Impact of Negative Symptom Domains and Other Clinical Characteristics on Functional Outcomes in Patients with Schizophrenia.

Clinicians and researchers consider that there are a variety of symptoms that constitute negative symptoms in schizophrenia, and they may use different definitions for the same symptoms. These differences are also reflected in a variety of negative symptom rating scales. Both research and clinical work are negatively affected by the lack of consensus regarding the symptoms that constitute negative symptoms in schizophrenia. Leading research groups have investigated ways to reduce heterogeneity in the domain of negative symptoms in schizophrenia; however, little attention has been paid to regional differences in the concepts of negative symptoms in schizophrenia. The objective of this review was to collect and summarize information about the assessment and treatment of negative symptoms of schizophrenia in Central and Eastern Europe (CEE). Nineteen experts from 17 countries in CEE participated in this project. The participants collected information about their countries, including the following: (1) the most important publications about negative symptoms in schizophrenia (irrespective of the time of their publication); (2) the most frequently used negative symptom of schizophrenia in clinical practice; (3) definitions of frequently used negative symptoms; and (4) treatment of negative symptoms in schizophrenia. The participating experts/countries most frequently reported the following five negative symptoms: avolition, blunted affect, alogia, asociality, and anhedonia. Several experts also considered other symptoms as belonging to the negative symptom domain, such as a decrease in energy level and changes in personality. The importance of evaluating the long-term course and the relationship between negative symptoms and other symptom domains was also noted. No noticeable differences were reported in the treatment of negative symptoms compared to currently published guidelines and algorithms. The most frequently reported negative symptoms included those defined by the NIMH-MATRICS consensus statement on negative symptoms and recently endorsed in a guidance paper of the European Psychiatric Association. The main differences in the concepts, names, and definitions of primary negative symptoms, especially those related to personality changes, and to the evaluation of the long-term course and relationship between different symptom domains in CEE compared to the current English language literature deserve the attention of psychiatrists and other professionals in this field.

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.

Type 2 diabetes mellitus (T2DM) and impaired glucose metabolism are more prevalent among patients with schizophrenia than in the general population. The incidence of T2DM is associated with lifestyle factors that are often influenced by the negative symptoms of schizophrenia; comorbid T2DM may contribute to the reduced life expectancy observed in patients with schizophrenia. The existing literature reveals a scarcity of data regarding the potential causal relationship between T2DM and negative symptoms. A scoping review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, utilizing the PubMed database to identify clinical studies investigating the association between T2DM and the negative (but not cognitive) symptom domain of schizophrenia. Subsequently, the reference lists of these identified publications were searched. Seventeen publications were included. There is evidence supporting the association between impaired glucose tolerance and increased negative symptoms in patients with first-episode psychosis, and several studies indicate that poorer glucose metabolic status correlates with more severe negative symptoms. Patients with T2DM and chronic schizophrenia, however, had milder negative symptom scores compared to those without diabetes, although this association was less pronounced than in early disease stages. There is insufficient confirmatory evidence regarding the potential causality of T2DM on the negative symptoms of schizophrenia. Further, preferably prospective studies are needed to explore the complex and potentially causal relationship between T2DM and negative symptoms of schizophrenia. If T2DM were found to have a causal relationship with negative symptoms or to exacerbate pre-existing symptoms, it could lead to significant changes in therapeutic approaches for schizophrenia.

Despite the clinical relevance of negative symptoms in schizophrenia, our understanding of negative symptoms remains limited. Although various courses and stages of schizophrenia have been identified, variations in the negative symptom networks between distinct stages of schizophrenia remain unexplored. We examined 405 patients with early schizophrenia (ES) and 330 patients with chronic schizophrenia (CS) using the Scale for the Assessment of Negative Symptoms. Network analysis and exploratory graph analysis were used to identify and compare the network structures and community memberships of negative symptoms between the two groups. Further, associations between communities and social functioning were evaluated. The potential influences of other symptom domains and confounding factors were also examined. Multidimensional differences were found in the networks of negative symptoms between ES and CS. The global connectivity strength was higher in the network of ES than in the network of CS. In ES, central symptoms were mainly related to expressive deficits, whereas in CS they were distributed across negative symptom domains. A three-community structure was suggested across stages but with different memberships and associations with social functioning. Potential confounding factors and symptom domains, including mood, positive, disorganization, and excitement symptoms, did not affect the network structures. Our findings revealed the presence of stage-specific network structures of negative symptoms in schizophrenia, with negative symptom communities having differential significance for social functioning. These findings provide implications for the future development of tailored interventions to alleviate negative symptoms and improve functionality across stages.

Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions. To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up. Adult psychiatric services, treating people with schizophrenia. Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity. Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study. The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich's Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale. No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference -1.3, 95% confidence interval -2.5 to -0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation. The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies. Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge. European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2009-009235-30 and Current Controlled Trials ISRCTN42305247. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 29. See the NIHR Journals Library website for further project information.

A-172 Evaluating Associations Between the Five Negative Symptom Domains and Cognition in Schizophrenia

Clinical symptoms, mainly negative symptoms, mediate the influence of neurocognition and social cognition on functional outcome of schizophrenia

Background: Early-onset psychosis (EOP) is among the leading causes of disease burden in adolescents. Negative symptoms and cognitive deficits predicts poorer functional outcome. A better understanding of the association between negative symptoms and cognitive impairment may inform theories on underlying mechanisms and elucidate targets for development of new treatments. Two domains of negative symptoms have been described in adult patients with schizophrenia: apathy and diminished expression, however, the factorial structure of negative symptoms has not been investigated in EOP. We aimed to explore the factorial structure of negative symptoms and investigate associations between cognitive performance and negative symptom domains in adolescents with EOP. We hypothesized that (1) two negative symptom factors would be identifiable, and that (2) diminished expression would be more strongly associated with cognitive performance, similar to adult psychosis patients.Methods: Adolescent patients with non-affective EOP (n = 169) were included from three cohorts: Youth-TOP, Norway (n = 45), Early-Onset Study, Norway (n = 27) and Adolescent Schizophrenia Study, Mexico (n = 97). An exploratory factor analysis was performed to investigate the underlying structure of negative symptoms (measured with the Positive and Negative Syndrome Scale (PANSS)). Factor-models were further assessed using confirmatory factor analyses. Associations between negative symptom domains and six cognitive domains were assessed using multiple linear regression models controlling for age, sex and cohort. The neurocognitive domains from the MATRICS Consensus Cognitive Battery included: speed of processing, attention, working memory, verbal learning, visual learning, and reasoning and problem solving.Results: The exploratory factor analysis of PANSS negative symptoms suggested retaining only a single factor, but a forced two factor solution corroborated previously described factors of apathy and diminished expression in adult-onset schizophrenia. Results from confirmatory factor analysis indicated a better fit for the two-factor model than for the one-factor model. For both negative symptom domains, negative symptom scores were inversely associated with verbal learning scores.Conclusion: The results support the presence of two domains of negative symptoms in EOP; apathy and diminished expression. Future studies on negative symptoms in EOP should examine putative differential effects of these symptom domains. For both domains, negative symptom scores were significantly inversely associated with verbal learning.

The interaction between positive, negative and depressive symptoms experienced by people with schizophrenia is complex. We used longitudinal data to test the hypothesis that depressive symptoms mediate the links between positive and negative symptoms. We analyzed data from the European Schizophrenia Cohort, randomly sampled from outpatient services in France, Germany and the UK (N = 1208). Initial measures were repeated after 6 and 12 months. Depressive symptoms were identified using the Calgary Depression Scale for Schizophrenia (CDSS), while positive and negative symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Latent variable structural equation modelling was used to investigate the mediating role of depression assessed at 6 months in relation to the longitudinal association between positive symptoms at baseline and negative symptoms at 12 months. We found longitudinal associations between positive symptoms at baseline and negative symptoms at 12 months, as well as between both of these and CDSS levels at 6 months. However depression did not mediate the longitudinal association between PANSS scores; all the effect was direct. Our findings are incompatible with a mediating function for depression on the pathway from positive to negative symptoms, at least on this timescale. The role of depression in schizophrenic disorders remains a challenge for categorical and hierarchical diagnostic systems alike. Future research should analyze specific domains of both depressive and negative symptoms (e.g. motivational and hedonic impairments). The clinical management of negative symptoms using antidepressant treatments may need to be reconsidered.

