Cognitive impairment (CI) is one of the most prevalent and burdensome consequences of COVID-19 infection, which can persist up to months or even years after remission of the infection. Current guidelines on post-COVID CI are based on available knowledge on treatments used for improving CI in other conditions. The current review aims to provide an updated overview of the existing evidence on the efficacy of treatments for post-COVID CI.

A systematic literature search was conducted for studies published up to December 2023 using three databases (PubMed–Scopus–ProQuest). Controlled and noncontrolled trials, cohort studies, case series, and reports testing interventions on subjects with CI following COVID-19 infection were included.

After screening 7790 articles, 29 studies were included. Multidisciplinary approaches, particularly those combining cognitive remediation interventions, physical exercise, and dietary and sleep support, may improve CI and address the different needs of individuals with post-COVID-19 condition. Cognitive remediation interventions can provide a safe, cost-effective option and may be tailored to deficits in specific cognitive domains. Noninvasive brain stimulation techniques and hyperbaric oxygen therapy showed mixed and preliminary results. Evidence for other interventions, including pharmacological ones, remains sparse. Challenges in interpreting existing evidence include heterogeneity in study designs, assessment tools, and recruitment criteria; lack of long-term follow-up; and under-characterization of samples in relation to confounding factors.

Further research, grounded on shared definitions of the post-COVID condition and on the accurate assessment of COVID-related CI, in well-defined study samples and with longer follow-ups, is crucial to address this significant unmet need.

The conceptualization of negative symptoms (NS) in schizophrenia is still controversial. Recent confirmatory factor-analytic studies suggested that the bi-dimensional model (motivational deficit [MAP] and expressive deficit [EXP]) may not capture the complexity of NS structure, which could be better defined by a five-factor (five NS domains) or a hierarchical model (five NS domains as first-order factors, and MAP and EXP, as second-order factors). A validation of these models is needed to define the structure of NS. To evaluate the validity and temporal stability of the five-factor or the hierarchical structure of the brief negative symptom scale (BNSS) in individuals with schizophrenia (SCZ), exploring associations between these models with cognition, social cognition, functional capacity, and functioning at baseline and at 4 years follow-up.

Clinical variables were assessed using state-of-the-art tools in 612 SCZ at two-time points. The validity of the five-factor and the hierarchical models was analyzed through structural equation models.

The two models had both a good fit and showed a similar pattern of associations with external validators at the two-time points, with minor variations. The five-factor solution had a slightly better fit. The associations with external validators favored the five-factor structure.

Our findings suggest that both five-factor and hierarchical models provide a valid conceptualization of NS in relation to external variables and that five-factor solution provides the best balance between parsimony and granularity to summarize the BNSS structure. This finding has important implications for the study of pathophysiological mechanisms and the development of new treatments.

Autistic symptoms represent a frequent feature in schizophrenia spectrum disorders (SSD). However, the prevalence and the cognitive and functional correlates of autistic symptoms in unaffected first-degree relatives of people with SSD remain to be assessed.

A total of 342 unaffected first-degree relatives related to 247 outpatients with schizophrenia were recruited as part of the multicenter study of the Italian Network for Research on Psychoses (NIRP). Autistic features were measured with the PANSS Autism Severity Scale. Three groups of participants, defined on the presence and severity of autistic symptoms, were compared on a wide array of cognitive and functional measures.

Of the total sample, 44.9% presented autistic symptoms; 22.8% showed moderate levels of autistic symptoms, which can be observed in the majority of people with SSD. Participants with higher levels of autistic symptoms showed worse performance on Working Memory (p = 0.014) and Social Cognition (p = 0.025) domains and in the Global Cognition composite score (p = 0.008), as well as worse on functional capacity (p = 0.001), global psychosocial functioning (p < 0.001), real-world interpersonal relationships (p < 0.001), participation in community activities (p = 0.017), and work skills (p = 0.006).

A high prevalence of autistic symptoms was observed in first-degree relatives of people with SSD. Autistic symptoms severity showed a negative correlation with cognitive performance and functional outcomes also in this population and may represent a diagnostic and treatment target of considerable scientific and clinical interest in both patients and their first-degree relatives.

