Characterising Negative Symptoms in Schizophrenia: CHANSS study protocol

Fluvoxamine improves negative symptoms in treated chronic schizophrenia: An add-on double-blind, placebo-controlled study

IntroductionThe prevalence of schizophrenia in the world is between 0.4 and 1.4%, and the number of patients with negative symptoms (NS) in this group reaches 90%. NS are considered key components of schizophrenia that negatively affect social functioning (SF) and quality of life in patients with schizophrenia. The purpose of the study was to determine the features of SF among patients with NS in schizophrenia.ObjectivesFeatures of SF in 252 patients with NS in schizophrenia (main group) and in 79 patients with positive symptoms (PS) in schizophrenia (comparison group) were examined.MethodsA set of methods was used: Scale of personal and social functioning (PSP), which is a semi-structured interview and allows to assess the social status of patients, their functioning and satisfaction with the relevant field and statistical methods.ResultsThe analysis of the social and personal functioning of patients was carried out in four domains: socially useful activities, personal and social relationships, attention to oneself and one’s condition, restless and aggressive behavior patterns. In the sphere of socially useful activities, including work and study, in a significant part of patients with NS in schizophrenia, SF violations were expressed at moderate (41.27 ± 1.26) % and significant (33.33 ± 1.08) % levels. In the sphere of personal and social interaction, 41.27 % of patients had significant violations, 28.97% of patients had moderate violations, and 21.83% had severe violations in the social sphere. In the field of self-care, 21.83% of patients had no violations, in 36.90% - violations in self-care were weakly expressed, and in 26.19% of people - moderately expressed.When comparing the obtained results with patients with PS in schizophrenia, it was established that among patients with NS in schizophrenia there were more patients with significant impairments in the sphere of social activity (33.33%, p = 0.033, DC = 1.42, MI = 0, 07).. Patients with NS in schizophrenia were distinguished by a greater number of patients with significant impairments in the sphere of social interaction (41.27%, p = 0.001, DC = 2.58, MI = 0.24).. In the field of self-care, there were more persons with no violations among patients with NS in schizophrenia (21.83%, p = 0.008, DC = 3.33, MI = 0.20). There were more patients with the absence and weak expression of aggressive behavior patterns among patients with NS in schizophrenia (30.95%, p = 0.0001, DC = 10.87, MI = 1.55 and 45.63%, p = 0, 0001, DC = 6.54, MI = 1.16, respectively) in comparison with patients with PS in schizophrenia.ConclusionsThe obtained data should be taken into account when creating psychocorrective programs for patients with NS in schizophrenia.Disclosure of InterestNone Declared

Negative symptoms in schizophrenia differ across environmental contexts in daily life

Background: secondary negative symptoms (SNS) in schizophrenia represent a significant clinical challenge, driven by a range of factors including depression, positive symptoms, cognitive impairments, side effects of antipsychotics, as well as social and somatic causes. Their differential diagnosis remains a complex task due to substantial clinical overlap and the lack of standardized assessment methods. The aim of review was to explore, based on an analysis of scientific publications, the mechanisms underlying the development of SNS, as well as to describe their clinical, psychopathological, and dynamic characteristics. Materials and Methods: the narrative review involved searching for and analyzing sources from databases PubMed and e-Library. A total of 93 publications relevant to the topic were included in the final analysis. Conclusion: the mechanisms behind the formation of secondary negative symptoms, as well as their clinical, psychopathological, and dynamic features depending on etiology are shown. Key differential diagnostic criteria for SNS are presented according to their origin. Based on the findings of this review, it appears that SNS can be reversible or partially reversible following the removal of secondary causes, thereby making them an important target for targeted intervention strategies.

