The effects of the COVID-19 pandemic on hallucinations and delusions in youth at clinical high-risk for psychosis and outpatients with schizophrenia.

Although the COVID-19 pandemic has had detrimental effects on mental health in the general population, the impact on those with schizophrenia-spectrum disorders has received relatively little attention. Assessing pandemic-related changes in positive symptoms is particularly critical to inform treatment protocols and determine whether fluctuations in hallucinations and delusions are related to telehealth utilization and treatment adherence. In the current longitudinal study, we evaluated changes in the frequency of hallucinations and delusions and distress resulting from them across three-time points. Participants included: (1) outpatients with chronic schizophrenia (SZ: n = 32) and healthy controls (CN: n = 31); (2) individuals at clinically high risk for psychosis (CHR: n = 25) and CN (n = 30). A series of questionnaires were administered to assess hallucination and delusion severity, medication adherence, telehealth utilization, and protective factors during the pandemic. While there were no significant increases in the frequency of hallucinations and delusions in SZ and CHR, distress increased from pre-pandemic to early pandemic in both groups and then decreased at the third time point. Additionally, changes in positive symptom severity in SZ were related to psychiatric medication adherence. Findings suggest that positive symptoms are a critical treatment target during the pandemic and that ongoing medication services will be beneficial.

The impact of the COVID-19 pandemic on negative symptoms in individuals at clinical high-risk for psychosis and outpatients with chronic schizophrenia.

Negative symptoms are core features of schizophrenia-spectrum disorders that are frequently observed across all phases of illness. By their nature, COVID-19 social isolation, physical distancing, and health precautions induce behavioural aspects of negative symptoms. However, it is unclear whether these prevention measures also lead to increases in experiential negative symptoms, whether such effects are equivalent across individual negative symptom domains, and if exacerbations occur equivalently across phases of illness. The current study compared negative symptom severity scores obtained during the pandemic to pre-pandemic assessments in two samples: (1) outpatients with chronic schizophrenia (SZ: n = 32) and matched healthy controls (CN: n = 31) and (2) individuals at clinical high risk for psychosis (CHR: n = 25) and matched CN (n = 30). Pre-pandemic ratings of negative symptoms were clinically elevated in SZ and CHR groups, which did not differ from each other in severity. In SZ, ratings obtained during the pandemic were significantly higher than pre-pandemic ratings for all 5 domains (alogia, blunted affect, anhedonia, avolition, and asociality) and item-level analyses indicated that exacerbations occurred on both experiential and behavioral symptoms of anhedonia, avolition, and asociality. In contrast, CHR only exhibited increases in anhedonia and avolition items during the pandemic compared to pre-ratings. Findings suggest that negative symptoms should be a critical treatment target during and after the pandemic in the schizophrenia spectrum given that they are worsening and critically related to risk for conversion, functional outcome, and recovery.

Racial differences in attenuated psychotic symptoms during the COVID-19 pandemic.

AIM: Rates of attenuated psychotic symptoms (APS) have increased during the COVID-19 pandemic; however, it is unclear whether this is most evident among individuals from marginalized racial groups. METHODS: The current study evaluated APS screening data across a six-year period in the state of Georgia in the United States, spanning several years prior to and during the COVID-19 pandemic to evaluate interactions between time and race. Participants included 435 clinical help-seeking individuals. RESULTS: The rate of individuals scoring above the APS screening cut-off was higher during the pandemic compared to pre-pandemic (41% vs 23%). This pandemic-related increase in APS was significant for Black, but not White or Asian participants. CONCLUSIONS: Findings indicate APS are increasing during the COVID-19 pandemic among clinical help-seeking populations. Black individuals may be at greater risk for developing a psychotic disorder during the pandemic, suggesting increased need for screening, mental health monitoring, and treatment.

Network intervention analysis indicates that roluperidone achieves its effect on negative symptoms of schizophrenia by targeting avolition.

