Search

Abstract Background Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium’s clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations. Content This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors’ preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections. Conclusions Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium’s ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.

Abstract Stress affects the brain and alters its neuroarchitecture and function; these changes can be severe and lead to psychiatric disorders. Recent evidence suggests that astrocytes and microglia play an essential role in the stress response by contributing to the maintenance of cerebral homeostasis. These cells respond rapidly to all stimuli that reach the brain, including stressors. Here, we used a recently validated rodent model of post-traumatic stress disorder in which rats can be categorized as resilient or vulnerable after acute inescapable footshock stress. We then investigated the functional, molecular, and morphological determinants of stress resilience and vulnerability in the prefrontal cortex, focusing on glial and neuronal cells. In addition, we examined the effects of a single subanesthetic dose of ketamine, a fast-acting antidepressant recently approved for the treatment of resistant depression and proposed for other stress-related psychiatric disorders. The present results suggest a prompt glial cell response and activation of the NF-κB pathway after acute stress, leading to an increase in specific cytokines such as IL-18 and TNF-α. This response persists in vulnerable individuals and is accompanied by a significant change in the levels of critical glial proteins such as S100B, CD11b, and CX43, brain trophic factors such as BDNF and FGF2, and proteins related to dendritic arborization and synaptic architecture such as MAP2 and PSD95. Administration of ketamine 24 h after the acute stress event rescued many of the changes observed in vulnerable rats, possibly contributing to support brain homeostasis. Overall, our results suggest that pivotal events, including reactive astrogliosis, changes in brain trophic factors, and neuronal damage are critical determinants of vulnerability to acute traumatic stress and confirm the therapeutic effect of acute ketamine against the development of stress-related psychiatric disorders.

BackgroundAffective temperament, defined as the fundamental predisposition from which normal affective states originate or as the constitutional core of personality, play a crucial role in mood disorders, particularly bipolar disorders. Understanding the relationship between temperaments, treatment adherence, and self-care is crucial for effective management and improved clinical results.ObjectivesThis study aims to (1) assess the correlation between affective temperaments and treatment adherence, (2) investigate the relationship between affective temperaments and self-care abilities, (3) identify predictors of treatment adherence, and (4) explore the moderating effect of self-care on the relationship between treatment adherence and depressive temperament in individuals with bipolar disorder.MethodsA cross-sectional study was conducted with 231 individuals diagnosed with bipolar disorder (BD) type I (N=160) and type II (N=71). The participants were evaluated using the following psychometric tools: Temperament Evaluation of Memphis, Pisa, and San Diego (TEMPS) to assess affective temperaments, Personal and Social Performance Scale (PSP) to evaluate social functioning and self-care abilities, and Morisky Medication Adherence Scale (MMAS) to measure treatment adherence. The study involved statistical analyses to examine correlations, identify predictors, and explore moderating effects.ResultsThe findings revealed significant correlations between affective temperaments and both treatment adherence and self-care abilities. Specifically, hyperthymic temperament was positively associated with higher treatment adherence, whereas cyclothymic and depressive temperaments were linked to lower adherence. Self-care abilities were found to mediate the relationship between depressive temperament and treatment adherence, suggesting that improved self-care can enhance adherence in individuals with depressive temperament.ConclusionsAffective temperaments significantly influence treatment adherence and self-care abilities in individuals with bipolar disorder. The mediating role of self-care highlights the importance of developing targeted interventions to improve self-care practices, thereby enhancing treatment adherence and overall well-being. Personalized treatment strategies based on temperament assessments could lead to better clinical outcomes and quality of life for individuals with bipolar disorder.

IntroductionEating Disorders (EDs) affect individuals globally and are associated with significant physical and mental health challenges. However, access to adequate treatment is often hindered by societal stigma, limited awareness, and resource constraints.MethodsThe project aims to utilize the power of Artificial Intelligence (AI), particularly Machine Learning (ML) and Deep Learning (DL), to improve EDs diagnosis and treatment. The Master Data Plan (MDP) will collect and analyze data from diverse sources, utilize AI algorithms for risk factor identificat io n, treatment planning, and relapse prediction, and provide a patient-facing chatbot for information and support. This platform will integrate patient data, support healthcare professionals, and empower patients, thereby enhancing care accessibility, personalizing treatment plans, and optimizing care pathways. Robust data governance measures will ensure ethical and secure data management.ResultsAnticipated outcomes include enhanced care accessibility and efficiency, personalized treatment plans leading to improved patient outcomes, reduced waiting lists, heightened patient engagement, and increased awareness of EDs with improved resource allocation.DiscussionThis project signifies a pivotal shift towards data-driven, patient-centered ED care in Italy. By integrat ing AI and promoting collaboration, it seeks to redefine mental healthcare standards and foster better well- being among individuals with EDs.

Abstract Background Multiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD patients. Results Here, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of 344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid cPTSD compared with BD patients without cPTSD. Conclusions The results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and more effective treatments.

Abstract Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser9 were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II–III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.

Background: Patients with panic disorder (PD) may experience increased vulnerability to dissociative and anxious phenomena in the presence of repeated traumatic events, and these may be risk factors for the development of complex post-traumatic stress disorder (cPTSD). The present study aims to find out whether the presence of cPTSD exacerbates anxiety symptoms in patients suffering from panic disorder and whether this is specifically associated with the occurrence of dissociative symptoms. Methods: One-hundred-and-seventy-three patients diagnosed with PD were recruited and divided into two groups based on the presence (or absence) of cPTSD using the International Trauma Questionnaire (ITQ) scale. Dissociative and anxious symptoms were assessed using the Cambridge Depersonalization Scale (CDS) and Hamilton Anxiety Scale (HAM-A), respectively. Results: Significant differences in re-experienced PTSD (p < 0.001), PTSD avoidance (p < 0.001), PTSD hyperarousal (p < 0.001), and DSO dysregulation (p < 0.001) were found between the cPTSD-positive and cPTSD-negative groups. A statistically significant association between the presence of cPTSD and total scores on the HAM-A (p < 0.001) and CDS (p < 0.001) scales was found using regression analysis. Conclusions: This study highlights the potential link between dissociative symptoms and a more severe clinical course of anxiety-related conditions in patients with PD. Early intervention programs and prevention strategies are needed.

