal oxytocin may be more efficacious. If future studies are conducted, an effort to reach adequate CNS concentrations for a sufficient duration is required.

Elucidating negative symptoms in the daily life of individuals in the early stages of psychosis.

BACKGROUND: It remains poorly understood how negative symptoms are experienced in the daily lives of individuals in the early stages of psychosis. We aimed to investigate whether altered affective experience, anhedonia, social anhedonia, and asociality were more pronounced in individuals with an at-risk mental state for psychosis (ARMS) and individuals with first-episode psychosis (FEP) than in controls. METHODS: We used the experience sampling methodology (ESM) to assess negative symptoms, as they occurred in the daily life of 51 individuals with FEP and 46 ARMS, compared with 53 controls. RESULTS: Multilevel linear regression analyses showed no overall evidence for a blunting of affective experience. There was some evidence for anhedonia in FEP but not in ARMS, as shown by a smaller increase of positive affect (BΔat-risk v. FEP = 0.08, p = 0.006) as the pleasantness of activities increased. Against our expectations, no evidence was found for greater social anhedonia in any group. FEP were more often alone (57%) than ARMS (38%) and controls (35%) but appraisals of the social situation did not point to asociality. CONCLUSIONS: Overall, altered affective experience, anhedonia, social anhedonia and asociality seem to play less of a role in the daily life of individuals in the early stages of psychosis than previously assumed. With the experience of affect and pleasure in daily life being largely intact, changing social situations and appraisals thereof should be further investigated to prevent development or deterioration of negative symptoms.

The Role of Defeatist Performance Beliefs in State Fluctuations of Negative Symptoms in Schizophrenia Measured in Daily Life via Ecological Momentary Assessment.

BACKGROUND AND HYPOTHESIS: The Cognitive Model of Negative Symptoms is a prominent model that posits that defeatist performance beliefs (DPB) are a key psychological mechanism underlying negative symptoms in those with schizophrenia (SZ). However, the ecological validity of the model has not been established, and temporally specific evaluations of the model's hypotheses have not been conducted. This study tested the model's key hypotheses in real-world environments using ecological momentary assessment (EMA). STUDY DESIGN: Fifty-two outpatients with SZ and 55 healthy controls (CN) completed 6 days of EMA. Multilevel models examined concurrent and time-lagged associations between DPB and negative symptoms in daily life. STUDY RESULTS: SZ displayed greater DPB in daily life than CN. Furthermore, greater DPB were associated with greater concurrently assessed negative symptoms (anhedonia, avolition, and asociality) in daily life. Time-lagged analyses indicated that in both groups, greater DPB at time t led to elevations in negative symptoms (anhedonia, avolition, or asociality) at t + 1 above and beyond the effects of negative symptoms at time t. CONCLUSIONS: Results support the ecological validity of the Cognitive Model of Negative Symptoms and identify a temporally specific association between DPB and subsequent negative symptoms that is consistent with the model's hypotheses and a putative mechanistic pathway in Cognitive Behavioral Therapy for negative symptoms. Findings suggest that DPB are a psychological factor contributing to negative symptoms in real-world environments. Implications for measuring DPB in daily life and providing just-in-time mobile health-based interventions to target this mechanism are discussed.

An exploration of blood-based biomarkers of negative symptoms of psychosis in men.

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

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia.

BACKGROUND: Accumulating evidence suggests that the inflammatory cytokine interleukin-6 (IL-6) contributes to the pathophysiology of psychiatric disorders. However, there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia (EOS). AIM: To investigate the relationship between serum IL-6 concentration and the clinical features of EOS. METHODS: We measured serum IL-6 Levels from 74 patients with chronic schizophrenia, including 33 with age at onset < 21 years (EOS group) and 41 with onset ≥ 21 years in [adult-onset schizophrenia (AOS) group], and from 41 healthy controls. Symptom severities were evaluated using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls (F = 22.32, P < 0.01), but did not differ significantly between EOS and AOS groups (P > 0.05) after controlling for age, body mass index, and other covariates. Negative symptom scores were higher in the EOS group than the AOS group (F = 6.199, P = 0.015). Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score (r = -0.389, P = 0.032) and avolition/asociality subscore (r = -0.387, P = 0.026). CONCLUSION: Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness. IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.