Roluperidone, a 5-HT2A, sigma2, and ɑ1A-adrenergic receptor antagonist, has proven efficacious for treating negative symptoms of schizophrenia in phase 2b and phase 3 clinical trials. Using network analysis, we demonstrated that the improvements observed in the phase 2b trial resulted from targeting avolition which was highly central and spurred a cascading effect of global negative symptom reductions when successfully treated. The current study aims to replicate these network findings using the phase 3 roluperidone clinical trial data. Participants included 496 schizophrenia patients with moderate to severe negative symptoms who were randomized to either roluperidone 32 mg/day (n =167), 64 mg/day (n = 162), or placebo (n = 167). Negative symptoms were assessed at baseline and weeks 2,4,8, and 12. Network intervention analysis (NIA) evaluated treatment-induced symptom changes over time to identify direct and indirect treatment effects. This analytic approach extends prior work by determining whether the symptoms with highest centrality have causal effects on the entire negative symptom construct and directly lead to symptom improvement. NIA indicated that the efficacious 64 mg/day dose of roluperidone had a direct effect on avolition, suggesting that changes in avolition propels treatment effects across the entire negative symptom constellation. These phase 3 findings replicated the phase 2b findings, indicating that from a network perspective, roluperidone achieves its effect by influencing the extent to which avolition drives other negative symptoms. These findings are relevant for understanding negative symptoms and how to treat them in neuropsychiatric disorders.

CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.

Environmental resource reductions predict greater severity of negative symptoms in schizophrenia.

No pharmacological or psychosocial interventions effectively treat negative symptoms in schizophrenia (SZ), despite the identification of biological and psychological mechanistic targets. Limited treatment progress may result from failure to account for non-person-level environmental factors that present barriers to performing recreational, social, and goal-directed activities. The bioecosystem model of negative symptoms proposes that four interactive ecosystems (i.e. microsystem, mesosystem, exosystem, and macrosystem) influence person-level factors (e.g., dysfunctional beliefs, glutamate, cortico-striatal functioning) to initiate and maintain negative symptoms. The current study tested this hypothesis by examining whether indirect environmental factors (e.g., access to resources for performing activities in the built environment) were associated with dysfunctional beliefs (defeatist performance, asocial, anhedonic) and negative symptoms (anhedonia, avolition, asociality). Self-reports of indirect environmental factors (i.e., the built environment), dysfunctional beliefs, and negative symptoms were collected from 31 individuals with SZ and 29 matched healthy controls. Mediation analyses were conducted with dysfunctional beliefs as the predictor, indirect environmental factors as mediator, and negative symptoms as the outcome. Individuals with SZ reported reduced access to environmental resources for performing recreational, goal-directed, and social activities; these reductions were associated with greater negative symptom severity. Mediation analyses indicated that the effect of dysfunctional beliefs on negative symptoms was mediated by participants' satisfaction with resources for performing activities in their environment. These findings suggest that psychosocial treatments could be augmented to not only target dysfunctional beliefs, but also environmental processes that lead these beliefs to emerge and contribute to negative symptoms.

Beliefs About the Uncontrollability and Usefulness of Emotion in the Schizophrenia-Spectrum: Links to Emotion Regulation and Negative Symptoms.

Background: Beliefs about the usefulness and controllability of emotions are associated with emotion regulation and psychological distress in the general population. Although individuals with schizophrenia-spectrum disorders evidence emotion regulation abnormalities, it is unclear whether emotional beliefs contribute to these difficulties and their associated poor clinical outcomes. Methods: Participants included 72 individuals with schizophrenia-spectrum diagnoses (outpatients with schizophrenia n = 38; youth at clinical high-risk for psychosis, n = 34) and healthy controls (CN: n = 61) who completed the Emotional Beliefs Questionnaire, Emotion Regulation Questionnaire, and measures of clinical symptom severity. Results: Those with schizophrenia-spectrum diagnoses reported believing that emotions were less controllable than CN; however, groups did not differ regarding beliefs about the usefulness of emotion. Greater beliefs of the uncontrollability of emotion were associated with greater use of suppression, less use of reappraisal, and increased negative symptoms. Emotion regulation partially mediated the association between emotional beliefs and negative symptoms. Conclusions: Individuals in the schizophrenia-spectrum display superordinate beliefs that emotions are uncontrollable. These beliefs may influence emotion regulation strategy selection and success, which contributes to negative symptoms. Findings suggest that beliefs of emotional uncontrollability reflect a novel process related to both emotion regulation and negative symptoms that could be targeted in psychosocial treatments. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10357-w.