Background and Objectives: Traumatic events adversely affect the clinical course of obsessive–compulsive disorder (OCD). Our study explores the correlation between prolonged interpersonal trauma and the severity of symptoms related to OCD and anxiety disorders. Materials and Methods: The study follows a cross-sectional and observational design, employing the International Trauma Questionnaire (ITQ) to examine areas linked to interpersonal trauma, the Hamilton Anxiety Rating Scale (HAM-A), and the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) to assess anxious and obsessive–compulsive symptoms, respectively. Descriptive analysis, analysis of variance (ANOVA), and logistic regression analyses were conducted. Results: We recruited 107 OCD-diagnosed patients, categorizing them into subgroups based on the presence or absence of complex post-traumatic stress disorder (cPTSD). The ANOVA revealed statistically significant differences between the two groups in the onset age of OCD (p = 0.083), psychiatric familial history (p = 0.023), HAM-A, and Y-BOCS (p < 0.0001). Logistic regression indicated a statistically significant association between the presence of cPTSD and Y-BOCS scores (p < 0.0001). Conclusions: The coexistence of cPTSD in OCD exacerbates obsessive–compulsive symptoms and increases the burden of anxiety. Further advancements in this field are crucial for mitigating the impact of early trauma on the trajectory of OCD and associated anxious symptoms.

Background: Several studies have shown the possible link between trauma and sleep disturbances, particularly in anxiety disorders. This issue could be because sympathetic hyperarousal is central to both disorders, probably caused by a dysregulation of the noradrenergic system. This study aimed to establish if the comorbidity with complex post-traumatic stress disorder (cPTSD) is associated with sleep disturbances in panic disorder (PD) and if the presence of poor sleep quality is associated with a higher psychopathological burden. Methods: Participants (N = 211) with PD completed the International Trauma Questionnaire concerning their most troubling experience, the Hamilton Anxiety Rating Scale (HAM-A), and the Pittsburgh Sleep Quality Index (PSQI) to assess anxiety symptoms and sleep disturbances, respectively. Results: The sample was divided into two subgroups based on the presence of cPTSD. No significant differences emerged in the bivariate analyses for what concerns sociodemographic features. As for the scores of the psychopathological scales, the analysis highlighted statistically significant differences between the subgroups. Subjects with cPTSD reported significantly higher HAM-A total scores. As for the disturbances in self-organization (DSO) and PSQI scores, these were all significantly higher in the cPTSD subsample. At the logistic regression, the presence of cPTSD was inserted as the dependent variable, while the PSQI scores of the subscales evaluating subjective sleep quality, sleep duration, sleep efficacy, and the use of hypnotics were used as independent variables. The presence of cPTSD was significantly associated with the PSQI subscores for subjective sleep quality and use of hypnotics. Conclusions: Patients with PD exhibit more severe sleep disturbances and a higher anxiety burden when experiencing prolonged trauma. Therapeutic advances are needed in this field to target these symptomatologic domains.

IntroductionDissociative symptoms have been recently related to bipolar disorder (BD) symptomatology. Moreover, the disease burden carries on a share of perceived self-stigma that amplifies the BD impairment. Internalized stigma and dissociative symptoms often seem overlapping, leading toward common outcomes, with reduced treatment seeking and poor adherence. We hypothesize a potential relationship between dissociation and self-stigma in patients suffering from BD.Materials and methodsIn this cross-sectional study we enrolled a total of 120 adult clinically stable BD outpatients. All participants completed the Internalized Stigma of Mental Illness (ISMI), Dissociative Experiences Scale-II (DES-II), and Manchester Short Assessment of Quality of Life (MANSA).ResultsAverage age and age at BD (BD-I n = 66, 55%; BD-II n = 54, 45%) onset were 46.14 (±4.23), and 27.45 (±10.35) years, with mean disease duration of 18.56 (±13.08) years. Most participants were female (n = 71; 59.2%) and 40 (33%) of them experienced lifetime abuse, with an average of 1.05 (±0.78) suicide attempts. DES scores (mean 31.8, ±21.6) correlated with ISMI total-score, with significant association with spikes in Alienation (13.1, SD±3.1) (p < 0.001) and Stereotype (13.8, SD±3.9) (p < 0.001). Linear regression analysis has shown a significant association between DES total score and alienation (p < 0.001), stereotype (p < 0.001) and MANSA total-score (p < 0.001).DiscussionFor the first time, our data suggests that self-stigma is associated to dissociative symptoms, reducing overall quality of life in BD. The early identification of at-risk patients with previous lifetime abuse and high perceived stigma could lead the way for an ever more precise tailoring of treatment management.

IntroductionSex differences were demonstrated in bipolar disorders (BD) concerning epidemiological, clinical, and psychopathological characteristics, but consensus is lacking. Moreover, data concerning the influence of sex on treatment response in BD is contrasting. The present cross-sectional study aimed to analyze sex differences in a population of BD subjects, with specific focus on psychopathological features and treatment response.Materials and MethodsSubjects diagnosed with BD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th version (DSM-5) were recruited. Socio-demographic and clinical characteristics were collected. The Hamilton Rating Scale for Depression, the Mania Rating Scale (MRS), the brief version of the Temperament Evaluation of Memphis, Pisa and San Diego—Münster version (briefTEMPS-M), and the Barratt Impulsiveness Scale−11 items (BIS-11) were used for psychopathological assessment. Treatment response was appraised with the Alda Scale. We performed bivariate analyses to compare socio-demographic, clinical, and psychopathological characteristics between men and women (p < 0.05). A logistic regression was run to analyze features that were significantly associated with female sex.ResultsAmong the recruited 219 BD subjects, 119 (54.3%) were females. Women had a lower scholarity (p = 0.015) and were less frequently employed (p = 0.001). As for psychopathological features, a higher MRS total score (p < 0.001) was detected among women, as well as higher BIS-11 total score (p = 0.040), and briefTEMPS-M score for anxious temperament (p = 0.006). Men showed higher prevalence of DSM-5 mixed features (p = 0.025), particularly during a depressive episode (p = 0.014). Women reported longer duration of untreated illness (DUI) (p < 0.001). There were no sex differences in the Alda Scale total score when considering the whole sample, but this was significantly higher among men (p = 0.030) when evaluating subjects treated with anticonvulsants. At the logistic regression, female sex was positively associated with longer DUI (p < 0.001; OR 1.106, 95% CI 1.050–1.165) and higher MRS total score (p < 0.001; OR 1.085, 95% CI 1.044–1.128) and negatively associated with employment (p = 0.003; OR 0.359, 95% CI 0.185–0.698) and DSM-5 mixed features (p = 0.006; OR 0.391, 95% CI 0.200–0.762).ConclusionsThe clinical presentation of BD may differ depending on sex. The severity of BD should not be neglected among women, who may also display worse treatment response to anticonvulsants.