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

AimsTraditional antipsychotic treatment improves positive symptoms in schizophrenia but has little impact on negative and cognitive symptoms. TMS is a non-invasive neuromodulation technique which has been suggested to impact negative and cognitive symptoms of schizophrenia. This systematic review critically appraised the research evaluating the effect of TMS on negative and cognitive symptoms of schizophrenia. Furthermore, we carried out a meta-analysis of randomised controlled trials of the effect of TMS on negative symptoms in schizophrenia.MethodsSystematic review was carried out according to PRISMA guidelines. Cochrane Library, Ovid Medline, Science Direct and PubMed databases were searched for relevant studies using the search terms: “transcranial magnetic stimulation” OR “TMS” OR “repetitive transcranial magnetic stimulation” OR “r-TMS” OR “theta burst stimulation” OR “TBS” AND “negative symptoms” OR “cognitive dysfunction” OR “cognitive impairment” AND “schizophrenia” OR “psychosis”. Only randomised controlled trials evaluating the effect of TMS (rTMS or iTBS, intermittent theta burst) on negative and/or cognitive symptoms in schizophrenia were selected. Thirty-three studies were included in the systematic review. The Standardised mean difference (SMD) with 95% confidence interval (CI) was calculated for each study and pooled across studies using an inverse variance random effect model.ResultsSixteen studies demonstrated significant improvement in negative symptoms with a superior effect of TMS compared with sham intervention. Eight studies showed improvement in certain domains of cognition and one study showed a delayed effect on negative symptoms. Studies which showed positive effects on negative symptoms have used similar TMS parameters such as 10 Hz over L-DLPFC (Left dorsolateral prefrontal cortex) except for a few studies. Ten studies reported negative results for negative and/or cognitive symptoms, TMS parameters and duration of treatment used varied among these studies. Overall, SMD for SANS (Scale for Assessment of Negative Symptoms) was 0.89 (95%CI: 0.46–1.32, P < 0.00001) and for PANSS-N (Positive and Negative Syndrome scale-negative) was 0.67 (95%CI: 0.22–1.12, P < 0.00001), both in favour of TMS. The heterogeneity of the included studies was high, I2- 85% for SANS and 92% for the PANSS-N subscale with a small to moderate risk of publication bias.ConclusionHigh-frequency rTMS is more effective than sham in improving negative and cognitive symptoms in schizophrenia. Our results suggest the need for well-designed randomised controlled trials with larger sample sizes and standard harmonised cognitive assessments to assess the effect of TMS on negative and cognitive symptoms to provide sufficient evidence for inclusion in routine clinical practice.

BackgroundThere are currently no treatment options for key symptom domains in certain psychiatric and neurological diseases. For example, antipsychotics effectively treat the positive symptoms of schizophrenia, however both the cognitive impairments associated with schizophrenia (CIAS) and negative symptoms, both key predictors of functional outcome, are not treated by current therapies. Additionally, psychotic symptoms associated with neurological diseases such as Alzheimer’s Disease (AD) are not adequately treated with current antipsychotics. Therefore, novel mechanisms to address these unmet medical needs are urgently required and are under investigation.GPR52 is a Gs-coupled orphan g-protein coupled receptor which has an intriguing pattern of brain expression. In cortex, GPR52 is expressed primarily on glutamatergic neurons and co-localized with the Gs-coupled D1 receptor (D1R). Deficiencies in D1R activation are associated with both cognitive deficit and negative symptoms of schizophrenia. In contrast, in the striatum, GPR52 is almost exclusively co-expressed with the Gi-coupled D2 receptor (D2R), which mediates the reduction in positive symptoms by antipsychotics. Based on GPR52’s functional coupling and co-localization, agonists may be predicted to resemble D1R agonists in cortical regions, thus treating cognitive or negative symptoms, while resembling D2R antagonists in striatal regions. Thus, GPR52 agonists have the potential to provide a novel therapeutic strategy for the currently untreated CIAS and negative symptom domains in addition to the psychotic symptoms of AD.MethodsTo assess the antipsychotic potential of GPR52 agonists, they were tested for their ability to decrease psychostimulant-induced hyperlocomotion. The efficacy of GPR52 agonists for CIAS and sociability, an aspect of negative symptoms, was assessed in the sub-chronic phencyclidine (scPCP) model for schizophrenia, known to induce long-lasting cognitive and social behaviour deficits, in addition to a reduction in parvalbumin-positive GABAergic interneurons in hippocampus and pre-frontal cortex. Rats were treated with PCP twice daily for 7 days followed by 7 days washout and then tested in the attentional set shifting task (ASST) for executive function and the social interaction test for sociability respectively following treatment with a GPR52 agonist.ResultsGPR52 agonist 1 dose-dependently reversed psychostimulant-induced hyperlocomotion in rats at doses which were behaviorally quiescent when administered alone. Additionally, GPR52 agonist 2 showed a robust, dose-dependent rescue of scPCP induced deficits in the extra dimensional shift phase of the ASST, achieving significance after a 4 mg/kg p.o. application. Likewise, GPR52 agonist 2 significantly rescued scPCP induced deficits in social interaction at identical doses as in ASST without effects on object exploration or locomotor activity.DiscussionGPR52 agonists were efficacious in animal models assessing the three main symptoms domains associated with schizophrenia. Efficacy in ASST and SI demonstrate both pro-cognitive efficacy and restoration of an aspect of negative symptoms, respectively, in a well-established model inducing behavioral and neuropathological deficits associated with schizophrenia. Furthermore, GPR52 agonists reduced psychostimulant-induced hyperlocomotion, an effect associated with antipsychotic efficacy. Taken together, these data demonstrate the potential of this innovative mechanism to simultaneously treat the three core symptoms domains of schizophrenia as well as potentially treat the psychotic symptoms associated with other neurological disorders.

