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Claudio Brasso, Silvio Bellino, Paola Bozzatello, Cristiana Montemagni, Paola Rocca Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, Italy Aims: Paliperidone palmitate 3-month (PP3M) represents a new long-acting injectable antipsychotic therapeutic option. This review aims: 1) to summarize available data relating to efficacy, safety, tolerability and costs of PP3M; 2) to describe hospitalization rate, occupational status, treatment preference, satisfaction, adherence and caregiver burden of patients with schizophrenia who participate in PP3M clinical trials; 3) to examine ethical implications, pros and cons of PP3M use and 4) to propose study designs to further assess PP3M.Methods: On August 21, 2017, a search on PubMed about PPM3, without any filter restriction, was conducted and all available records were analyzed. Records written in a language other than English were excluded.Results: Twenty-two records were included in this review: 6 reviews, 1 report, 4 pharmacokinetic studies, 2 cost-effectiveness analyses, 1 open-label clinical trial, 2 randomized controlled trials (RCTs), 5 studies based on these 2 RCTs and 1 observational study.Discussion: According to these last 9 studies, when compared with placebo, PP3M showed a longer time to relapse and good safety and tolerability profiles. Furthermore, when compared with paliperidone palmitate 1 month (PP1M), PP3M treatment showed: 1) non-inferiority in terms of efficacy, safety, tolerability, rate of hospitalization, symptomatic and functional remission, treatment preference and variations of the occupational status; 2) a longer time to relapse after treatment discontinuation and 3) a similar reduction of the caregiver burden.Conclusion: PP3M is the only 3-monthly long-acting injectable antipsychotic available on the market. This makes it a unique option of treatment, which could be chosen both in early and advanced phases of illness. Nonetheless, longer naturalistic follow-up studies, two-arm head-to-head superiority trials and mirror studies, based on real-world samples of patients, are needed to further assess long-term safety and advantages of this new option of treatment and to define patients’ sub-populations that would most beneficiate from it. Keywords: PP3M, paliperidone palmitate, LAI, antipsychotic, clinical assessment, advantages and disadvantages

Background: As compared to natives, higher rates of involuntary admission were found among migrants in most European countries. A possible strategy to reduce this phenomenon is to develop preventive strategies targeting risk and protective factors of compulsory admission specific to the migrant population. Aims: The first aim of the present study was to evaluate compulsory admission rates in the migrant population as compared to natives admitted for an acute mental disorder. The second aim was investigate whether sociodemographic, clinical, and care-related variables associated with compulsory admission differed between migrants and natives. Moreover, in the whole sample we assessed whether migrant status affected the risk of compulsory admission. Methods: Retrospective single-center study on patients hospitalized in the period between January 1, 2018 and December 31, 2020 in a large metropolitan academic hospital. We compared sociodemographic, clinical, and care-related variables between migrants and natives, voluntary or compulsory admitted. We investigated the association between compulsory admission and the variables collected in the whole sample and in the migrants' and natives’ groups with a correlation analysis followed by hierarchical logistic regression models. Results: The sample included 185 migrant patients and 933 native patients. The prevalence of compulsory admission was significantly higher in the migrants' group. Male gender, lower education, non-comprehension of the local language, a diagnosis of a schizophrenia spectrum disorder, and aggressive behavior were associated with compulsory admission in the migrants’ sample, partially differing from the natives. Conclusion: Our study highlighted how migrant status is associated with a higher risk for compulsory admission. Inclusion policies or the presence of cultural mediators in emergency settings might be preventive strategies in this context.

Major depressive disorder (MDD) is a recurrent episodic mood disorder that represents the third leading cause of disability worldwide. In MDD, several factors can simultaneously contribute to its development, which complicates its diagnosis. According to practical guidelines, antidepressants are the first-line treatment for moderate to severe major depressive episodes. Traditional treatment strategies often follow a one-size-fits-all approach, resulting in suboptimal outcomes for many patients who fail to experience a response or recovery and develop the so-called "therapy-resistant depression". The high biological and clinical inter-variability within patients and the lack of robust biomarkers hinder the finding of specific therapeutic targets, contributing to the high treatment failure rates. In this frame, precision medicine, a paradigm that tailors medical interventions to individual characteristics, would help allocate the most adequate and effective treatment for each patient while minimizing its side effects. In particular, multi-omic studies may unveil the intricate interplays between genetic predispositions and exposure to environmental factors through the study of epigenomics, transcriptomics, proteomics, metabolomics, gut microbiomics, and immunomics. The integration of the flow of multi-omic information into molecular pathways may produce better outcomes than the current psychopharmacological approach, which targets singular molecular factors mainly related to the monoamine systems, disregarding the complex network of our organism. The concept of system biomedicine involves the integration and analysis of enormous datasets generated with different technologies, creating a "patient fingerprint", which defines the underlying biological mechanisms of every patient. This review, centered on precision medicine, explores the integration of multi-omic approaches as clinical tools for prediction in MDD at a single-patient level. It investigates how combining the existing technologies used for diagnostic, stratification, prognostic, and treatment-response biomarkers discovery with artificial intelligence can improve the assessment and treatment of MDD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stolfi, Abreu, Sinella, Nembrini, Centonze, Landra, Brasso, Cappellano, Rocca and Chiocchetti.)