IntroductionAdolescents and young adults represent a vulnerable population in the context of the Coronavirus disease 2019 (COVID-19) pandemic. The present retrospective study aims to investigate the pandemic’s psychological impact on adolescents and young adults by analyzing data from an outpatient mental health service dedicated to youths in Umbria, central Italy.Materials and MethodsThe clinical charts of subjects aged 14–24 who first accessed the service in the timeframe between March 1st, 2019, and February 28th, 2021, were reviewed. Subjects were divided into two subgroups according to the period of time when they accessed the service (pre-COVID-19 vs. during- COVID-19 outbreak). Bivariate analyses were performed using the Chi-square test and the Welch’s t-test. A secondary analysis was performed considering only subjects suffering from psychiatric disorders. Furthermore, data concerning individuals who were already followed by the service before the pandemic were analyzed by the McNemar’s test and the t-paired test to assess changes in treatment features.ResultsThe number of new accesses during the pandemic period remained stable. After the emergency onset, youths accessing the service showed a higher prevalence of anxiety disorders (p = 0.022). During the COVID-19 period, services were more frequently delivered by using a digital mental health approach (p = 0.001). Psychopharmacological treatment was more frequently prescribed among subjects that were referred to the service after the pandemic onset (p = 0.033). As for substance use, a highly significant reduction in opioid use was observed (p = 0.003). Family therapy was delivered less frequently in the during-COVID-19 subgroup, especially in the subpopulation of subjects suffering from psychiatric disorders (p = 0.013). When considering subjects referred to the service in the pre-COVID-19 period, the number of interventions provided to this population increased after the pandemic outbreak (p = 0.038).ConclusionIn the context of the COVID-19-related public health crisis, youths represent an at-risk population for which pathways to care should be reinforced, and targeted interventions, including psychosocial treatments, should be implemented.

The therapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) was investigated in young (6-month-old) and adult (12-month-old) 3 × Tg-AD mice, which received um-PEA for 3 months via a subcutaneous delivery system. Mitochondrial bioenergetics, ATP homeostasis, and magnetic resonance imaging/magnetic resonance spectroscopy were evaluated in the frontal cortex (FC) and hippocampus (HIPP) at the end of um-PEA treatment. Glutamate release was investigated by in vivo microdialysis in the ventral HIPP (vHIPP). We demonstrated that chronic um-PEA treatment ameliorates the decrease in the complex-I respiration rate and the FoF1-ATPase (complex V) activity, as well as ATP content depletion in the cortical mitochondria. Otherwise, the impairment in mitochondrial bioenergetics and the release of glutamate after depolarization was not ameliorated by um-PEA treatment in the HIPP of both young and adult 3 × Tg-AD mice. Moreover, progressive age- and pathology-related changes were observed in the cortical and hippocampal metabolism that closely mimic the alterations observed in the human AD brain; these metabolic alterations were not affected by chronic um-PEA treatment. These findings confirm that the HIPP is the most affected area by AD-like pathology and demonstrate that um-PEA counteracts mitochondrial dysfunctions and helps rescue brain energy metabolism in the FC, but not in the HIPP.

Abstract Background Bipolar disorder (BD) is one of the most burdensome mental disorders, with a lifetime prevalence of 2.4%, with a prevalence of 0.6% for bipolar type I and 0.4% for bipolar type II. Several interventions have been developed to implement the treatment strategy of bipolar disorder, including the Interpersonal and Social Rhythm Therapy (IPSRT). This intervention has been specifically developed to manage patients’ stressful life events, improve the disruptions of social and circadian rhythms and increase adherence to medications. The aim of the present study is to assess the efficacy of IPSRT on affective and anxiety psychopathology, social functioning, response to pharmacological treatment and affective morbidity index (AMI) in BD patients. Methods BD patients were consecutively recruited at the Mood Disorder Unit of the University of Campania “Luigi Vanvitelli” and randomly assigned to the experimental group receiving the IPSRT or to the Treatment as Usual (TAU) group. Patients were assessed at baseline, after 3 and 6 months with several validated assessment tools and with the affective morbidity index. Results At the end of the intervention, compared to controls, patients from the experimental group reported a significant improvement in anxious depressive and manic symptomatology, global functioning; and response to mood stabilizers. Patients in the IPSRT group reported a reduction at the AMI score. Conclusions IPSRT has been confirmed to be effective in improving the clinical symptomology of BD patients and in improving the affective morbidity index. Further studies with longer follow-up are needed in order to assess the stability of the results. Trial registration The study was approved by the local ethical review board (N001567/28.01.2018)

Abstract Background The 11th revision of the International Classification of Diseases and Related Disorders (ICD-11) has been released. In order to test the clinical consistency and the clinical utility of the proposed guidelines the World Health Organization (WHO) has carried out the Ecological Implementation Field Studies in various countries. In this paper the results of the Italian field trials on the clinical utility of the ICD-11 diagnostic guideline concerning schizophrenia and related disorders will be presented. Methods In Italy, field trials have been carried out at the Department of Psychiatry of the University of Campania “L. Vanvitelli”. All patients showing any psychotic symptom and referring to the outpatient and inpatient units have been recruited. Patients were interviewed by two clinicians with whom they had not had any prior clinical contact. At the end of each interview, clinicians were asked to complete 12 questions about the clinical utility of the diagnostic guidelines as applied to each patient. Results Fourteen clinicians and 100 patients have been involved. The ICD-11 clinical guidelines were perceived as easy to use, with an adequate goodness of fit, clear and understandable and with an adequate level of details and specificity to describe the essential features of the diagnoses. Clinicians rated very positively their usefulness in describing the threshold between patient’s disorder and normality. Despite still very positive, the guidelines have been perceived as less useful to select a treatment, to assess patients’ prognosis and to communicate with other mental health professionals. Conclusions The 11th revision of the chapter on Mental, Behavioural and Neurodevelopmental Disorders has made substantive changes to the conceptualization of mental disorders which could have impacted on their reliability and clinical utility. Results of the Italian field studies, in line with those reported by the international sample, highlight that ICD-11 has been rated as highly clinically useful by participating clinician, more than the ICD-10. This could be considered a good reason to be optimistic about the implementation of the ICD-11 among global clinicians. Trial registration The study has been approved by the Ethical Review Board of the University of Campania “L. Vanvitelli” (N. 416, 2016)