The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations.

To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis.

Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points.

The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016).

The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.

Negative symptoms represent a fundamental aspect of schizophrenia: they have a substantial impact on patients’ real-life functioning and do not respond satisfactorily to currently available treatments. Therefore, a better understanding of the pathophysiological mechanisms underlying these symptoms could favor the development of new treatments.

To date, the most validated pathophysiological hypothesis indicates an association between the Motivational domain (consisting of avolition, anhedonia and asociality) and alterations in the neuronal circuits involved in motivation. The Expressive Deficit domain (consisting of blunted affect and alogia) would be subtended by widespread alterations of cortical connectivity and associated with impaired neurocognition, social cognition, and the presence of neurological soft signs.

The aim of the present study is to examine the neurobiological correlates of the two domains of negative symptoms, starting from the brain areas that have been most commonly found in the literature to be associated with negative symptoms.

Resting-state (rs) fMRI data were acquired in 62 subjects with schizophrenia (SZ) and 46 healthy controls (HC). The two negative symptom domains were assessed using the Brief Negative Symptom Scale. In addition, the following assessment tools were used: the Positive and Negative Syndrome Scale for the assessment of positive symptoms and disorganization, the Calgary Depression Scale for Schizophrenia for depression and the St. Hans Rating Scale for extrapyramidal symptoms. The study of the possible relationships between rs-brain activity and the negative symptoms domains was conducted through partial correlations, checking for possible confounding factors (positive, depressive, extrapyramidal symptoms and disorganization).

The SZ, compared to the HC, showed higher rs-brain activity of the right inferior parietal lobule and of the right temporoparietal junction and lower rs-brain activity of the right dorsolateral prefrontal cortex, bilateral anterior dorsal cingulate cortex, bilateral ventral caudate and bilateral dorsal caudate. Furthermore, in the group of patients, the rs-brain activity of the left ventral caudate showed a moderate negative correlation with the Expressive deficit domain (r = -0.401; p = 0.003), but not with the Motivational domain.

The results of the present study, in line with the literature, demonstrated how the two domains of negative symptomatology are subtended by different pathophysiological mechanisms. Given the role played by the ventral caudate in neurocognitive processes, these results are in line with the hypothesis that Expressive deficit may have a common etiopathogenesis with cognitive deficits. A better understanding of the neurobiology of negative symptoms could foster the development of innovative treatment strategies targeting the two negative symptom domains.

None Declared

Negative symptoms (NS) represent a heterogeneous construct of schizophrenia, whose conceptualization is still to be clarified. In the last decade, the conceptualization model that has received the most support from the literature has described 2 NS domains: the expressive deficit (EXP), which includes blunted affect and alogia, and the motivational deficit (MAP), which includes avolition, asociality, and anhedonia. However, different confirmatory factor-analytic studies suggest that the bi-dimensional model may not capture the complexity of this construct, which could be better defined by a 5-factor model (5 individual negative symptoms) or a hierarchical model (5 individual negative symptoms as first-order factors, and the 2 domains, MAP and EXP domains, as second-order factors). However, to our knowledge, no study has investigated associations between negative symptom models with social cognition and functional capacity, which are largely documented to correlate with negative symptoms, nor the associations with external validators over time, looking at the potential stability of negative symptom models validity through the course of the illness.

In the light of this observations, we investigated, the external validity of the five-factor model and the hierarchical model of the BNSS in subjects with schizophrenia, looking at associations with cognition, social cognition, functioning and functional capacity at baseline and at four years follow-up.

NS were assessed in 612 subjects with schizophrenia using the Brief Negative Symptom Scale at the baseline and after 4-year follow-up. State of the art assessment instruments were used to assess cognitive and functioning related variables. Structural equation models (SEM) that included the NS models and 4 external variables were used to our aim.