Objectives: The aim of the current study was 3-fold: 1) to examine the factorial structure of the Comprehensive Assessment of At-Risk Mental States (CAARMS) in help-seeking individuals undergoing an assessment on suspicion of psychosis risk; 2) to investigate the association of CAARMS factors with functioning; 3) and to test the association of any derived factors with the longitudinal outcome of transition to psychosis., Methods: The study included 101 patients. First, a principal component analysis (PCA) was conducted using the Varimax rotation method. A minimum initial eigenvalues of greater than or equal to 1.0, analysis of Scree plots, percentage of variance explained by each component, reliability (Cronbach's alpha) of factors above 0.7 and Parallel Analysis were the criteria used to determine the appropriate number of factors Second, Spearman correlations were run to analyze the relationship between CAARMS factors and sociodemographic and functional variables (i.e. age, schooling, Social and Occupational Functioning Assessment Scale-SOFAS- and Health of the Nation Outcome Scales-HoNOS- scores). Third, we performed a Logistic regression analysis to evaluate the association between baseline CAARMS factors and the risk of transition to psychosis at the 6-month follow-up., Results: A total of 101 consecutive patiens were recruited. We found that: 1) a 6 factor model solution as the most appropriate, jointly accounting for 65% of the variance; 2) factors 1 ("negative-interpersonal"), 2 ("cognitive-disorganization"), 3 ("positive"), and 4 ("motor-physical changes") were negatively correlated with SOFAS total score; factors 1, 2, and 3 showed positive correlations with HoNOS total score; factors 2 and 3 present similar patterns of correlations, factor 3 manifesting the strongest association with HoNOS symptoms, HONOS and SOFAS total score. Both factors 5 and 6 show significant associations with HoNOS behavioral impairment; 3) after 6 months 28 participants (30.1%) converted to psychosis. Factors 2 and 3 were positively associated with the risk of transition to psychosis; whereas, the factor 5 ("affective factor") was negatively associated with the outcome variable., Conclusions: It is thus crucial to recognize the type and severity of psychopathology in help-seeking individuals in order to intensive clinical monitoring of subclinical psychopathology risk profiles, and design specific care pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Montemagni, Carluccio, Brasso, Vischia and Rocca.)

Deficits in social cognition (SC) interfere with recovery in schizophrenia (SZ) and may be related to resting state brain connectivity. This study aimed at assessing the alterations in the relationship between resting state functional connectivity and the social-cognitive abilities of patients with SZ compared to healthy subjects. We divided the brain into 246 regions of interest (ROI) following the Human Healthy Volunteers Brainnetome Atlas. For each participant, we calculated the resting-state functional connectivity (rsFC) in terms of degree centrality (DC), which evaluates the total strength of the most powerful coactivations of every ROI with all other ROIs during rest. The rs-DC of the ROIs was correlated with five measures of SC assessing emotion processing and mentalizing in 45 healthy volunteers (HVs) chosen as a normative sample. Then, controlling for symptoms severity, we verified whether these significant associations were altered, i.e., absent or of opposite sign, in 55 patients with SZ. We found five significant differences between SZ patients and HVs: in the patients' group, the correlations between emotion recognition tasks and rsFC of the right entorhinal cortex (R-EC), left superior parietal lobule (L-SPL), right caudal hippocampus (R-c-Hipp), and the right caudal (R-c) and left rostral (L-r) middle temporal gyri (MTG) were lost. An altered resting state functional connectivity of the L-SPL, R-EC, R-c-Hipp, and bilateral MTG in patients with SZ may be associated with impaired emotion recognition. If confirmed, these results may enhance the development of non-invasive brain stimulation interventions targeting those cerebral regions to reduce SC deficit in SZ., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Borderline personality disorder (BPD) is a severe and complex mental disorder that traditionally has been found to be more frequent in the female gender in clinical samples. More recently, epidemiological studies have provided conflicting data about the prevalence of borderline disorder in the two genders in community samples. In order to explain this heterogeneity, some authors hypothesized the presence of a bias in the diagnostic criteria thresholds (more prevalent in one gender than another), in the population sampling (community versus clinical), in the instruments of evaluation (clinician versus self-report measures), and in the diagnostic construct of BPD. Beyond the question of the different prevalence of the disorder between genders, the debate remains open as to how personality and clinical characteristics, and attitude toward treatments express themselves in the two genders. This narrative review is aimed to provide an updated overview of the differences among genders in BPD in terms of diagnosis, temperamental and clinical characteristics, comorbidities, findings of neuroimaging, and treatment attitudes. Studies that specifically investigated the gender differences in BPD patients are rather limited. Most of the investigations did not consider gender as a variable or were characterized by a significant imbalance between the two genders (more commonly in favor the female gender). The main results indicated that men were more likely to endorse the criteria "intense and inappropriate anger" and "impulsivity," whereas women endorsed the criteria "chronic feelings of emptiness," "affective instability," and "suicidality/self-harm behaviors." These findings reflect differences in temperament and symptoms of the two genders. Other relevant differences concern pattern of comorbidity, specific neurobiological mechanisms and attitude to treatments. Main limitations were that only one database was searched, time of publications was limited, non-English manuscripts were excluded, and the quality of each paper was not commented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Bozzatello, Blua, Brandellero, Baldassarri, Brasso, Rocca and Bellino.)