We hypothesized that shifting from oral second-generation antipsychotics (SGA) to their long-acting injectable (LAI) counterpart would be beneficial for the psychopathological, cognitive, social, and general health domains in outpatients suffering from schizophrenia. We aimed to evaluate the prospective usefulness of SGA-LAI treatment by carrying out a head-to-head comparison of two different medications (i.e., aripiprazole monohydrate (Ari-LAI) and paliperidone palmitate 1 and 3 month (PP1M, PP3M)) in a real-world setting, assessing the effectiveness and tolerability of Ari-LAI and PP1M/PP3M over a 15 month follow-up. A total of 69 consecutive individuals affected by schizophrenia were screened for eligibility. Finally, 46 outpatients (29 treated with Ari-LAI, 13 with PP1M, and four with PP3M) were evaluated through clinical, functional, and neuropsychological assessment administrated at baseline and after 3-, 12-, and 15-month follow-up periods. Moreover, periodic general medical evaluations were carried out. We estimated an overall improvement over time on the explored outcomes, without differences with respect to the type of LAI investigated, and with a global 16.4% dropout rate. Our findings suggest that switching from oral SGA to SGA-LAIs represents a valid and effective treatment strategy, with significant improvements on psychopathological, cognitive, social, and clinical variables for patients suffering from schizophrenia, regardless of the type of molecule chosen.

Background: Dissociative symptoms are under recognized and scarcely studied by clinicians and researchers in patients with bipolar disorder (BD). We examined the relationship between dissociative symptoms and the psychotic features in patients with BD and assessed clinical and socio-demographic characteristics more frequently associated with dissociative symptoms and treatment response.Methods: Participants were 100 adult outpatients with BD. They were screened with semi-structured interview to collect socio-demographic and clinical characteristics; the Dissociative Experiences Scale-II (DES-II) and the ALDA scale were used to assess dissociative psychopathologies and response to treatment with mood stabilizers, respectively.Results: DES score (mean 31.7 ± 21.7) correlated with clinical variables, BD features, and course of illness. Psychotic symptoms, mixed features, and previous suicide attempts significantly predicted DES score [F(3, 47) = 39.880, p < 0.001, R2 corrected = 0.713]. Dissociative symptoms were inversely correlated with poor response to treatment (r = −0.593; p < 0.001).Limitations: Cross-sectional design with a small sample and backward clinical assessment of psychotic symptoms.Conclusions: Dissociative phenomena are closely related to the presence of psychotic symptoms, mixed features, and previous suicide attempts in BD, especially in BD-I. Given the close association between dissociative and psychotic symptoms, this association could represent a diagnostic indicator of BD-I that may guide the clinician to plan the most appropriate treatment.

Calcium (Ca++) metabolism may be impaired in several psychiatric diseases. We hypothesize that calcium imbalance might also correlate with a specific chronotype and could be recognized as a marker of illness severity in bipolar disorder (BD). We aimed to (1) identify the association between calcium imbalance and a specific chronotype in a cohort of BD patients, and (2) test the mediation role of high parathyroid hormone (PTH) levels towards a specific chronotype and illness severity in BD patients. Patients’ socio-demographic and clinical characteristics were collected with an ad-hoc schedule. We administered the Hamilton Depression Rating Scale (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Young Mania Rating Scale (YMRS), and the Morningness Eveningness Questionnaire (MEQ). 100 patients affected by BD were recruited. The Kruskal-Wallis test showed a significant difference between the three MEQ groups in PTH levels (p < 0.001) and vitamin D levels (p = 0.048) but not in Ca++ levels (p = 0.426). Dwass-Steel-Critchlow-Fligner Pairwise analyses performed concerning three MEQ groups revealed significantly higher scores on PTH levels in MEQ-E subjects compared to MEQ-M and MEQ-I (in both cases, p < 0.001). No differences emerged between calcium levels among the three chronotypes. The mediation analysis has shown that elevated PTH levels are directly influenced by more severe HAM-A, HAM-D, and YMRS scores. MEQ-E could be a marker related to BD and predispose to various factors influencing mood symptoms. The combination of vitamin D therapy in MEQ-E may help to improve prognosis in this subtype of patients affected by BD.

Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological functions, including analgesic, neuroprotective, immune-modulating, and anti-inflammatory effects. Although the properties of PEA were first characterized nearly 65 years ago, the identity of the receptor mediating these actions has long remained elusive, causing a period of research stasis. In the last two decades, a renewal of interest in PEA occurred, and a series of interesting studies have demonstrated the pharmacological properties of PEA and clarified its mechanisms of action. Recent findings showed the ability of formulations containing PEA in promoting oligodendrocyte differentiation, which represents the first step for the proper formation of myelin. This evidence opens new and promising research opportunities. White matter defects have been detected in a vast and heterogeneous group of diseases, including age-related neurodegenerative disorders. Here, we summarize the history and pharmacology of PEA and discuss its therapeutic potential in restoring white matter defects.

Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy.