Deconstructing emotion regulation in schizophrenia: The nature of abnormalities at the selection and implementation stages.

Difficulties with emotion regulation are observed across psychiatric diagnoses, including psychotic disorders. Past studies using trait self-report indicate that people with schizophrenia (SZ) are less likely to use adaptive emotion regulation strategies and more likely to use maladaptive emotion regulation strategies than controls (CN). However, more recent evidence using ecological momentary assessment (EMA) indicates that regulation effectiveness and adaptiveness may vary across strategies. The present study aimed to systematically understand abnormalities in state-level emotion regulation strategy selection, effectiveness, and adaptiveness in SZ compared to CN using EMA. Participants (n = 50 SZ; n = 53 CN) completed 6 days of EMA surveys assessing emotional experience, emotion regulation, and symptoms. Results indicated that SZ selected interpersonal emotion regulation and avoidance more often than CN, while both groups selected reappraisal and distraction more often than avoidance and suppression. Overall, strategies were effective at reducing negative emotion and adaptive for reducing delusions over time. Reappraisal, avoidance, and suppression all significantly down-regulated delusions over time. Although some selection abnormalities were present in terms of rate of selection and effort exertion, people with SZ select strategies which are effective and adaptive in the short term. The present results have implications for how cognitive therapy for psychosis may target delusions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The association between early traumatic experiences and the five domains of negative symptoms in participants at clinical high risk for psychosis.

AIM: Youth at clinical high risk (CHR) for psychosis have high rates of early life trauma, but it is unclear how trauma exposure impacts later negative symptom severity in CHR. The current study examined the association between early childhood trauma and the five domains of negative symptoms (anhedonia, avolition, asociality, blunted affect, alogia). METHOD: Eighty nine participants completed interviewer-rated measures of childhood trauma and abuse experienced before age 16, psychosis risk, and negative symptoms. RESULTS: Higher global negative symptom severity was associated with greater exposure to childhood psychological bullying, physical bullying, emotional neglect, psychological abuse, and physical abuse. Greater severity of avolition and asociality was associated with physical bullying. Greater severity of avolition was associated with emotional neglect. CONCLUSION: Early adversity and childhood trauma is associated with negative symptoms during adolescence and early adulthood among participants at CHR for psychosis.

Development and Validation of the Negative Symptom Inventory-Psychosis Risk.

BACKGROUND AND HYPOTHESES: Early identification and prevention of psychosis is limited by the availability of tools designed to assess negative symptoms in those at clinical high-risk for psychosis (CHR). To address this critical need, a multi-site study was established to develop and validate a clinical rating scale designed specifically for individuals at CHR: The Negative Symptom Inventory-Psychosis Risk (NSI-PR). STUDY DESIGN: The measure was developed according to guidelines recommended by the NIMH Consensus Conference on Negative Symptoms using a transparent, iterative, and data-driven process. A 16-item version of the NSI-PR was designed to have an overly inclusive set of items and lengthier interview to support the ultimate intention of creating a new briefer measure. Psychometric properties of the 16-item NSI-PR were evaluated in a sample of 218 CHR participants. STUDY RESULTS: Item-level analyses indicated that men had higher scores than women. Reliability analyses supported internal consistency, inter-rater agreement, and temporal stability. Associations with measures of negative symptoms and functioning supported convergent validity. Small correlations with positive, disorganized, and general symptoms supported discriminant validity. Structural analyses indicated a 5-factor structure (anhedonia, avolition, asociality, alogia, and blunted affect). Item response theory identified items for removal and indicated that the anchor range could be reduced. Factor loadings, item-level correlations, item-total correlations, and skew further supported removal of certain items. CONCLUSIONS: These findings support the psychometric properties of the NSI-PR and guided the creation of a new 11-item NSI-PR that will be validated in the next phase of this multi-site scale development project.

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.

Digital phenotyping adherence, feasibility, and tolerability in outpatients with schizophrenia.