Objectives: The aim of this study was to evaluate the relative contributions of visual learning and conceptual disorganization to specific metacognitive domains in a sample of outpatients with stable schizophrenia., Methods: A total of 92 consecutive outpatients with stable schizophrenia were recruited in a cross-sectional study. We analyzed the data with five path analyses based on multiple regressions to analyze the specific effect of visual learning on metacognitive capacity and metacognitive domains and the possible mediating role of conceptual disorganization., Results: We found that (i) visual learning was negatively correlated to metacognitive capacity and its domains on the one hand and conceptual disorganization on the other hand; (ii) conceptual disorganization was negatively associated with metacognition and its domains; and (iii) when the mediation effect was considered, conceptual disorganization fully mediated the relationship between visual learning and mastery, whereas it served as a partial mediator of the effect of visual learning on the other metacognition domains, i.e., self-reflectivity, understanding others' mind, and decentration., Conclusion: These results delineate an articulated panorama of relations between different dimensions of metacognition, visual learning, and conceptual disorganization. Therefore, studies unable to distinguish between different components of metacognition fail to bring out the possibly varying links between neurocognition, disorganization, and metacognition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Montemagni, Brasso, Bellino, Bozzatello, Villari and Rocca.)

Schizophrenia (SZ) is among the twenty most disabling diseases worldwide. Subjective quality of life, well-being, and satisfaction are core elements to achieving personal recovery from the disorder. Long-acting injectable second-generation antipsychotics (SGA-LAIs) represent a valid therapeutic option for the treatment of SZ as they guarantee good efficacy and adherence to treatment. The aim of this rapid review is to summarize the evidence on the efficacy of SGA-LAIs in improving subjective quality of life, well-being, and satisfaction. The PubMed database was searched for original studies using SGA, LAI, risperidone, paliperidone, aripiprazole, olanzapine, SZ, and psychosis as keywords. Twenty-one studies were included: 13 clinical trials, 7 observational studies, and 1 post hoc analysis. It has been shown that SGA-LAIs bring an improvement to specific domains of subjective and self-rated quality of life, well-being, or satisfaction in prospective observational studies without a control arm and in randomized controlled trials versus placebo. The superiority of SGA-LAIs as compared with oral equivalents and haloperidol-LAI has been reported by some randomized controlled and observational studies. Although promising, the evidence is still limited because of the lack of studies and several methodological issues concerning the choice of the sample, the evaluation of the outcome variables, and the study design. New methodologically sound studies are needed.

Background: Resilience is defined as the ability to modify thoughts to cope with stressful events. Patients with schizophrenia (SCZ) having higher resilience (HR) levels show less severe symptoms and better real-life functioning. However, the clinical factors contributing to determine resilience levels in patients remain unclear. Thus, based on psychological, historical, clinical and environmental variables, we built a supervised machine learning algorithm to classify patients with HR or lower resilience (LR)., Methods: SCZ from the Italian Network for Research on Psychoses ( N = 598 in the Discovery sample, N = 298 in the Validation sample) underwent historical, clinical, psychological, environmental and resilience assessments. A Support Vector Machine algorithm (based on 85 variables extracted from the above-mentioned assessments) was built in the Discovery sample, and replicated in the Validation sample, to classify between HR and LR patients, within a nested, Leave-Site-Out Cross-Validation framework. We then investigated whether algorithm decision scores were associated with the cognitive and clinical characteristics of patients., Results: The algorithm classified patients as HR or LR with a Balanced Accuracy of 74.5% ( p < 0.0001) in the Discovery sample, and 80.2% in the Validation sample. Higher self-esteem, larger social network and use of adaptive coping strategies were the variables most frequently chosen by the algorithm to generate decisions. Correlations between algorithm decision scores, socio-cognitive abilities, and symptom severity were significant ( p FDR < 0.05)., Conclusions: We identified an accurate, meaningful and generalizable clinical-psychological signature associated with resilience in SCZ. This study delivers relevant information regarding psychological and clinical factors that non-pharmacological interventions could target in schizophrenia.