Background: Binge eating disorder (BED) is clinically relevant by virtue of the global impairment, poor quality of life, and increased overall medical morbidity. The high comorbidity with psychiatric disorders, particularly depression, has received attention as a possible mediator of the poor outcome. Further, BED and depression share cognitive dysfunctions. This naturalistic and uncontrolled pilot study aimed at evaluating the efficacy of vortioxetine (VTX) on depressive symptoms in patients with BED, secondly the efficacy in improving a broad array of executive functions, and third to explore the effect on eating behavior and body weight.Methods: This pilot study involved 30 patients with BED and comorbid MDD, treated with VTX for 24 weeks. Assessments were run at baseline (t0), 4 (t1), 8 (t2), 12 (t3), and 24 (t4) weeks. Changes in depressive symptoms (HDRS and BDI), executive functions, eating behaviors (binge frequency and severity, night eating, food addiction), and body weight were estimated after treatment with VTX through GLM.Results: Significant improvements emerged after treatment with VTX in: depression (HDRS p < 0.001; BDI p = 0.002) regardless the dose of VTX and first diagnosis (BED/MDD), working memory (RAVLT acquisition p = 0.01, delay recall p < 0.001, RCFT percentage of recall p = 0.01, and Attentional Matrices p = 0.05), binge days frequency (p < 0.001), binge eating severity (BES p < 0.001), night eating (p = 0.001), food addiction (YFAS 2.0 p = 0.039), and body weight (p = 0.039). The improvement in depressive symptoms was associated with the concurrent improvement in night eating as assessed by the I-NEQ.Conclusions: VTX can be a valid therapeutic choice for patients with BED with comorbid depression in controlling the depressive symptoms, working memory, and eating behavior. Indeed, by acting on affective symptoms, neurocognitive functioning, and eating behaviors, it confirms the results already obtained with VTX in other disorders, expanding them to BED.

Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called “entourage” effect. The present study investigated the ability of Adelmidrol (1 and 10 mg/Kg per os) to increase the endogenous level of PEA in the duodenum and colon of mice after 21-day oral administration in the presence and absence of PPAR-γ inhibitor (1 mg/kg). The level of PEA was analyzed by HPLC-MS. The expression of PEA-related enzymatic machinery was evaluated by western blot and RT-PCR analysis. Our findings demonstrated that Adelmidrol significantly increased PEA levels in the duodenum and colon in a dose/time-dependent manner. We also revealed that Adelmidrol up regulated the enzymatic machinery responsible for PEA metabolism and catabolism. Interestingly, the use of the selective irreversible PPAR-γ antagonist did not affect either PEA intestinal levels or expression/transcription of PEA metabolic enzymes following Adelmidrol administration. The “entourage effect” with Adelmidrol as an enhancer of PEA was thus PPAR-γ-independent. The findings suggest that Adelmidrol can maximize a PEA therapeutic-based approach in several intestinal morbidities.

Oligodendrocytes are cells fundamental for brain functions as they form the myelin sheath and feed axons. They perform these critical functions thanks to the cooperation with other glial cells, mainly astrocytes. The astrocyte/oligodendrocyte crosstalk needs numerous mediators and receptors, such as peroxisome proliferator-activated receptors (PPARs). PPAR agonists promote oligodendrocyte precursor cells (OPCs) maturation in myelinating oligodendrocytes. In the Alzheimer’s disease brain, deposition of beta-amyloid (Aβ) has been linked to several alterations, including astrogliosis and changes in OPCs maturation. However, very little is known about the molecular mechanisms. Here, we investigated for the first time the maturation of OPCs co-cultured with astrocytes in an in vitro model of Aβ1–42 toxicity. We also tested the potential beneficial effect of the anti-inflammatory and neuroprotective composite palmitoylethanolamide and luteolin (co-ultra PEALut), which is known to engage the isoform alfa of the PPARs. Our results show that Aβ1–42 triggers astrocyte reactivity and inflammation and reduces the levels of growth factors important for OPCs maturation. Oligodendrocytes indeed show low cell surface area and few arborizations. Co-ultra PEALut counteracts the Aβ1–42-induced inflammation and astrocyte reactivity preserving the morphology of co-cultured oligodendrocytes through a mechanism that in some cases involves PPAR-α. This is the first evidence of the negative effects exerted by Aβ1–42 on astrocyte/oligodendrocyte crosstalk and discloses a never-explored co-ultra PEALut ability in restoring oligodendrocyte homeostasis.

Non-invasive measurements of brain function and structure as neuroimaging in patients with mental illnesses are useful and powerful tools for studying discriminatory biomarkers. To date, functional MRI (fMRI), structural MRI (sMRI) represent the most used techniques to provide multiple perspectives on brain function, structure, and their connectivity. Recently, there has been rising attention in using machine‐learning (ML) techniques, pattern recognition methods, applied to neuroimaging data to characterize disease-related alterations in brain structure and function and to identify phenotypes, for example, for translation into clinical and early diagnosis. Our aim was to provide a systematic review according to the PRISMA statement of Support Vector Machine (SVM) techniques in making diagnostic discrimination between SCZ patients from healthy controls using neuroimaging data from functional MRI as input. We included studies using SVM as ML techniques with patients diagnosed with Schizophrenia. From an initial sample of 660 papers, at the end of the screening process, 22 articles were selected, and included in our review. This technique can be a valid, inexpensive, and non-invasive support to recognize and detect patients at an early stage, compared to any currently available assessment or clinical diagnostic methods in order to save crucial time. The higher accuracy of SVM models and the new integrated methods of ML techniques could play a decisive role to detect patients with SCZ or other major psychiatric disorders in the early stages of the disease or to potentially determine their neuroimaging risk factors in the near future.

Among the diverse cell types included in the general population named glia, astrocytes emerge as being the focus of a growing body of research aimed at characterizing their heterogeneous and complex functions. Alterations of both their morphology and activities have been linked to a variety of neurological diseases. One crucial physiological need satisfied by astrocytes is the cleansing of the cerebral tissue from waste molecules. Several data demonstrate that aquaporin-4 (AQP-4), a protein expressed by astrocytes, is crucially important for facilitating the removal of waste products from the brain. Aquaporins are water channels found in all district of the human organism and the most abundant isoform in the brain is AQP-4. This protein is involved in a myriad of astrocytic activities, including calcium signal transduction, potassium buffering, synaptic plasticity, astrocyte migration, glial scar formation and neuroinflammation. The highest density of AQP-4 is found at the astrocytic domains closest to blood vessels, the endfeet that envelop brain vessels, with low to zero expression in other astrocytic membrane regions. Increased AQP-4 expression and loss of polarization have recently been documented in altered physiological conditions. Here we review the latest findings related to aging and Alzheimer’s disease (AD) on this topic, as well as the available knowledge on pharmacological tools to target AQP-4.