Negative symptoms in schizophrenia differ across environmental contexts in daily life.

A recent environmental theory of negative symptoms posits that environmental contexts (e.g., location, social partner) play a significant-yet often unaccounted for-role in negative symptoms of schizophrenia (SZ). "Gold-standard" clinical rating scales offer limited precision for evaluating how contexts impact symptoms. To overcome some of these limitations, Ecological Momentary Assessment (EMA) was used to determine whether there were state fluctuations in experiential negative symptoms (anhedonia, avolition, and asociality) in SZ across contexts (locations, activities, social interaction partner, social interaction method). Outpatients with SZ (n = 52) and healthy controls (CN: n = 55) completed 8 daily EMA surveys for 6 days assessing negative symptom domains (anhedonia, avolition, and asociality) and contexts. Multilevel modeling demonstrated that negative symptoms varied across location, activity, social interaction partner, and social interaction method. For the majority of contexts, SZ and CN did not report significantly different levels of negative symptoms, with SZ only reporting higher negative symptoms than CN while eating, resting, interacting with a significant other, or being at home. Further, there were several contexts where negative symptoms were similarly reduced (e.g., recreation, most social interactions) or elevated (e.g., using the computer, working, running errands) in each group. Results demonstrate that experiential negative symptoms dynamically change across contexts in SZ. Some contexts may "normalize" experiential negative symptoms in SZ, while other contexts, notably some used to promote functional recovery, may increase experiential negative symptoms.

Thirty years of research on negative symptoms of schizophrenia: A scientometric analysis of hotspots, bursts, and research trends.

Research on negative symptoms of schizophrenia has received renewed interest since the 1980s. A scientometric analysis that objectively maps scientific knowledge, with changes in recent trends, is currently lacking. We searched the Web of Science Core Collection (WOSCC) on December 17, 2021 using relevant keywords. R-bibliometrix and CiteSpace were used to perform the analysis. We retrieved 27,568 references published between 1966 and 2022. An exponential rise in scientific interest was observed, with an average annual growth rate in publications of 16.56% from 1990 to 2010. The co-cited reference network that was retrieved presented 24 different clusters with a well-structured network (Q=0.7921; S=0.9016). Two distinct major research trends were identified: research on the conceptualization and treatment of negative symptoms. The latest trends in research on negative symptoms include evidence synthesis, nonpharmacological treatments, and computational psychiatry. Scientometric analyses provide a useful summary of changes in negative symptom research across time by identifying intellectual turning point papers and emerging trends. These results will be informative for systematic reviews, meta-analyses, and generating novel hypotheses.

Approaches to Studying and Improving Social Motivation in Schizophrenia.

Social motivation impairments, or "asociality," have long been considered a core clinical feature of schizophrenia. Although the prevalence and pervasive negative impact of poor social motivation is well-documented, our understanding is limited regarding causal mechanisms. Advances in definition, conceptualization, and characterization are needed to inform research aimed at understanding these mechanisms and developing effective interventions. This theme issue is intended to accelerate efforts to study and treat social motivation in schizophrenia by synthesizing the current knowledge and providing new frameworks to guide future research in this area.

Impact of negative symptoms on health-related quality of life in schizophrenia.

Evidence regarding the association of Negative Symptoms (NS) dimensions with Health-related Quality of Life (HRQoL) is limited and no prior study has looked into contributions of NS domains on HRQoL. This study bridges the gap by examining the associations of NS, its two dimensions (Motivation and Pleasure, and Emotional Expressivity) and five domains (Anhedonia, Avolition, Asociality, Blunted affect and Alogia) with HRQoL in schizophrenia. 274 individuals with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS). PANSS scores were mapped to EuroQol five-dimensional (EQ-5D-5L) utility scores using an algorithm previously validated in Singapore, and the resulting EQ-5D-5L scores were used as a measure of HRQoL. Multiple linear regression analyses of the two NS dimensions and five NS domains against EQ-5D-5L showed that a lower severity of NS, specifically that of the Motivation and Pleasure (MAP) dimension and asociality domain was associated with higher HRQoL. Our findings highlight the importance of targeting NS, particularly MAP and asociality, in improving HRQoL in schizophrenia.