Introduction: The spread of the coronavirus disease 2019 (COVID-19) pandemic and the subsequent restrictions significantly affected mental health, especially major depressive disorder (MDD) whose incidence increased by 27.6% in 2020, after the COVID-19 outbreak. Few studies focused on the impact of the pandemic on the clinical characteristics of outpatients with MDD and even fewer on inpatients admitted for a major depressive episode (MDE). We aimed to compare the characteristics of MDD of two groups of patients admitted for an MDE before and after the pandemic outbreak and to investigate which variables are significantly related to post-lockdown hospitalizations., Methods: This retrospective study included 314 patients with MDD hospitalized from January 2018 to December 2021 for an MDE (DSM-5) before ( n = 154) and after ( n = 160) the Italian lockdown (9th of March 2020). We compared patients' sociodemographic and clinical characteristics. The characteristics significantly different between the two groups were included in a logistic regression to identify the factors more strictly associated with post-lockdown hospitalizations., Results: During post-lockdown hospitalization, we found a higher rate of severe MDE (33 patients, 21.4%, in the pre-lockdown and 55 patients, 34.4%, in the post), MDE with psychotic features (3 patients, 2.0%, in the pre-lockdown and 11 patients, 6.9%, in the post-lockdown), and suicidal ideation (42, 27.3%, in the pre-lockdown and 67, 41.9%, in the post-lockdown), with a lower proportion of patients followed by psychiatric services before admission (106 patients, 68.8%, in the pre-lockdown and 90 patients, 56.3%, in the post-lockdown) and a higher percentage of them in treatment with psychotherapy (18 patients, 11.7% in the pre-lockdown and 32, 20.0%, in the post-lockdown) and more frequent increase of the antidepressant dosage (16 patients, 10.4% in the pre-lockdown and 32 patients, 20.0% in the post-lockdown) and adoption of augmentation strategies (13 patients, 8.4%, in the pre-lockdown and 26 patients, 16.3%, in the post-lockdown) to treat the MDE. In the regression model, post-lockdown hospitalizations were significantly associated with suicidal ideation (OR = 1.86; p = 0.016) and psychotic features (OR = 4.41; p = 0.029) at admission, the increase in the antidepressant daily dose (OR = 2.45; p = 0.009), and the employment of an augmentation therapy (OR = 2.25; p = 0.029)., Discussion: These results showed an association between the COVID-19 pandemic and the occurrence of MDE with more severe clinical features. This might be true also for future calamities, suggesting that in these emergency contexts, patients with MDD would require more attention, resources, and intense treatments with a specific focus on suicide prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brasso, Cisotto, Del Favero, Giordano, Villari and Rocca.)

Schizophrenia is among the fifteen most disabling diseases worldwide. Negative symptoms (NS) are highly prevalent in schizophrenia, negatively affect the functional outcome of the disorder, and their treatment is difficult and rarely specifically investigated. Serotonin-dopamine activity modulators (SDAMs), of which aripiprazole, cariprazine, brexpiprazole, and lumateperone were approved for schizophrenia treatment, represent a possible therapy to reduce NS. The aim of this rapid review is to summarize the evidence on this topic to make it readily available for psychiatrists treating NS and for further research. We searched the PubMed database for original studies using SDAM, aripiprazole, cariprazine, brexpiprazole, lumateperone, schizophrenia, and NS as keywords. We included four mega-analyses, eight meta-analyses, two post hoc analyses, and 20 clinical trials. Aripiprazole, cariprazine, and brexpiprazole were more effective than placebo in reducing NS. Only six studies compared SDAMs with other classes of antipsychotics, demonstrating a superiority in the treatment of NS mainly for cariprazine. The lack of specific research and various methodological issues, related to the study population and the assessment of NS, may have led to these partial results. Here, we highlight the need to conduct new methodologically robust investigations with head-to-head treatment comparisons and long-term observational studies on homogeneous groups of patients evaluating persistent NS with first- and second-generation scales, namely the Brief Negative Symptom Scale and the Clinical Assessment Interview for Negative Symptoms. This rapid review can expand research on NS therapeutic strategies in schizophrenia, which is fundamental for the long-term improvement of patients' quality of life.

Von Economo neurons (VENs) are rod, stick, or corkscrew cells mostly located in layer V of the frontoinsular and anterior cingulate cortices. VENs are projection neurons related to human-like social cognitive abilities. Post-mortem histological studies found VEN alterations in several neuropsychiatric disorders, including schizophrenia (SZ). This pilot study aimed to evaluate the role of VEN-containing areas in shaping patterns of resting-state brain activation in patients with SZ (n = 20) compared to healthy controls (HCs; n = 20). We performed a functional connectivity analysis seeded in the cortical areas with the highest density of VENs followed by fuzzy clustering. The alterations found in the SZ group were correlated with psychopathological, cognitive, and functioning variables. We found a frontotemporal network that was shared by four clusters overlapping with the salience, superior-frontal, orbitofrontal, and central executive networks. Differences between the HC and SZ groups emerged only in the salience network. The functional connectivity of the right anterior insula and ventral tegmental area within this network were negatively correlated with experiential negative symptoms and positively correlated with functioning. This study provides some evidence to show that in vivo, VEN-enriched cortical areas are associated with an altered resting-state brain activity in people with SZ.