IntroductionIn patients with schizophrenia, numerous studies have shown a relationship between negative symptoms and cognitive deficits (both neurocognition and social cognition deficits) and a similar impact of these domains on different clinical features such as onset, course and prognostic relevance. However, this relationship is still today subject of scientific debate.ObjectivesThe aim of the present study is to conduct a systematic review of the literature on data concerning the relationships between neurocognition and social cognition deficits and the two different domains of negative symptoms – avolition-apathy and expressive deficit.MethodsA systematic review of the literature was carried out following PRISMA guidelines and examining articles in English published in the last fifteen years (2007 - March 2022) using three different databases (Pubmed, Scopus and PsychINFO). The included studies involved subjects with one of the following diagnoses: high risk of psychosis, first episode of psychosis, or chronic schizophrenia. Other inclusion criteria of the reviewed studies included: evaluation of at least one neurocognitive or social cognition domain and at least one negative symptom using standardized scales; analysis of the relationship between at least one neurocognitive or social cognition domain and a negative symptom.ResultsDatabases search produced 8497 results. After title and abstract screening, 395 articles were selected, of which 103 met inclusion criteria. The analysis of retrieved data is still ongoing. Preliminary evidence highlighted: a correlation between social cognition and negative symptoms, in particular with the “expressive deficit” domain; a positive correlation between the severity of negative symptoms and that of neurocognitive deficits (in particular with the “processing speed” domain); an association of verbal working memory deficits with alogia and anhedonia.ConclusionsThe study of the relationship between negative symptoms, neurocognitive deficits and social cognition could contribute to the understanding of the aetiology of psychotic disorders and therefore to the identification of therapies for the improvement of overall functioning and quality of life. The studies analysed so far show some interesting associations between cognition and negative symptoms, but the presence of often inconsistent results, partially attributable to the different conceptualizations of the various domains of negative symptoms adopted, hinders the generalization of the results.Disclosure of InterestNone Declared

The chapter focuses on the relationship of negative and positive symptoms in schizophrenia. Negative symptoms should be evaluated in a relation to positive symptoms both cross-sectionally and long term (prospectively/retrospectively). Two types of long-term interaction between negative and positive symptoms could be distinguished: (1) relatively synchronized, and (2) relatively desynchronized. Synchronization of negative and positive symptoms is characterized by their unidirectional long-term course. Desynchronization is characterized by their bidirectional long-term relations: (1) negative schizophrenia with minimal positive symptoms at the beginning of the disease and further progression of negative symptoms; or (2) schizophrenia with negative symptoms ‘that stopped at the very beginning’, and the later course is characterized by positive symptoms. Considering every single time point of the long-term relationship between negative and positive symptoms (cross-sectionally), the chapter describes the concept of ‘mutual/common syndromes’ (consisting of both positive and negative symptoms) at different stages of schizophrenia, including residual deficit states.

In this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia. The Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome. One hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome. Our results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.