Working alliance in treating staff and patients with Schizophrenia Spectrum Disorder living in Residential Facilities.

OBJECTIVES: Working Alliance (WA) is important in the care of patients with Schizophrenia Spectrum Disorders (SSD). This study aims to determine which sociodemographic and clinical factors are associated with WA, as assessed by patients and staff members in Residential Facilities (RFs), and may predict WA dyads' discrepancies. METHODS: Three hundred and three SSD patients and 165 healthcare workers were recruited from 98 RFs and characterized for sociodemographic features. WA was rated by the Working Alliance Inventory (WAI) for patients (WAI-P) and staff members (WAI-T). SSD patients were assessed for the severity of psychopathology and psychosocial functioning. RESULTS: Pearson's correlation revealed a positive correlation (ρ = .314; p < .001) between WAI-P and WAI-T ratings. Linear regression showed that patients with higher education reported lower WAI-P ratings (ß = -.50, p = .044), while not being engaged in work or study was associated with lower WAI-T scores (ß = -4.17, p = .015). A shorter lifetime hospitalization was associated with higher WAI-P ratings (ß = 5.90, p = .008), while higher psychopathology severity negatively predicted WAI-T (ß = -.10, p = .002) and WAI-P ratings (ß = -.19, p < .001). Better functioning level positively foresaw WAI-T (ß = .14, p < .001) and WAI-P ratings (ß = .12, p < .001). Regarding discrepancies, staff members' age was associated with higher dyads discrepancy in Total scale and Agreement subscale scores, which were also associated with more severe negative symptoms, while patients' age was negatively correlated to Relationship subscale discrepancy. CONCLUSIONS: This study provides insight into the factors that influence WA in SSD patients and health workers in RFs. The findings address interventions to improve WA and ultimately patient outcomes.

Exposure to violence in childhood and risk of violence in adult schizophrenia: Results from a multinational study.

This study investigated the connection between childhood violence exposure and violent behavior in adults with schizophrenia spectrum disorders (SSDs). The case-control study included 398 SSD patients: 221 cases with a history of severe interpersonal violence in the past and 177 controls with no history of violence. The findings indicated that cases were significantly more likely to report childhood exposure to all forms of witnessed or personally sustained violence both within and outside the family, with those who had witnessed intra-familial violence being more likely to assault a family member in adulthood. Cases reported exposure to violence before the age of 12 years significantly more frequently than controls, and those with early-life violence exposure were significantly more likely to report that they were in a state of intense anger when they behaved violently. A dose-response relationship was observed, with evidence of an increased risk of later violence when the exposure occurred before the age of 12 and an increased likelihood of intrafamilial violence. The evidence suggests that childhood violence exposure was associated with an increased risk of violent behavior in adult SSD patients, and early exposure was linked to an increased likelihood of physical violence occurring in states of intense anger.

Eating Disorders and Disturbed Eating Behaviors Underlying Body Weight Differences in Patients Affected by Endometriosis: Preliminary Results from an Italian Cross-Sectional Study.

This study aimed to characterize the prevalence of eating disorders (EDs), disturbed eating behaviors (DEBs), and emotional eating attitudes (EEAs) among patients affected by endometriosis in order to understand a potential crosslink between this impacting gynecological disease and a Body Mass Index shift. A total of 30 patients were recruited at an endometriosis outpatient clinic in Bologna and were assessed by using standardized instruments and specific questionnaires for EDs, DEBs, and EEAs. Sociodemographic information and endometriosis clinical features and history information were collected by adopting a specific questionnaire. Retrospective reports of lifetime Body Mass Index (BMI) changes, current BMI, peak pain severity during the last menstrual period, and the average of pain intensity during the last intermenstrual period were used for a correlation with the mean score from eating-behavior scales' assessment. The preliminary results indicate that, although only 3.33% of endometriosis patients are affected by ED, statistically significant differences at the mean scores of DEBs and EEAs assessment scales were found by stratifying patients on the basis of BMI levels at risk for infertility and coronary heart disease and on the basis of moderate/severe pain levels. The enrichment of the sample size and the recruitment of the control group to complete the study enrollment will allow us to investigate more complex and strong correlation findings and to assess the prevalence of EDs among endometriosis patients.