(1) Background: although studies of cognitive functions are still limited in borderline personality disorder (BPD), the initial evidence suggested that BPD patients have deficits of executive functions and social cognition. In addition, patients who report physical and psychic traumatic experiences in childhood and adolescence show considerable neurocognitive impairment and severe BPD symptoms. The present study has a twofold aim: (1) to evaluate the differences in neurocognitive performances between BPD patients and healthy controls and (2) to verify in the BPD patients group whether neurocognitive deficits have the role of mediating the effect of early traumas on BPD psychopathology. (2) Methods: 69 subjects were enrolled: 38 outpatients with a diagnosis of BPD (DSM-5) and 31 healthy controls. BPD patients were tested with the Borderline Personality Disorder Severity Index (BPDSI), and the Childhood Trauma Questionnaire-Short Form (CTQ-SF). All subjects were evaluated with the Iowa Gambling task (IGT), the Berg card sorting test (BCST), the Tower of London task (ToL), and the Reading-the-mind-in-the-eyes-test (RMET). Statistical analysis was performed with the analysis of variance to compare the cognitive performances between BPD patients and controls. A mediation analysis was conducted with the Sobel Test in the BPD patients group. The significance level was p ≤ 0.05. (3) Results: significant differences between the two groups were found for several parameters of all the cognitive tests examined: BCST, IGT, ToL, and RMET. Mediation analysis with the Sobel test demonstrated that the percentage of correct answers in the BCST (BCSTc) and the RMET score significantly mediated the relation between the CTQ total score and BPDSI total score. (4) Conclusions: BPD patients showed an impairment of the following executive functions: set shifting, decision making, planning and problem solving, and social cognition abilities, in comparison with controls. Our results suggested that the effect of early trauma on BPD psychopathology was mediated by a deficit in two cognitive domains: cognitive flexibility and social cognition.

Background: Deficits in social cognition (SC) are significantly related to community functioning in schizophrenia (SZ). Few studies investigated longitudinal changes in SC and its impact on recovery. In the present study, we aimed: (a) to estimate the magnitude and clinical significance of SC change in outpatients with stable SZ who were assessed at baseline and after 4 years, (b) to identify predictors of reliable and clinically significant change (RCSC), and (c) to determine whether changes in SC over 4 years predicted patient recovery at follow-up., Methods: The reliable change index was used to estimate the proportion of true change in SC, not attributable to measurement error. Stepwise multiple logistic regression models were used to identify the predictors of RCSC in a SC domain (The Awareness of Social Inference Test [TASIT]) and the effect of change in TASIT on recovery at follow-up., Results: In 548 participants, statistically significant improvements were found for the simple and paradoxical sarcasm of TASIT scale, and for the total score of section 2. The reliable change index was 9.8. A cut-off of 45 identified patients showing clinically significant change. Reliable change was achieved by 12.6% and RCSC by 8% of participants. Lower baseline TASIT sect. 2 score predicted reliable improvement on TASIT sect. 2. Improvement in TASIT sect. 2 scores predicted functional recovery, with a 10-point change predicting 40% increase in the probability of recovery., Conclusions: The RCSC index provides a conservative way to assess the improvement in the ability to grasp sarcasm in SZ, and is associated with recovery.

Therapeutic drug monitoring (TDM) receives growing interest in different psychiatric clinical settings (emergency, inpatient, and outpatient services). Despite its usefulness, TDM remains underemployed in mental health. This is partly due to the need for evidence about the relationship between drug serum concentration and efficacy and tolerability, both in the general population and even more in subpopulations with atypical pharmacokinetics. This work aims at reviewing the scientific literature published after 2017, when the most recent guidelines about the use of TDM in mental health were written. We found 164 pertinent records that we included in the review. Some promising studies highlighted the possibility of correlating early drug serum concentration and clinical efficacy and safety, especially for antipsychotics, potentially enabling clinicians to make decisions on early laboratory findings and not proceeding by trial and error. About populations with pharmacokinetic peculiarities, the latest studies confirmed very common alterations in drug blood levels in pregnant women, generally with a progressive decrease over pregnancy and a very relevant dose-adjusted concentration increase in the elderly. For adolescents also, several drugs result in having different dose-related concentration values compared to adults. These findings stress the recommendation to use TDM in these populations to ensure a safe and effective treatment. Moreover, the integration of TDM with pharmacogenetic analyses may allow clinicians to adopt precise treatments, addressing therapy on an individual pharmacometabolic basis. Mini-invasive TDM procedures that may be easily performed at home or in a point-of-care are very promising and may represent a turning point toward an extensive real-world TDM application. Although the highlighted recent evidence, research efforts have to be carried on: further studies, especially prospective and fixed-dose, are needed to replicate present findings and provide clearer knowledge on relationships between dose, serum concentration, and efficacy/safety.

Previous studies have shown, although not consistently, that first generation antipsychotics (FGA) are associated with a prevalence of extrapyramidal symptoms (EPS) higher than second generation antipsychotics (SGA). We assessed the prevalence and the incidence of antipsychotic-induced EPS in a large sample of community-dwelling Italian persons with schizophrenia before and after a 4-year naturalistic treatment, to shed light on their natural evolution and to identify possible predicting factors. EPS and psychopathology were assessed in 571 subjects with schizophrenia before (baseline) and after 4-year follow-up. Patients underwent treatment with SGA and/or FGA according to the referring clinicians' judgment. Relationships between EPS and psychopathology were assessed by network analysis, while a linear multiple regression investigated factors correlated to the presence of EPS at follow-up. EPS were significantly more frequent in the FGA- than in the SGA-treated group, and patients with EPS presented a more severe psychopathology. Parkinsonism was directly and positively connected with poor emotional expression at baseline and with poor emotional expression and disorganization at follow-up. Over the 4-year follow-up, emergent EPS were more frequent in FGA-treated patients, while relieved EPS occurred more frequently in SGA-treated persons. The presence of EPS at follow-up was significantly associated with EPS at baseline, illness duration, antipsychotic generation and the daily dose of antipsychotic medications. After a 4-year naturalistic treatment, EPS disappeared more frequently in SGA-treated patients, while they emerged more frequently in FGA-treated individuals. Therefore, although SGA did not eliminate the risk of EPS, these drugs seem to be associated to a more favorable EPS natural evolution., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier B.V.)