Abstract Background Neuroglial cells that provide homeostatic support and form defence of the nervous system contribute to all neurological disorders. We analyzed three major types of neuroglia, astrocytes, oligodendrocytes, and microglia in the brains of an animal model of autism spectrum disorder, in which rats were exposed prenatally to antiepileptic and mood stabilizer drug valproic acid; this model being of acknowledged clinical relevance. Methods We tested the autistic-like behaviors of valproic acid-prenatally exposed male rats by performing isolation-induced ultrasonic vocalizations, the three-chamber test, and the hole board test. To account for human infancy, adolescence, and adulthood, such tasks were performed at postnatal day 13, postnatal day 35, and postnatal day 90, respectively. After sacrifice, we examined gene and protein expression of specific markers of neuroglia in hippocampus, prefrontal cortex, and cerebellum, these brain regions being associated with autism spectrum disorder pathogenesis. Results Infant offspring of VPA-exposed dams emitted less ultrasonic vocalizations when isolated from their mothers and siblings and, in adolescence and adulthood, they showed altered sociability in the three chamber test and increased stereotypic behavior in the hole board test. Molecular analyses indicate that prenatal valproic acid exposure affects all types of neuroglia, mainly causing transcriptional modifications. The most prominent changes occur in prefrontal cortex and in the hippocampus of autistic-like animals; these changes are particularly evident during infancy and adolescence, while they appear to be mitigated in adulthood. Conclusions Neuroglial pathological phenotype in autism spectrum disorder rat model appears to be rather mild with little signs of widespread and chronic neuroinflammation.

Abstract Background Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity. Methods Diarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPARα-mediated, PPARα−/− mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPARα−/− mice. Results HIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPARα−/− mice, PEA displayed no effects. In wildtype rats, PEA, via PPARα-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation. Conclusions EGCs mediate HIV-1 Tat-induced diarrhea by sustaining the intestinal neuroinflammatory response. These effects are regulated by PEA through a selective PPARα-dependent mechanism. PEA might be considered as an adjuvant therapy in HIV-1-induced diarrhea.

Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1β) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1β, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in angiotensin-converting enzyme-2 (ACE-2) following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.

Abstract Despite the effectiveness of combined anti-retroviral therapy, human immunodeficiency virus (HIV) infected-patients frequently report diarrhea and neuropsychological deficits. It is claimed that the viral HIV-1 Trans activating factor (HIV-1 Tat) protein is responsible for both diarrhea and neurotoxic effects, but the underlying mechanisms are not known. We hypothesize that colonic application of HIV-1 Tat activates glial cells of the enteric nervous system (EGCs), leading to a neuroinflammatory response able to propagate to the central nervous system. We demonstrated that HIV-1 Tat-induced diarrhea was associated with a significant activation of glial cells within the colonic wall, the spinal cord and the frontal cortex, and caused a consistent impairment of the cognitive performances. The inhibition of glial cells activity by lidocaine, completely abolished the above-described effects. These observations point out the role of glial cells as putative effectors in HIV-1 Tat-associated gastrointestinal and neurological manifestations and key regulators of gut-brain signaling.

Abstract Background Admixture analysis of age at onset (AAO) has helped delineating the clinical profile of early onset (EO) bipolar disorder (BD). However, there is scarce evidence comparing the distributional properties of AAO as well as the clinical features of EO BD type 1 (BD1) with EO BD type 2 (BD2). To this end, we studied 515 BD patients (224 BD1, 279 BD2, and 12 BD not otherwise specified [NOS]) diagnosed according to DSM-IV-TR criteria. Methods AAO was defined as the first reliably diagnosed hypo/manic or depressive episode according to diagnostic criteria. We used normal distribution mixture analysis to identify subgroups of patients according to AAO. Models were chosen according to the Schwarz’s Bayesian information criteria (BIC). Clinical correlates of EO were analysed using univariate tests and multivariate logistic regression models. Results A two normal components model best fitted the observed distribution of AAO in BD1 (BIC = −1599.3), BD2 (BIC = −2158.4), and in the whole sample (BIC = −3854.9). A higher number of EO BD2 patients had a depression-(hypo)mania-free interval (DMI) course, while a higher rate of (hypo)mania-depression-free interval (MDI) course was found in EO BD1. EO BD2 had also a higher rate of comorbidity with alcohol dependence compared to EO BD1. The latter finding was confirmed by multivariate logistic regression analysis. Conclusions In conclusion, both BD1 and BD2 had bimodal AAO distributions, but EO subgroups had a diagnostic-specific clinical delineation.

The worldwide prevalence of sleep disorders is approximately 50%, with an even higher occurrence in a psychiatric population. Bipolar disorder (BD) is a severe mental illness characterized by shifts in mood and activity. The BD syndrome also involves heterogeneous symptomatology, including cognitive dysfunctions and impairments of the autonomic nervous system. Sleep abnormalities are frequently associated with BD and are often a good predictor of a mood swing. Preservation of stable sleep–wake cycles is therefore a key to the maintenance of stability in BD, indicating the crucial role of circadian rhythms in this syndrome. The symptom most widespread in BD is insomnia, followed by excessive daytime sleepiness, nightmares, difficulty falling asleep or maintaining sleep, poor sleep quality, sleep talking, sleep walking, and obstructive sleep apnea. Alterations in the structure or duration of sleep are reported in all phases of BD. Understanding the role of neuroglia in BD and in various aspects of sleep is in nascent state. Contributions of the different types of glial cells to BD and sleep abnormalities are discussed in this paper.

Old age is a risk factor for Alzheimer’s disease (AD), which is characterized by hippocampal impairment together with substantial changes in glial cell functions. Are these alterations due to the disease progression or are they a consequence of aging? To start addressing this issue, we studied the expression of specific astrocytic and microglial structural and functional proteins in a validated transgenic model of AD (3×Tg-AD). These mice develop both amyloid plaques and neurofibrillary tangles, and initial signs of the AD-like pathology have been documented as early as three months of age. We compared male 3×Tg-AD mice at 6 and 12 months of age with their wild-type age-matched counterparts. We also investigated neurons by examining the expression of both the microtubule-associated protein 2 (MAP2), a neuronal structural protein, and the brain-derived neurotrophic factor (BDNF). The latter is indeed a crucial indicator for synaptic plasticity and neurogenesis/neurodegeneration. Our results show that astrocytes are more susceptible to aging than microglia, regardless of mouse genotype. Moreover, we discovered significant age-dependent alterations in the expression of proteins responsible for astrocyte–astrocyte and astrocyte–neuron communication, as well as a significant age-dependent decline in BDNF expression. Our data promote further research on the unexplored role of astroglia in both physiological and pathological aging.