Characterisation of medication side effects in patients with mostly resistant depression in a real-world setting.

OBJECTIVES: This study aimed to identify factors associated with side effects of psychotropic drugs in a real-world setting enriched with treatment-resistant depression (TRD) patients. METHODS: A total of 1410 depressed patients were treated in a naturalistic setting. Side effects were measured with the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU); the total score and UKU subscales were considered. Clinical-demographic variables were tested for association with side effects in univariate and then multivariate analyses. RESULTS: Total, psychic and neurological side effects were associated with depressive symptom severity, while autonomic side effects were higher in those with somatic comorbidities and other side effects were lower in patients receiving trazodone. In multivariate analyses, depressive symptom severity was associated with psychic and total side effects, while generalised anxiety disorder (GAD) with neurological side effects and somatic comorbidities remained associated with autonomic side effects. Trazodone was associated with lower side effects and with augmentation treatments. Augmentation therapies showed opposite effects depending on response status, i.e. increased or decreased the risk of side effects in responders and non-responders/resistant patients, respectively. CONCLUSIONS: Psychic side effects may be difficult to distinguish from depressive symptoms and factors associated with different types of side effects are heterogeneous and likely interacting.

Epigenetic Basis of Psychiatric Disorders: A Narrative Review.

BACKGROUND: Psychiatric disorders are complex, multifactorial illnesses with a demonstrated biological component in their etiopathogenesis. Epigenetic modifications, through the modulation of DNA methylation, histone modifications and RNA interference, tune tissue-specific gene expression patterns and play a relevant role in the etiology of psychiatric illnesses. OBJECTIVE: This review aims to discuss the epigenetic mechanisms involved in psychiatric disorders, their modulation by environmental factors and their interactions with genetic variants, in order to provide a comprehensive picture of their mutual crosstalk. METHODS: In accordance with the PRISMA guidelines, systematic searches of Medline, EMBASE, PsycINFO, Web of Science, Scopus, and the Cochrane Library were conducted. RESULTS: Exposure to environmental factors, such as poor socio-economic status, obstetric complications, migration, and early life stressors, may lead to stable changes in gene expression and neural circuit function, playing a role in the risk of psychiatric diseases. The most replicated genes involved by studies using different techniques are discussed. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions and they interact with genetic variants in determining the risk of psychiatric disorders. CONCLUSION: An increasing amount of evidence suggests that epigenetics plays a pivotal role in the etiopathogenesis of psychiatric disorders. New therapeutic approaches may work by reversing detrimental epigenetic changes that occurred during the lifespan.

Compulsory and voluntary admissions in comparison: A 9-year long observational study.

BACKGROUND: Few studies, so far, have been specifically designed to highlight the features related to Compulsory Admissions (CA) and Voluntary Admissions (VA) in Italian psychiatric emergency wards. AIMS: The main purpose of this observational study was to compare the sociodemographic and clinical characteristics of VA and CA and to explore possible predictors of re-admissions. METHODS: During a 6-month Index Period (February, the 1st-July, the 31st 2008) all psychiatric admissions were documented and then followed-up through all available informatic systems for the next 9 years. RESULTS: Out of 390 hospitalizations, 101 (25.9%) were compulsory (CA rate was 2.79 per 10,000 inhabitants per year, mean duration of hospitalizations of 7.33 ± 7.84 days). Diagnoses were recorded for the 325 patients who had been hospitalized during index period: schizophrenic psychoses ([p = .042], in particular schizophrenia [p = .027]), manic episode (p = .044), and delusional disorders (p = .009) were associated with CA; conversely, the diagnosis of unipolar major depression (p = .005) and personality disorders (p = .048) were significantly more frequent in VA. The 325 admitted patients were followed up for 1,801 person-years. No significant differences were found in terms of drop-outs, transferring, and discharge rates, and mortality rates due to both natural causes and suicides. Factors associated with at least one compulsory readmission were younger age and having had a previous CA (p = .011); conversely having been engaged with psychiatric services for over 1 year prior to index hospitalization was protective for a subsequent CA (p = .013). CONCLUSIONS: After a 40-year old political reform, the current study shows that, in a context of integrated outpatient and inpatient services, engagement with outpatient care may be protective for compulsory rehospitalization.