According to recent multicenter studies, our results confirmed the validity of the 5-factor- and the hierarchical-model of negative symptoms. In particular, these 2 models proved to be equivalent in terms of fit to the data at baseline and follow-up. As regard to the relationship of the two BNSS models with external variables, we found that there was a similar pattern of associations at the two time points despite minor variations.

The five factor and the hierarchical models provide an optimal conceptualization of negative symptoms in relation to external variables. The similar pattern of associations with external variables of the two models at the two time points despite minor variations, suggests that the simple and widely used 5-factor solution provides the best balance between parsimony and granularity to summarize BNSS structure. This data is of important relevance with consequent implications in the study of pathophysiological mechanisms and the development of targeted treatments for NS.

None Declared

Treatment resistance schizophrenia (TRS) develops in ~ 30% of patients in about 5 years from starting treatment with 5-HT2/D2 APs, resulting in increased morbidity, suicidality, and mortality. Findings from neurochemistry, neurometabolism, functional imaging in TRS patients indicate abnormalities in glutamatergic neurotransmission (Moghaddam B et al 2012; 37 4-15) rather than excess of dopamine synthesis (Demjaha A et al 2014; 75 11-3; Mouchlianitis E et al 2016; 42 744-52), suggesting the need to add a drug that attenuates glutamate release. Evenamide, a selective inhibitor of voltage-gated Na+ channels, is devoid of biological activity at >130 CNS targets, normalizes glutamate release without affecting basal levels, and demonstrated benefits in animal models of psychosis as monotherapy and as an add on to APs (including clozapine), reversing deficits produced by amphetamine, scopolamine, phencyclidine, or ketamine

Studies 014/015 were designed to evaluate the safety and preliminary efficacy of evenamide given orally at 3 fixed doses (7.5, 15 and 30 mg bid) in patients with TRS not responding to a therapeutic dose of an AP. Assessment of efficacy was based on changes of PANSS and CGI-S/C, while tolerability was assessed based on all safety measures

Study 014 is a 6-week, randomized, rater-blinded, international study with completers continuing assigned doses for an additional 46 weeks in an extension study (Study 015). Patients were initially randomized to 7.5 or 15 mg bid; the Independent Safety Monitoring Board (ISMB) allowed randomization to 30 mg bid after reviewing safety data from the first 50 patients. At baseline, patients were moderately to severely ill (CGI-S of 4 to 6), with a PANSS total score of 70-90 and predominant positive symptoms (score of 4 or more on at least 2 core symptoms and a PANSS positive total score ≥ 20), along with functional deficits (GAF ≤50). Efficacy ratings were performed by a psychiatrist blinded to the evenamide dose. Data were analyzed as a single group using descriptive statistics to assess changes from baseline to endpoint (Week 30)

Interim, group-blinded, 30-week results for safety and efficacy data (PANSS and CGI) for the first 100 patients (including 6 on 30 mg bid) will be presented. Patients randomized to 7.5, 15, and 30 mg bid had all safety and efficacy data pooled in a single group to maintain the blind in the study. All results will be submitted to the ISMB, relevant health authorities and the FDA

This trial is the first international TRS trial of an NCE AP used as an add-on to a single typical or atypical AP. Results of this study may change the treatment of future TRS patients

None Declared

In recent years the increasing presence of refugees and asylum seekers displaced from their country of origin, determined significant social, economic, humanitarian and public health implications in host nations. Advancing the knowledge on factors contributing to these implications, could foster the implementation of new public-health plans for these population. As a matter of fact, to date, the rates of mental disorders in these population are uncertain due to the high variability of methods used in the studies on topic, and of risk and protective factors analyzed. The most replicated finding is the high prevalence of Post-Traumatic Stress Disorder (PTSD) and depression in refugees and asylum seekers as compared to the population of host countries.

The aim of the present study was to investigate the needs for mental health prevention, care and rehabilitation of adult refugees and asylum seekers in Italy, performing a multidisciplinary evaluation of migrants who were guests in two refugees’ centers in Campania (Salerno and Avellino).