Digital phenotyping has potential for use as an objective and ecologically valid form of symptom assessment in clinical trials for schizophrenia. However, there are critical methodological factors that must be addressed before digital phenotyping can be used for this purpose. The current study evaluated levels of adherence, feasibility, and tolerability for active (i.e., signal and event contingent ecological momentary assessment surveys) and passive (i.e., geolocation, accelerometry, and ambulatory psychophysiology) digital phenotyping methods recorded from smartphone and smartband devices. Participants included outpatients diagnosed with schizophrenia (SZ: n = 54) and demographically matched healthy controls (CN: n = 55), who completed 6 days of digital phenotyping. Adherence was significantly lower in SZ than CN for active recordings, but not markedly different for passive recordings. Some forms of passive recordings had lower adherence (ambulatory psychophysiology) than others (accelerometry and geolocation). Active digital phenotyping adherence was predicted by higher psychosocial functioning, whereas passive digital phenotyping adherence was predicted by education, positive symptoms, negative symptoms, and psychosocial functioning in people with SZ. Both groups found digital phenotyping methods tolerable and feasibility was supported by low frequency of invalid responding, brief survey completion times, and similar impediments to study completion. Digital phenotyping methods can be completed by individuals with SZ with good adherence, feasibility, and tolerability. Recommendations are provided for using digital phenotyping methods in clinical trials for SZ.

The Latent Structure of Negative Symptoms in Individuals With Attenuated Psychosis Syndrome and Early Psychosis: Support for the 5 Consensus Domains.

Negative symptoms are prevalent in the prodromal and first-episode phases of psychosis and highly predictive of poor clinical outcomes (eg, liability for conversion and functioning). However, the latent structure of negative symptoms is unclear in the early phases of illness. Determining the latent structure of negative symptoms in early psychosis (EP) is of critical importance for early identification, prevention, and treatment efforts. In the current study, confirmatory factor analysis was used to evaluate latent structure in relation to 4 theoretically derived models: 1. a 1-factor model, 2. a 2-factor model with expression (EXP) and motivation and pleasure (MAP) factors, 3. a 5-factor model with separate factors for the 5 National Institute of Mental Health (NIMH) consensus development conference domains (blunted affect, alogia, anhedonia, avolition, and asociality), and 4. a hierarchical model with 2 second-order factors reflecting EXP and MAP, as well as 5 first-order factors reflecting the 5 consensus domains. Participants included 164 individuals at clinical high risk (CHR) who met the criteria for a prodromal syndrome and 377 EP patients who were rated on the Brief Negative Symptom Scale. Results indicated that the 1- and 2-factor models provided poor fit for the data. The 5-factor and hierarchical models provided excellent fit, with the 5-factor model outperforming the hierarchical model. These findings suggest that similar to the chronic phase of schizophrenia, the latent structure of negative symptom is best conceptualized in relation to the 5 consensus domains in the CHR and EP populations. Implications for early identification, prevention, and treatment are discussed.

Geolocation as a Digital Phenotyping Measure of Negative Symptoms and Functional Outcome.

OBJECTIVE: Negative symptoms and functional outcome have traditionally been assessed using clinical rating scales, which rely on retrospective self-reports and have several inherent limitations that impact validity. These issues may be addressed with more objective digital phenotyping measures. In the current study, we evaluated the psychometric properties of a novel "passive" digital phenotyping method: geolocation. METHOD: Participants included outpatients with schizophrenia or schizoaffective disorder (SZ: n = 44), outpatients with bipolar disorder (BD: n =19), and demographically matched healthy controls (CN: n = 42) who completed 6 days of "active" digital phenotyping assessments (eg, surveys) while geolocation was recorded. RESULTS: Results indicated that SZ patients show less activity than CN and BD, particularly, in their travel from home. Geolocation variables demonstrated convergent validity by small to medium correlations with negative symptoms and functional outcome measured via clinical rating scales, as well as active digital phenotyping behavioral indices of avolition, asociality, and anhedonia. Discriminant validity was supported by low correlations with positive symptoms, depression, and anxiety. Reliability was supported by good internal consistency and moderate stability across days. CONCLUSIONS: These findings provide preliminary support for the reliability and validity of geolocation as an objective measure of negative symptoms and functional outcome. Geolocation offers enhanced precision and the ability to take a "big data" approach that facilitates sophisticated computational models. Near-continuous recordings and large numbers of samples may make geolocation a novel outcome measure for clinical trials due to enhanced power to detect treatment effects.