BackgroundRecent research on the negative symptoms of schizophrenia has produced reliable and validated scales such as the Scale for the Assessment of Negative Symptoms (SANS), the Schedule for the Deficit Syndrome, the Negative Symptoms Scale of Lewine, and others (1–3). More than 30 negative symptoms have been described, among these, avolition which is considered a core negative symptom (4). The DSM-5 recognizes five main negative symptoms: blunted affect, avolition, alogia, anhedonia and asociality (5). Other researchers consider attention impairment, poor self- care, and psychomotor retardation as negative symptoms (1, 6). There is a need to derive a short list of the core negative symptoms (CNS) of schizophrenia that are reliable and useful in clinical settings and clinical research.MethodsThe Standard for Clinicians’ Interview in Psychiatry (SCIP) is a new valid and reliable diagnostic interview that was tested in an international multisite study in three countries (USA, Canada and Egypt) between 2000 and 2012 (7–10). A total of 700 patients were interviewed at William R. Sharpe Jr. Hospital in Weston, West Virginia (670 patients) and Chestnut Ridge Center in Morgantown, West Virginia (30 patients). Mean patient age was 34, 59% male, 95% White and 34% had less than 12 years of education. The SCIP includes 8 items covering the main negative symptoms of schizophrenia: avolition, blunted affect, alogia, psychomotor retardation, poor self-care, anhedonia, attention impairment, and asociality.ResultsInter-rater reliability Kappa (k) and standard error (SE) were calculated for each of the main negative symptoms: avolition (k=0.74, SE=0.04), blunted affect (k=0.68, SE=0.05), alogia (k=0.62, SE=0.05), psychomotor retardation (k=0.72, SE=0.04), poor self-care (k=0.79, SE=0.06), anhedonia (k=0.87, SE=0.04), attention impairment (k=0.92, SE=0.12), asociality (k=0.74, SE=0.04).Cronbach’s alpha for internal consistency and the mean interitem correlation (MIC) of several models were calculated. Cronbach’s alpha and the MIC of the five-factor negative dimension (blunted affect, avolition, alogia, psychomotor retardation and poor self-care) were: alpha = 0.83, MIC=0.49. The item-rest correlations (IRCs) of each of the 5 negative symptoms were: blunted affect = 0.68, avolition = 0.57, alogia = 0.67, psychomotor retardation = 0.61 and poor self-care = 0.57. The high item-rest correlations of all five negative symptoms may indicate that they represent the Core Negative Symptoms (CNS) of schizophrenia.Adding anhedonia to the five-factor model to create a six-factor model resulted in a low item-rest correlation (IRC) of anhedonia (IRC=0.06) and a lower alpha (0.76).Similarly, adding attention impairment to the five-factor model to create a six-factor model resulted in a low item-rest correlation (IRC) of attention impairment (IRC=0.02) and a lower alpha (0.75). Similarly, adding asociality to the five-factor model to create a six-factor model resulted in a low item-rest correlation (IRC) of asociality (IRC=0.05) and a lower alpha (0.75). Finally, adding anhedonia, attention impairment and asociality to the five-factor model to create an eight-factor model resulted in low IRCs for anhedonia, attention impairment and asociality (IRCs are 0.12, 0.06, 0.10 respectively) and a lower alpha (0.67).DiscussionThe Core Negative Symptoms (CNS) Scale includes five negative items. Three items (avolition, psychomotor retardation and poor self-care) have good agreement (kappa >0.7) and two items (alogia and blunted affect) have fair agreement (kappa ranges from 0.5 to 0.7). Cronbach’s alpha was also high (0.83). The CNS scale can therefore be considered reliable at the dimensional level.

Introduction. Deficits in the initiation and persistence of goal-directed behaviour are key aspects of schizophrenia. In this study, the association between these motivational deficits and discounting of reward value in function of increasing physical effort costs was investigated.Methods. Effort-based decision-making was investigated in 40 patients with a DSM-IV diagnosis of schizophrenia and 30 age- and sex-matched healthy control subjects by means of an effort discounting task. To assess negative symptom severity, we made use of the Scale for the Assessment of Negative Symptoms as well as objective measurements of hedonic response to stimuli and motor activity levels.Results. Patients as well as control subjects discounted the subjective value of rewards significantly with increasing physical effort costs. However, we failed to find a difference in the discounting curves between patients and controls. Furthermore, effort discounting was not associated with any of the negative symptoms measures.Conclusions. Physical effort discounting was not found to be associated with motivational symptoms in schizophrenia if other decision costs are constant. However, recent findings show that more cognitive effort and/or an interaction between effort and other decision costs (e.g. temporal delay or uncertainty) are associated with negative symptoms in schizophrenia. This should be investigated further in future research.

Levosulpiride versus pimozide in negative symptoms of schizophrenia

The effects of mid-late gestational maternal immune activation in rats on behaviours related to the negative and cognitive symptoms of schizophrenia