Investigation of momentary negative symptoms in patients with early psychosis in daily life: An experience sampling study.

Negative symptoms are a key therapeutic target in promoting functional recovery in early psychosis intervention, but momentary negative symptom manifestations remain understudied in the early stage of illness. We employed an experience-sampling methodology (ESM) to evaluate momentary affective experiences, hedonic capacity for an event recalled, current activities and social interactions, and associated appraisals for 6 consecutive days in 33 clinically-stable early psychosis patients (within 3 years of treatment for first-episode psychosis) and 35 demographically-matched healthy controls. Adjusted multilevel linear-mixed models revealed higher intensity and variability of negative affect in patients than controls, but no group difference in affect instability as well as positive affect intensity and variability. Patients demonstrated no significantly greater anhedonia for event, activity or social interactions relative to controls. Higher preference for company (when alone) and to be alone (when in company) was observed in patients than controls. No significant group difference in pleasantness to be alone or proportion of time being alone. Our results indicate no evidence for blunting of affective experiences, anhedonia (social and non-social) and asociality in early psychosis. Future research complementing ESM with multiple digital phenotyping measures will facilitate more refined negative symptom assessment in the daily life of patients with early psychosis.

Negative Symptom Inventory-Self-Report (NSI-SR): Initial development and validation.

Negative symptoms (i.e., anhedonia, avolition, asociality, blunted affect, alogia) are frequently observed in the schizophrenia-spectrum (SZ) and associated with functional disability. While semi-structured interviews of negative symptoms represent a gold-standard approach, they require specialized training and may be vulnerable to rater biases. Thus, brief self-report questionnaires measuring negative symptoms may be useful. Existing negative symptom questionnaires demonstrate that this approach may be promising in schizophrenia, but no measure has been devised for use across stages of psychotic illness. The present study reports initial psychometric validation of the Negative Symptom Inventory-Self-Report (NSI-SR), the self-report counterpart of the Negative Symptom Inventory-Psychosis Risk clinical interview. The NSI-SR is a novel transphasic negative symptoms measure assessing the domains of anhedonia, avolition, and asociality. The NSI-SR and related measures were administered to two samples: 1) undergraduates (n = 335), 2) community participants, including: SZ (n = 32), clinical-high risk for psychosis (CHR, n = 25), and healthy controls matched to SZ (n = 31) and CHR (n = 30). The psychometrically trimmed 11-item NSI-SR showed good internal consistency and a three-factor solution reflecting avolition, asociality, and anhedonia. The NSI-SR demonstrated convergent validity via moderate to large correlations with clinician-rated negative symptoms and related constructs in both samples. Discriminant validity was supported by lower correlations with positive symptoms in both samples; however, correlations with positive symptoms were still significant. These initial psychometric findings suggest that the NSI-SR is a reliable and valid brief questionnaire capable of measuring negative symptoms across phases of psychotic illness.

Discrepancies between ideal and actual affect in schizophrenia: Implications for understanding negative symptoms.

Anhedonia is a core symptom of schizophrenia (SZ). However, psychological mechanisms underlying anhedonia are unclear, making it difficult to develop personalized psychosocial treatments. The current study explored the novel hypothesis that anhedonia is driven by discrepancies between ideal and actual affect (i.e., how positive or negative someone wants to feel compared to how they do feel), which impact the frequency of recreational, goal-directed, and social behaviors. Participants included 32 outpatients with SZ and 29 healthy controls (CN) who completed the Affect Valuation Index and measures of negative symptom severity. Results indicated that individuals with SZ displayed greater positive and negative emotion discrepancy scores than CN, suggesting that they strongly desire to feel more positive and less negative in the future than they actually do. Additionally, greater ideal relative to actual positive and negative affect was associated with greater severity of anhedonia, avolition, and asociality. The discrepancy between ideal and actual affective states may be demotivating, leading individuals with SZ to develop dysfunctional beliefs after repeated experiences of failing to achieve their desired emotional goal state. These findings suggest that ideal affect may be a novel psychological mechanism underlying negative symptoms that could be targeted in psychosocial treatments.