Background: COVID-19 pandemic has affected the physical health, psychological wellbeing, and mental health of the whole population. Young people are among those most at risk of developing mental health symptoms or disorders related to the pandemic., Purpose: the present narrative review is aimed at providing an updated overview of the current literature concerning the psychological impact of the SARS-CoV-2 infection but also of the COVID-19 outbreak, environmental restriction, and social distancing on mental health outcomes among the youth population aged between 15 and 25 years., Methods: in December 2021, an electronic search on this topic was performed on PubMed. Relevant publications from January 2020 until December 2021 were included., Findings: 53 cross-sectional studies, 26 longitudinal studies, 4 ecological studies, 1 qualitative study, and 1 systematic review were included. We found many methodological limitations in the studies included, especially poor choice of study samples and short follow-ups. Little literature was in support of a strong relationship between SARS-CoV-2 infection and consequences on youth mental health. On the contrary, many studies showed how extraordinary measures to limit the spread of the virus have impacted young people in terms of onset of new mental disorders and symptoms, suicidality, and access to emergency psychiatric services. Depressive and anxiety symptoms and disorders show the greatest increase in incidence, especially in girls and young women., Conclusions: it seems important to pay attention to the mental health of young people in relation to the consequences of the COVID-19 pandemic. However, studies with more robust methodologies and longer follow-ups are needed to establish precise indications for targeted interventions in this context.

Intrinsic motivation was described as the mental process of pursuing a task or an action because it is enjoyable or interesting in itself and was found to play a central role in the determination of the functional outcome of schizophrenia. Neurocognition is one of the most studied determinants of intrinsic motivation in clinically stable schizophrenia while little is known about the role of insight. Following this need we decided to focus on the contribution of different aspects of insight and of neurocognition to intrinsic motivation in a large sample (n = 176) of patients with stable schizophrenia. We performed three hierarchical linear regressions from which resulted that, among different insight aspects, the ability to correctly attribute signs and symptoms to the mental disorder made the strongest contribution to intrinsic motivation. Neurocognition, also, was significantly related to intrinsic motivation when analyzed simultaneously with insight. Moreover, even after accounting for sociodemographic and clinical variables significantly correlated with intrinsic motivation, the relationship between insight and neurocognition and intrinsic motivation remained statistically significant. These findings put the emphasis on the complex interplay between insight, neurocognition, and intrinsic motivation suggesting that interventions targeting both insight and neurocognition might possibly improve this motivational deficit in stable schizophrenia should., (© 2022. The Author(s).)

Objective: Earlier evidence suggested that structural-functional covariation in schizophrenia patients (SCZ) is associated with cognition, a predictor of functioning. Moreover, studies suggested that functional brain abnormalities of schizophrenia may be related with structural network features. However, only few studies have investigated the relationship between structural-functional covariation and both diagnosis and functioning in SCZ. We hypothesized that structural-functional covariation networks associated with diagnosis are related to real-world functioning in SCZ., Methods: We performed joint Independent Component Analysis on T1 images and resting-state fMRI-based Degree Centrality (DC) maps from 89 SCZ and 285 controls. Structural-functional covariation networks in which we found a main effect of diagnosis underwent correlation analysis to investigate their relationship with functioning. Covariation networks showing a significant association with both diagnosis and functioning underwent univariate analysis to better characterize group-level differences at the spatial level., Results: A structural-functional covariation network characterized by frontal, temporal, parietal and thalamic structural estimates significantly covaried with temporo-parietal resting-state DC. Compared with controls, SCZ had reduced structural-functional covariation within this network (p FDR  = 0.005). The same measure correlated positively with both social and occupational functioning (both p FDR  = 0.042). Univariate analyses revealed grey matter deviations in SCZ compared with controls within this structural-functional network in hippocampus, cerebellum, thalamus, orbito-frontal cortex, and insula. No group differences were found in DC., Conclusions: Findings support the existence of a phenotypical association between group-level differences and inter-individual heterogeneity of functional deficits in SCZ. Given that only the joint structural/functional analysis revealed this association, structural-functional covariation may be a potentially relevant schizophrenia phenotype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Primary psychosis, which includes schizophrenia and other psychoses not caused by other psychic or physical conditions, has a strong impact worldwide in terms of disability, suffering and costs. Consequently, improvement of strategies to reduce the incidence and to improve the prognosis of this disorder is a current need. The purpose of this work is to review the current scientific literature on the main risk and protective factors of primary psychosis and to examine the main models of prevention, especially those related to the early detection of the onset. The conditions more strongly associated with primary psychosis are socio-demographic and economic factors such as male gender, birth in winter, ethnic minority, immigrant status, and difficult socio-economic conditions while the best-established preventive factors are elevated socio-economic status and an economic well-being. Risk and protective factors may be the targets for primordial, primary, and secondary preventive strategies. Acting on modifiable factors may reduce the incidence of the disorder or postpone its onset, while an early detection of the new cases enables a prompt treatment and a consequential better prognosis. According to this evidence, the study of the determinants of primary psychosis has a pivotal role in designing and promoting preventive policies aimed at reducing the burden of disability and suffering of the disorder.