The Mini-International Neuropsychiatric Interview (MINI) was assessed in 303 migrants, in order to evaluate the presence or not of a psychiatric diagnosis. Analysis of variance (ANOVA) was used to investigate differences between migrants with a mental disorder vs migrants without a mental disorder in terms of cognitive functions, depressive and anxiety symptoms, traumatic events and pre-migration risk factors. Person’s correlation was performed to investigate relationships between the Hopkins Symptom Checklist-25 (HSCL-t25) psychopathological index with all the other above-mentioned variables. Logistic regression was used to evaluate factors associated to the presence of a current mental disorder.

At least one mental disorder was found in 90 subjects (29.7% of the sample). Most prevalent diagnoses were major depressive disorder, lifetime panic disorder, PTSD, and generalized anxiety disorder. People with at least one psychiatric illness showed impaired global (F=6.62; p=.011) and social (F=8.22; p=.004) cognition, higher trauma levels (F=70.59; p<.0001) and more severe anxiety and depressive symptoms (F=61.84; p<.0001) compared to healthy migrants. Only trauma levels significantly correlated with HSCL-t25 psychopathological index. Trauma levels, global cognition, occupation, and migration status were associated to the presence of a current mental disorder.

The results of the present study demonstrated that almost 1/3 of the guests of refugee centers in Campania have a mental disorder. The identification of risk factors associated to the onset of mental disorder and to severity of psychopathology in refugees and asylum seekers, may contribute to plan preventive and early psychiatric care in this population.

None Declared

Negative symptoms (NS) represent an unmet need of treatment in schizophrenia (SCZ). As a result, these symptoms pose a significant burden on patients, their families, and the health care system. In the last decade, the conceptualization model that has received the most support from the literature has described 2 domains of NS: the expressive deficit (EXP), which includes blunted affect and alogia, and the motivational deficit (MAP), which includes avolition, asociality, and anhedonia. However, different confirmatory factor-analytic studies suggest that the bi-dimensional model may not capture the complexity of this construct, which could be better defined by the 5-factor model. To date no study exploiting innovative tools and state of the art assessment instruments has yet been conducted to evaluate the NS structure stability over time.

The aim of this study was to investigate the stability of the latent structure of NS in subjects with SCZ.

NS were assessed in 612 subjects with SCZ using the Brief Negative Symptom Scale (BNSS) at the baseline and after 4-year follow-up. A network invariance analysis was conducted for the data collected longitudinally.

Results showed that the BNSS’ items aggregated to form 5 distinct domains (avolition, asociality, blunted affect, alogia and anhedonia). The result of the network invariance test indicated that the network structure remained unchanged over time (network invariance test = 0.13; p = 0.169) while its overall strength decreased significantly (6.28 baseline, 5.79 at follow-up; global strength invariance test = 0.48; p = 0.016).

The results of this study show how the construct of NS can be better explained by the 5 individual negative symptoms and that this model is almost stable over time. Therefore the 2-dimensional model may be insufficient to describe the characteristics of NS. This data is of important relevance with consequent implications in the study of pathophysiological mechanisms and the development of targeted treatments for NS.

None Declared

In 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.

The 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.

A 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.

Databases 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.

The 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.

None Declared

After coronavirus disease 2019 (COVID-19) infection, many individuals reported neurological and psychiatric sequelae, including cognitive impairment, even several months after the acute infection.

The present study aims to provide a critical overview of the literature on the relationships between post-acute COVID-19 infection and cognitive impairment, highlighting limitations and confounding factors.

A systematic search of articles published from January 1st, 2020, to July 1st, 2022 was performed in Pubmed/Medline. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Only studies using validated instruments for the assessment of cognitive impairment were included. Out of 5478 screened records, 72 studies met inclusion criteria. Time of patients’ assessment varied from 4 weeks to 12 months after the infection. The available evidence revealed the presence of impairment in executive functions, attention and memory in subjects recovered from COVID-19. However, several limitations of the literature reviewed should be highlighted: most studies were performed on small samples, not stratified by severity of disease and age, used a cross-sectional or a short-term longitudinal design, and provided a limited assessment of the different cognitive domains. Few studies investigated neurobiological correlates of cognitive deficits in individuals recovered from COVID-19.