Perinatal depression (PD) is a severe and disabling condition impacting negatively on children in terms of adverse neonatal outcomes and on the well-being of women and their families. All pregnant women attending the unit of Gynecology and Obstetrics Service of the University of Campania “L. Vanvitelli” will be screened for PD using the Edinburgh Postpartum Depression Scale (EPDS). Women with a score ≥10 at the EPDS will be invited to receive a full psychiatric assessment. The required sample size is of 126 women with PD which will be randomly allocated to either an experimental group, receiving a uni-familiar psychoeducational intervention, or to a control group, receiving the Best Treatment Option (BTO). Patients will be evaluated through several assessment instruments: Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), Manchester Short Assessment of Quality of Life (MANSA), Family Assessment Device (FAD), Family Coping Questionnaire (FCQ), and Pattern of Care Schedule (PCS). Patients will be evaluated at baseline, 3, 6, 9, and 12 months post-randomization. The severity of depressive symptoms at the HAM-D scale has been selected as primary outcome. Other outcome measures include improvement in the severity of anxiety symptoms, of global and personal functioning, an improvement in family members' coping strategies and in the level of quality of life. It has been highlighted the importance of developing screening and treating programs for PD, and our study will use rigorous study design to evaluate the efficacy of the adaption of a well-known family psychoeducational model to the treatment of PD. The aims of present trial are to: (1) develop an informative package for pregnant women with PD; (2) promote a screening programme for PD; (3) identify those (socio-demographic and pregnancy-related environmental) factors associated with a higher risk to develop a perinatal or postnatal depression; (4) evaluate the efficacy of a new experimental psychoeducational intervention in reducing the depressive symptoms during pregnancy compared to the BTO.

The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD.

Post-Traumatic Stress Disorder (PTSD) is a complex disorder involving dysregulation of stress-related hormones and neurotransmitter systems. Research focused on the endocannabinoid system (eCBS) for anxiety and stress regulation, cognitive and emotional responses modulation and aversive memories extinction, leading to the hypothesis that it could represent a possible alternative treatment target for PTSD. In this systematic review, we summarize evidence about the efficacy and safety of medicinal cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), and nabilone in PTSD treatment. The PRISMA statement guidelines were followed. A systematic literature search was conducted in MEDLINE/PubMed, Scopus and Web of Science by two independent researchers, who also performed data extraction and quality assessment. Among the initial 495 papers, 234 were screened for eligibility and 10 were included. Studies suggested that different medicinal cannabinoids at distinct doses and formulations could represent promising treatment strategies for the improvement of overall PTSD symptomatology as well as specific symptom domains (e.g., sleep disorders, arousal disturbances, suicidal thoughts), also influencing quality of life, pain and social impact. Although there is a robust rationale for treatment with drugs that target the eCBS and the results are promising, further studies are needed to investigate the safety and efficacy profile of their prolonged use.

Background and Objectives: Bipolar Disorder (BD) is a severe psychiatric disorder that worsens quality of life and functional impairment. Personality disorders (PDs), in particular Cluster B personality, have a high incidence among BD patients and is considered a poor prognostic factor. The study of this co-morbidity represents an important clinical and diagnostic challenge in psychiatry. Particularly, clinical overlap has been shown between antisocial personality disorder (ASPD) and BD that could worsen the course of both disorders. We aimed to detect the frequency of ASPD in bipolar patients with greater accuracy and the impact of ASPD on the clinical course of BD. Materials and Methods: A systematic literature search was conducted in PubMed, Embase, MEDLINE and the Cochrane Library through December 2020 without language or time restriction, according to PRISMA statement guidelines. Results: Initially, 3203 items were identified. After duplicates or irrelevant paper deletion, 17 studies met the inclusion criteria and were included in this review. ASPD was more frequent among BD patients, especially in BD type I. BD patients with ASPD as a comorbidity seemed to have early onset, higher number and more severe affective episodes, higher levels of aggressive and impulsive behaviors, suicidality and poor clinical outcome. ASPD symptoms in BD seem to be associated with a frequent comorbidity with addictive disorders (cocaine and alcohol) and criminal behaviors, probably due to a shared impulsivity core feature. Conclusions: Considering the shared symptoms such as impulsive and dangerous behaviors, in patients with only one disease, misdiagnosis is a common phenomenon due to the overlapping symptoms of ASPD and BD. It may be useful to recognize the co-occurrence of the disorders and better characterize the patient with ASPD and BD evaluating all dysfunctional aspects and their influence on core symptoms.

Background and objectives: Bipolar disorder (BD) is one of the most burdensome psychiatric illnesses, being associated with a negative long-term outcome and the highest suicide rate. Although affective temperaments can impact on BD long-term outcome, their role remains poorly investigated. The aims of the present study are to describe the clinical characteristics of patients with BD more frequently associated with the different affective temperaments and to assess the relation between affective temperaments and severity of clinical picture in a sample of patients with BD. Materials and Methods: A total of 199 patients have been recruited in the outpatients units of two university sites. Patients’ psychiatric symptoms, affective temperaments, and quality of life were investigated through validated assessment instruments. Results: Predominant cyclothymic and irritable temperaments are associated to higher number of relapses, poorer quality of life, higher rates of aggressive behaviors, and suicide attempts. Conversely, the predominant hyperthymic disposition was a protective factor for several outcome measures, including relapse rate, severity of anxiety, depressive and manic symptoms, suicidality, and earlier age at onset. One limitation of the present study is that the recruitment took place in two university sites; therefore, our findings cannot be fully generalized to the whole community of BD patients. Other limitations are the lack of a control group and the cross-sectional design of the study. Conclusions: The early identification of affective temperaments can help clinicians to identify those BD patients who are more likely to show a poor long-term outcome. An early screening of affective temperaments can be useful to develop targeted integrated pharmacological and psychosocial interventions.