The aims of the study were: (1) the evaluation of the agreement between therapeutic drug monitoring (TDM) and a self-assessment of adherence to psychopharmacological treatments; (2) the identification of predictors of TDM results.Adherence in patients admitted into a psychiatric emergency service (PES) for a relapse of a schizophrenia spectrum disorder (SSD) or a bipolar disorder (BD; DSM-5) was assessed both directly with TDM and indirectly with a self-reported measure (Medication Adherence Report Scale -MARS- 10 items). The agreement between TDM and MARS was evaluated. Fifty-seven patients with SSD and 76 people with BD participated in the study. TDM was in range in about 50% of the global sample. No evidence of an association between MARS total scores and TDM results was found. Sensitivity, specificity, positive and negative predictive values of almost all MARS total scores were near to 50%. Smoking was strongly associated with a reduction of TDM results within the reference range. In the BD group, female sex was a predictor of TDM in range. In this clinical setting, self-assessment of adherence is neither reliable nor predictive. Furthermore, smoking is a strong predictor of poor adherence to psychopharmacological therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cognitive impairment is currently considered a core feature of schizophrenia (SZ) and is gaining attention as a fundamental therapeutic target. Standard treatment for SZ involves the use of antipsychotics that are successfully used to control positive symptoms and disorganized behaviour. However, it is still unclear whether they are effective on social cognition (SC) impairment. Furthermore, different medications are currently being studied to improve SC in patients with SZ. A literature search on this topic was conducted using the PubMed database. All kinds of publications (i.e., reviews, original contributions and case reports) written in English and published in the last 15 years were included. The aim of our literature review is to draw a picture of the current state of the pharmacological treatment of SC impairment in SZ.

The onset of prodromal symptoms in subjects who are at familial or clinical risk for bipolar disorder could be considered as an important alarm bell for the development of the disease and should be carefully detected. The management of prodromes in bipolar high-risk patients appears to be an important means of prevention; nevertheless, at the moment, there aren't clear and widely shared treatment indications. The aim of this review is to summarize the available treatment options (pharmacological, psychosocial and nutraceutical) for the management of prodromal symptoms in subjects who are at familial or clinical risk for bipolar disorder.

Importance: The goal of schizophrenia treatment has shifted from symptom reduction and relapse prevention to functional recovery; however, recovery rates remain low. Prospective identification of variables associated with real-life functioning domains is essential for personalized and integrated treatment programs., Objective: To assess whether baseline illness-related variables, personal resources, and context-related factors are associated with work skills, interpersonal relationships, and everyday life skills at 4-year follow-up., Design, Setting, and Participants: This multicenter prospective cohort study was conducted across 24 Italian university psychiatric clinics or mental health departments in which 921 patients enrolled in a cross-sectional study were contacted after 4 years for reassessment. Recruitment of community-dwelling, clinically stable persons with schizophrenia was conducted from March 2016 to December 2017, and data were analyzed from January to May 2020., Main Outcomes and Measures: Psychopathology, social and nonsocial cognition, functional capacity, personal resources, and context-related factors were assessed, with real-life functioning as the main outcome. Structural equation modeling, multiple regression analyses, and latent change score modeling were used to identify variables that were associated with real-life functioning domains at follow-up and with changes from baseline in these domains., Results: In total, 618 participants (427 male [69.1%]; mean [SD] age, 45.1 [10.5] years) were included. Five baseline variables were directly associated with real-life functioning at follow-up: neurocognition with everyday life (β, 0.274; 95% CI, 0.207-0.341; P < .001) and work (β, 0.101; 95% CI, 0.005-0.196; P = .04) skills; avolition with interpersonal relationships (β, -0.126; 95% CI, -0.190 to -0.062; P < .001); positive symptoms with work skills (β, -0.059; 95% CI, -0.112 to -0.006; P = .03); and social cognition with work skills (β, 0.185; 95% CI, 0.088-0.283; P < .001) and interpersonal functioning (β, 0.194; 95% CI, 0.121-0.268; P < .001). Multiple regression analyses indicated that these variables accounted for the variability of functioning at follow-up after controlling for baseline functioning. In the latent change score model, higher neurocognitive abilities were associated with improvement of everyday life (β, 0.370; 95% CI, 0.253-0.486; P < .001) and work (β, 0.102; 95% CI, 0.016-0.188; P = .02) skills, social cognition (β, 0.133; 95% CI, 0.015-0.250; P = .03), and functional capacity (β, 1.138; 95% CI, 0.807-1.469; P < .001); better baseline social cognition with improvement of work skills (β, 0.168; 95% CI, 0.075-0.261; P < .001) and interpersonal functioning (β, 0.140; 95% CI, 0.069-0.212; P < .001); and better baseline everyday life skills with improvement of work skills (β, 0.121; 95% CI, 0.077-0.166; P < .001)., Conclusions and Relevance: Findings of this large prospective study suggested that baseline variables associated with functional outcome at follow-up included domains not routinely assessed and targeted by intervention programs in community mental health services. The key roles of social and nonsocial cognition and of baseline everyday life skills support the adoption in routine mental health care of cognitive training programs combined with personalized psychosocial interventions aimed to promote independent living.