Association of negative symptom domains and other clinical characteristics of schizophrenia on long-term hospitalization.

Background: Recent studies suggest five domains for negative schizophrenia symptoms: anhedonia, asociality, avolition, blunted affect, and alogia. Avolition has been considered a characteristic symptom in community-dwelling patients. However, few studies have explored the association of these symptoms with long-term hospitalization. Purpose: This study explored the relative association of each of the five domains of negative symptoms in two groups of patients with schizophrenia: long-term hospitalized and community-dwelling patients. Methods: Participants included 56 long-term inpatients and 111 community-dwelling patients at Nasukougen Hospital in Japan. The nearest neighbor matching within caliper was used. After matching participants by age, sex, disease duration, and years of education, each group was assigned 30 participants. Model 1 was analyzed with a logistic regression analysis with 5 subdomains as independent variables. Model 2 was analyzed after adding positive symptoms, cognitive function, functional skills, and functional outcomes to the subdomains that were significant in model 1. Results: The results indicated that asociality was significantly associated with long-term hospitalization. When the characteristic clinical factors of schizophrenia were added, asociality, daily living skills, and social and role functions were found to be characteristic of long-term hospitalization. Among the negative symptoms, lack of social motivation was more characteristic among the group with a poor prognosis. Conclusions: Of the negative symptoms associated with long-term hospitalization, asociality, lack of social motivation, rather than avolition was found to be most strongly associated with community-dwelling patients' functional outcomes. Further studies are required to establish a causal association as it may have therapeutic implications.

Social preference in Roman rats: Age and sex variations relevance for modeling negative schizophrenia-like features.

Social withdrawal is one of the most relevant negative symptoms of schizophrenia. Animal models that mimic schizophrenia's symptoms, in general, and negative symptoms, in particular, are difficult to develop because of the high complexity of symptoms and neurochemical disturbances that schizophrenia patients display throughout their lives. In recent years we have shown that Roman High-Avoidance (RHA) rats exhibit some phenotypes that are thought to represent positive symptoms, cognitive/attentional symptoms, as well as some negative symptoms of the disease. In the present study, we aimed at elucidating whether the social interaction (SI) deficits exhibited by adult male RHA rats, compared to their Roman Low-Avoidance (RLA) counterparts, are also present during adolescence, as well as whether there are between-strain differences in adolescent and adult female rats. The results of the present study show that adult male RHA rats exhibited a deficit in social preference compared to their RLA counterparts. Such a deficit was not observed in adolescent RHA rats or female rats of any age. The results also show that the adult male rats of both strains had significant decreases in social preference compared to the adolescent male rats. Additionally, we also show that female adult RHA rats have greater social preference than their male counterparts. These results seem to be in line with previous rodent and human studies and add face validity to the RHA rats as a model of schizophrenia.

Two Factors, Five Factors, or Both? External Validation Studies of Negative Symptom Dimensions in Schizophrenia.

OBJECTIVES: Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms. METHODS: Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3). RESULTS: SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions-anhedonia, asociality, avolition, blunted affect, and alogia-proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions-motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples. CONCLUSIONS: Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints.

Reprint of: A review of negative symptom assessment strategies in youth at clinical high-risk for psychosis.

Studies attempting to deconstruct the heterogeneity of schizophrenia and the attenuated psychosis syndrome consistently find that negative symptoms are a core dimension that is distinct from other aspects of the illness (e.g., positive and disorganized symptoms). Negative symptoms are also highly predictive of poor community-based functional outcomes, suggesting they are a critical treatment target. Unfortunately, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet therapeutic need, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. A primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Although second-generation rating scales were developed for adults with schizophrenia, progress in this area has lagged behind for youth at clinical-high risk (CHR) for developing psychosis (i.e. those meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in CHR youth is paramount. The current paper discusses conceptual and methodological limitations inherent to existing scales that assess negative symptoms in CHR youth. The theoretical and clinical implications of these limitations are evaluated. It is concluded that new scales specifically designed to assess negative symptoms in CHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. Recent efforts to develop next-generation measures designed specifically for CHR youth to meet this urgent need in the field are discussed. These new approaches offer significant progress for addressing issues inherent to earlier scales.