Based on the literature reviewed, it is difficult, to date, to draw conclusions about the relationships between COVID-19 infection and cognitive impairment. Therefore, further studies with an adequate methodological design are needed in order to better understand these relationships, identify neurobiological correlates of COVID-related cognitive deficits and evaluate their course over time. Enhancing the knowledge on this topic could favor the development of effective therapeutic strategies for cognitive deficits in individuals recovered from COVID-19.

None Declared

The neurobiological underpinnings of negative symptoms in schizophrenia remain unclear. Previous studies have revealed that in schizophrenia, the anticipatory component of the hedonic experience (anticipatory anhedonia, failure to anticipate reward or pleasurable experiences) is more markedly impaired than the consummatory aspect of pleasure (consummatory anhedonia, in the moment experience of pleasure during pleasurable situations). Several neuroimaging focused on reward prediction deficit have shown dysfunctions in the neuronal circuits that sustain these processes in patients, but findings have not been consistent.

The current study aimed at investigating the impairment of reward anticipation in subjects with schizophrenia (SCZ) during the “Monetary Incentive Delay task” (MID task), employing the topographic analysis of event-related potentials (ERPs) with EEG recordings. Furthermore, the associations with negative symptoms and anticipatory and consummatory hedonic experience were investigated.

EEG data were recorded in thirty SCZ and twenty-three matched HC, during the MID task in which reward and loss cues (incentive cues of positive and negative value) of different magnitude, as well as neutral cues were presented. Anticipation and experience of pleasure were measured by the Temporal Experience of Pleasure Scale (TEPS), while negative symptom dimensions by the Schedule for the Deficit Syndrome (SDS). For the EEG data analysis, the topographic analysis of variance (TANOVA) that uses the global field power of difference maps was used to evaluate between-group differences in scalp topography. Correlation analyses between hedonic experience, negative symptoms and ERPs were performed.

The TANOVA interaction effect (group x cue) was significant in the time window between 140.6 and 195.3 msec after cue presentation (p<.05). Post-hoc analysis showed that significant differences in topography were observed for the reward condition (p=.0006) but not for the loss one (p=.6732) between SCZ and HC. Finally, a significant correlation (p<.01) between t-maps values obtained in the same time-frame and the anticipation of pleasure scores was detected, while no significant correlations were found with the experience of pleasure scores or the severity negative symptom.

SCZ are unable to integrate the incentive magnitude and reward value of future events in the context of their ongoing task. Topographic abnormalities in ERP could be traced already during early stages of reward processing and were associated with anticipation of pleasure, but not with the experience of pleasure or the avolition, suggesting that these constructs might be partially separate.

None Declared

Different electrophysiological (EEG) indices have been investigated as possible biomarkers of schizophrenia. However, these indices have a very limited use in clinical practice, as their associations with clinical and functional outcomes remain unclear. This study aimed to investigate the associations of multiple EEG markers with clinical variables and functional outcomes in subjects with schizophrenia (SCZs).

Resting-state EEGs (frequency bands and microstates) and auditory event-related potentials (MMN-P3a and N100-P3b) were recorded in 113 SCZs and 57 healthy controls (HCs) at baseline. Illness- and functioning-related variables were assessed both at baseline and at 4-year follow-up in 61 SCZs. We generated a machine-learning classifier for each EEG parameter (frequency bands, microstates, N100-P300 task, and MMN-P3a task) to identify potential markers discriminating SCZs from HCs, and a global classifier. Associations of the classifiers’ decision scores with illness- and functioning-related variables at baseline and follow-up were then investigated.

The global classifier discriminated SCZs from HCs with an accuracy of 75.4% and its decision scores significantly correlated with negative symptoms, depression, neurocognition, and real-life functioning at 4-year follow-up.

These results suggest that a combination of multiple EEG alterations is associated with poor functional outcomes and its clinical and cognitive determinants in SCZs. These findings need replication, possibly looking at different illness stages in order to implement EEG as a possible tool for the prediction of poor functional outcome.