Characterizing neuroanatomical markers of different stages of schizophrenia (SZ) to assess pathophysiological models of how the disorder develops is an important target for the clinical practice. We performed a meta-analysis of voxel-based morphometry studies of genetic and clinical high-risk subjects (g-/c-HR), recently diagnosed (RDSZ) and chronic SZ patients (ChSZ). We quantified gray matter (GM) changes associated with these four conditions and compared them with contrast and conjunctional data. We performed the behavioral analysis and networks decomposition of alterations to obtain their functional characterization. Results reveal a cortical-subcortical, left-to-right homotopic progression of GM loss. The right anterior cingulate is the only altered region found altered among c-HR, RDSZ and ChSZ. Contrast analyses show left-lateralized insular, amygdalar and parahippocampal GM reduction in RDSZ, which appears bilateral in ChSZ. Functional decomposition shows involvement of the salience network, with an enlargement of the sensorimotor network in RDSZ and the thalamus-basal nuclei network in ChSZ. These findings support the current neuroprogressive models of SZ and integrate this deterioration with the clinical evolution of the disease., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patients with schizophrenia (SCZ) have a core impairment in the communicative-pragmatic domain, characterized by severe difficulties in correctly inferring the speaker's communicative intentions. While several studies have investigated pragmatic performance of patients with SCZ, little research has analyzed the errors committed in the comprehension of different communicative acts. The present research investigated error patterns in 24 patients with SCZ and 24 healthy controls (HC) during a task assessing the comprehension of different communicative acts, i.e., sincere, deceitful and ironic, and their relationship with the clinical features of SCZ. We used signal detection analysis to quantify participants' ability to correctly detect the speakers' communicative intention, i.e., sensitivity, and their tendency to wrongly perceive a communicative intention when not present, i.e., response bias. Further, we investigated the relationship between sensitivity and response bias, and the clinical features of the disorder, namely symptom severity, pharmacotherapy, and personal and social functioning. The results showed that the ability to infer the speaker's communicative intention is impaired in SCZ, as patients exhibited lower sensitivity, compared to HC, for all the pragmatic phenomena evaluated, i.e., sincere, deceitful, and ironic communicative acts. Further, we found that the sensitivity measure for irony was related to disorganized/concrete symptoms. Moreover, patients with SCZ showed a stronger response bias for deceitful communicative acts compared to HC: when committing errors, they tended to misattribute deceitful intentions more often than sincere and ironic ones. This tendency to misattribute deceitful communicative intentions may be related to the attributional bias characterizing the disorder.

Cognitive flexibility is the ability to rapidly adapt established patterns of behaviour in the face of changing circumstance and depends critically on the orbitofrontal cortex (OFC). Impaired flexibility also results from altered serotonin transmission in the OFC. The Y1 (Y1R) and Y5 (Y5R) receptors for neuropeptide Y (NPY) colocalize in several brain regions and have overlapping functions in regulating cognition and emotional behaviour. The targeted disruption of gene encoding Y1R (Npy1r gene) in Y5R containing neurons (Npy1r Y5R-/- mice) increases anxiety-like behaviour and spatial reference memory. Here we used the same conditional system to analyse whether the coordinated expression of the Y1R and Y5R might be required for behavioural flexibility in reversal learning tasks, OFC serotoninergic tone and OFC neural activity, as detected by immunohistochemical quantification of the immediate-early gene, c-Fos. In addition, we investigated whether the acute treatment of Npy1r Y5R-/- mice with the selective serotonin reuptake inhibitor escitalopram affected behavioural flexibility and OFC c-Fos expression. Npy1r Y5R-/- male mice exhibit an impairment in performing the reversal task of the Morris water maze and the water T-maze but normal spatial learning, working memory and sociability, compared to their control siblings. Furthermore, Npy1r Y5R-/- male mice display decreased 5-hydroxytriptamine (5-HT) positive fibres and increased baseline neural activity in OFC. Importantly, escitalopram normalizes OFC neural activity and restores behavioural flexibility of Npy1r Y5R-/- male mice. These findings suggest that the inactivation of Y1R in Y5R containing neurons increases pyramidal neuron activity and dysregulates serotoninergic tone in OFC, whereby contributing to reversal learning impairment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)