Expectancy effects and attentional control in schizophrenia

BackgroundNegative symptoms in schizophrenia (SCZ) are poorly treated and interfere with the function of patients. Studies focusing on structural and functional imaging and non-invasive electrophysiology implicate perturbations of the frontocortico-temporal circuits and disruption of cortico-striatal loops to negative symptoms in SCZ. GPR139 is an orphan GPCR that is specifically expressed in the CNS and enriched in the habenula, a brain structure involved in reward and motivation. Structural and functional alterations of the habenula have been found in SCZ patients, who show deficits in feedback processing and lack habenula activation in response to negative outcomes. Rodent experiments demonstrate the involvement of direct projection from the cortex to the habenula controlling social behavior. Alteration in habenula activity have been correlated with depression, and normalization of aberrant habenula activity has been proposed as therapeutic strategy to reverse anhedonia. Building on data previously reported at SIRS2018, we further explored modulation of GPR139 receptors and habenula circuitry in vivo as a novel mechanism to treat negative symptoms in SCZ.MethodsAnimals were submitted to an unpredictable chronic mild stress (uCMS) protocol, an animal model of depression that produces deficits in several behavioral domains affected in depressed patients. The three-chamber (Crawley’s) paradigm has been used to study social interaction in rodents. Induction of the immediate early gene c-fos expression was studied as marker for habenula neuron activation in vivo. Dopamine release in the nucleus accumbens (NAc) was studied by standard in vivo microdialysis in freely moving rats.ResultsThe selective GPR139 agonist TAK-041 increased cFOS expression in the habenula in wild type mice, but not in GPR139 knock out mice. No desensitization of cFOS in the habenula was observed after chronic dosing of TAK-041. Microdialysis studies showed that TAK-041 reduced amphetamine- and nicotine-induced dopamine release in the NAc in rats. TAK-041 dosed acutely and chronically reversed anhedonia caused by uCMS in rats. TAK-041 also reversed anxiety related behavior assessed in the novelty suppressed feeding test and depressive-like behavior in the forced swim test in the uCMS model. uCMS-exposed animals develop a disrupted circadian regulation of corticosterone secretion, which was also normalized by TAK-041 treatment. Furthermore, TAK-041 reversed the uCMS-induced atrophy in the basal dendrites of pyramidal neurons in the hippocampus and the uCMS-induced hypertrophy of medium-spiny neurons in the NAc. These results suggest a potential benefit of TAK-041 in the treatment of anhedonia and possibly depression. TAK-041 also completely reversed social interaction (SI) deficits in the maternal immune activation poly-I:C model of SCZ, the subchronic PCP-SI model and in Balb/C and BTBR mice.DiscussionThe GPR139 agonist TAK-041 is proposed as a modulator of habenula circuitry to treat negative symptoms in SCZ based on efficacy in reversing anhedonia and social interaction deficits in multiple rodent models related to negative symptoms in SCZ.*Employed by Takeda when the study was done.

PL02-01 - Neurobiology of reward systems: relevance for learning, addiction and psychosis

Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia

Negative symptoms in schizophrenia – the remarkable impact of inclusion definitions in clinical trials and their consequences

Negative symptoms are common in schizophrenia, but often difficult to differentiate from depression. They are associated with long-term impairment and do not respond well to current treatment approaches. Even though antidepressants are commonly prescribed in schizophrenia, their beneficial effect is still under debate. In the present study, we aimed to investigate the effect of serotonergic versus noradrenergic antidepressant add-on therapy on negative symptoms in schizophrenia. Fifty-eight patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and with predominant negative symptoms were randomized in a double-blind design to add-on treatment with citalopram, reboxetine, or placebo for 4 weeks. Analysis of covariance with repeated-measures design was used to compare improvement between treatment groups in scores of the Positive and Negative Syndrome Scale and the Hamilton Rating Scale for Depression. A χ² test was used to compare responder rates between treatment groups. Repeated-measures analysis of covariance revealed no differences between treatment groups over time (treatment × time, not statistically significant) for Positive and Negative Syndrome Scale subscales. Although a subgroup analysis in subjects fulfilling the criteria for minor depression was suggestive of higher responder rates in the citalopram group compared with reboxetine, the results did not reach significance level. Our findings do not support a beneficial effect of adjunctive antidepressant treatment on negative symptoms in schizophrenia. However, depressive symptoms are reduced in patients with minor depression by citalopram but not reboxetine, which is in line with previous findings.

IntroductionNegative symptoms pose a significant challenge for the treatment and management of schizophrenia. They refer to the loss or diminishment of normal emotional and behavioural functions, which profoundly impact one’s quality of life and socio-occupational outcomes. They are often persistent and difficult to treat.ObjectivesTo explore and assess different treatment strategies for addressing negative symptoms of schizophrenia, including pharmacological, psychosocial, and non-invasive neurostimulation interventions. The goal is to provide an overview of current evidence and recommendations for enhancing the quality of life and functional outcomes in individuals with schizophrenia.MethodsWe conducted a review of the extant literature to determine treatment strategies for negative symptoms in schizophrenia. We incorporated findings from randomised controlled studies, meta-analyses and systematic reviews.ResultsWe have identified several treatment strategies for negative symptoms in schizophrenia. The literature indicates that second generation antipsychotics such as Cariprazine and Amisulpride are associated with better functional outcomes with lower cognitive impairment. Adding on an anti-depressant, particularly to first-generation antipsychotics, has demonstrated positive effects. Psychosocial interventions including Cognitive Remediation (CR), Social Skills Training (SST) and exercise programs also alleviate negative symptoms. Additionally, non-invasive neurostimulation intervention such as rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) has shown encouraging results in reducing negative symptoms.ConclusionsThe findings highlight the important of comprehensive and holistic treatment approach integrating both pharmacotherapy and non-pharmacotherapy strategies to address the heterogeneity of negative symptoms. There is a need for further research into personalised treatments that address individual symptom profiles.Disclosure of InterestNone Declared