Parathyroid hormone (PTH), vitamin D and serum calcium play a key role in several physiological and pathological conditions. Vitamin D and PTH receptors are largely expressed in the central nervous system and are involved in the modulation of inflammatory responses. Few studies investigated the association between calcium homeostasis imbalance and psychiatric disorders. This study aims to assess calcium homeostasis imbalance in patients with bipolar disorder (BD) and its impact on clinical outcome. We recruited 199 patients with BD, who were administered with validated assessment instruments to investigate depressive, manic and anxiety symptoms, affective temperaments, childhood trauma and global functioning. Serum calcium, vitamin D and PTH levels were assessed in all patients. Levels of PTH correlated with several clinical characteristics, including the diagnosis of bipolar disorder type I (BD-I), the presence of psychotic symptoms, lithium treatment, suicidality, total number of acute episodes and of hospitalizations (p < 0.0001) and seasonality (p < 0.05). At the regression analyses, higher levels of PTH were predicted by early age at onset, number of hospitalizations, aggressive behaviors (p < 0.05), higher Childhood Trauma Questionnaire total score (CTQ) (p < 0.001) and treatment with lithium (p = 0.01). Our findings suggest that the calcium homeostasis could play a role in BD patients, and that PTH levels are correlated with the clinical severity of the disorder.

Following publication of the original article [1], the authors reported an error in the legend of Table 2.

Patients with severe mental disorders die on average 20 years prior to the general population. This mortality gap is mainly due to the higher prevalence of physical diseases and the adoption of unhealthy lifestyle behaviors.The LIFESTYLE trial aims to evaluate the efficacy of a new psychosocial group intervention (including psychoeducational, motivational, and problem-solving techniques) focused on healthy lifestyle behavior compared to a brief educational group intervention in a community sample of patients with severe mental disorders. The trial is a national-funded, multicentric, randomized controlled trial with blinded outcome assessments, which is carried out in six outpatient units of the Universities of Campania “Luigi Vanvitelli” in Naples, Bari, Genova, L'Aquila, Pisa, and Rome—Tor Vergata. All patients are assessed at the following time points: baseline (T0); 2 months post-randomization (T1); 4 months post-randomization (T2); 6 months post-randomization (T3); 12 months post-randomization (T4); and 24 months post-randomization (T5). T1 and T2 assessments include only anthropometric tests. The BMI, a reliable and feasible anthropometric parameter, has been selected as primary outcome. In particular, the mean value of BMI at 6 months from baseline (T3) will be evaluated through a Generalized Estimated Equation model. The work hypothesis is that the LIFESTYLE psychosocial group intervention will be more effective than the brief educational group intervention in reducing the BMI. We expect a mean difference between the two groups of at least one point (and standard deviation of two points) at BMI. Secondary outcomes are: the improvement in dietary patterns, in smoking habits, in sleeping habits, physical activity, personal and social functioning, severity of physical comorbidities, and adherence to medications. The expected sample size consists of 420 patients (70 patients for each of the six participating centers), and they are allocated with a 1:1 ratio randomization, stratified according to center, age, gender, and educational level. Heavy smoking, sedentary behavior, and unhealthy diet pattern are very frequent and are associated with a reduced life expectancy and higher levels of physical comorbidities in people with severe mental disorders. New interventions are needed and we hope that the LIFESTYLE protocol will help to fill this gap.Trial registration number: 2015C7374S.

Although several findings indicate an association between adolescent cannabis abuse and the risk to develop schizophrenia later in life, the evidence for a causal relationship is still inconclusive. In the present study, we investigated the emergence of psychotic-like behavior in adult female rats chronically exposed to delta-9-tetrahydrocannabinol (THC) during adolescence.To this aim, female Sprague-Dawley rats were treated with THC during adolescence (PND 35–45) and, in adulthood (PND 75), a series of behavioral tests and biochemical assays were performed in order to investigate the long-term effects of adolescent THC exposure.Adolescent THC pretreatment leads to long-term behavioral alterations, characterized by recognition memory deficits, social withdrawal, altered emotional reactivity and sensitization to the locomotor activating effects of acute PCP.Moreover, since cortical disinhibition seems to be a key feature of many different animal models of schizophrenia and GABAergic hypofunction in the prefrontal cortex (PFC) has been observed in postmortem brains from schizophrenic patients, we then investigated the long-lasting consequences of adolescent THC exposure on GABAergic transmission in the adult rat PFC.Biochemical analyses revealed that adolescent THC exposure results in reduced GAD67 and basal GABA levels within the adult PFC. GAD67 expression is reduced both in parvalbumin (PV)- and cholecystokinin (CCK)-containing interneurons; this alteration may be related to the altered emotional reactivity triggered by adolescent THC, as silencing PFC GAD67 expression through a siRNA-mediated approach is sufficient to impact rats' behavior in the forced swim test. Finally, the cellular underpinnings of the observed sensitized response to acute PCP in adult THC-treated rats could be ascribed to the increased cFos immunoreactivity and glutamate levels in the PFC and dorsal striatum. The present findings support the hypothesis that adolescent THC exposure may represent a risk factor for the development of a complex psychotic-like behavior in adulthood.

Background and Objectives: Suicide is the leading cause of death in patients with Bipolar Disorder (BD). In particular, the high mortality rate is due to violent suicide attempts. Several risk factors associated with suicide attempts in patients with BD have been identified. Affective temperaments are associated with suicidal risk, but their predictive role is still understudied. The aim of this study is to assess the relationship between affective temperaments and personal history of violent suicide attempts. Materials and Methods: 74 patients with Bipolar Disorder type I (BD-I) or II (BD-II) were included. All patients filled in the short version of Munster Temperament Evaluation of the Memphis, Pisa, Paris and San Diego (short TEMPS-M) and the Temperament and Character Inventory, revised version (TCI-R). The sample was divided into two groups on the basis of a positive history for suicidal attempts and the suicidal group was further divided into two subgroups according to violent suicide attempts. Results: Violent suicide attempts were positively associated with the cyclothymic temperament and inversely to the hyperthymic one. BD-I patients and patients with a clinical history of rapid cycling were significantly more represented in the group of patients with a history of violent suicide attempts. Conclusions: Our study highlights that several clinical and temperamental characteristics are associated with violent suicide attempts, suggesting the importance of affective temperaments in the clinical management of patients with BPI.

BACKGROUND AND AIM:Angiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn's Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet. METHODS:The effects of PEA on inflammation-associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-α and -γ antagonists. RESULTS:Our results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-α dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in IBD and that PEA directly affects this pathway. CONCLUSIONS:Our results suggest that PEA may improve inflammation-driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis.

Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported.

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.