Psychiatric hospitalization during the two SARS-CoV-2 pandemic waves: New warnings for acute psychotic episodes and suicidal behaviors.

BACKGROUND: The subsequent waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have represented a dramatic health emergency characterized by significant consequences on mental health. Diachronic variations in the incidence rates of acute relapse of psychiatric disorders may represent significant "sentinel events" for assessing the mental health response to an unprecedented stressful event. AIM: To investigate the variation in psychiatric hospitalization rates and differences in sociodemographic and clinical-psychopathological peculiarities at Bologna "Maggiore" General Hospital Psychiatric Ward (GHPW) between the first two waves SARS-CoV-2 pandemic and the same periods of the previous 3 years. The secondary purpose of the study was to suggest a diachronic response pathway to stress by reporting additional literature data on coping strategies. METHODS: This observational and retrospective study collected information on admission to the GHPW at the "Maggiore" Hospital in Bologna in the index periods defined as follows: the first period between February 24, 2020 and April 30, 2020 (first epidemic wave) and the second period between October 8, 2020, and January 7, 2021 (second pandemic wave). Absolute numbers and proportion of admitted patients, their sociodemographic and clinical-psychopathological characteristics were compared with the same parameters recorded in the two same periods of the previous 3 years. No strict inclusion or exclusion criteria were provided in the data collection to collect information on all patients requiring acute psychiatric hospitalization. RESULTS: During the first wave, there was a significant reduction in hospitalization rates, although there was a simultaneous increase in compulsory hospitalizations and the acute relapse of schizophrenia spectrum and other psychotic disorders. During the second wave, hospitalization rates reached those recorded during the same period of the previous 3 years, mainly due to the rise of bipolar and related disorders, depressive disorders, anxiety disorders, trauma- and stressor-related disorders and suicidal behaviors. CONCLUSION: The coping strategies adopted during the first wave of the SARS-CoV-2 pandemic protected the vulnerable population from the general risk of clinical-psychopathological acute relapse, even if they increased the susceptibility to run into schizophrenia spectrum and other psychotic disorder relapses. In the medium-long term (as in the second pandemic wave), the same strategies do not play protective roles against the stress associated with the pandemic and social restriction measures. Indeed, during the second wave of the SARS-CoV-2 pandemic, an increase in total hospitalization rate, suicidal behaviors and the incidence rate of bipolar and related disorders, depressive disorders, anxiety disorders, trauma- and stressor-related disorders was observed.

A Perspective on Chronic and Long-Lasting Anorexia Nervosa.

Anorexia Nervosa (AN) is a severe eating disorder which typically develops in younger females. Many studies focus on this specific population, a majority of which will eventually partially or fully recover. A minority will become chronic despite extensive treatment. These patients are treatment-resistant and may not necessarily benefit from usual treatment. In this article we will reflect on possible mechanisms which may explain the maintenance of disease, and especially on the possible role of affective and anxiety disturbances. We will use, due to the lack of large-scale studies, data from risk and prognostic factors, treatment options and neurobiological correlates in chronic AN patients. Lastly, we will propose how these elements may advise further research and treatments.

Compulsory treatments in eating disorders: a systematic review and meta-analysis.

INTRODUCTION: The aims of this systematic review and meta-analysis are to provide a summary of the current literature concerning compulsory treatments in patients with eating disorders (ED) and to understand whether compulsorily and involuntarily treated patients differ in terms of baseline characteristics and treatment outcomes. METHODS: Relevant articles were identified following the PRISMA guidelines by searching the following terms: "treatment refusal", "forced feeding", "compulsory/coercive/involuntary/forced treatment/admission", "eating disorders", "feeding and eating disorders", "anorexia nervosa", "bulimia nervosa". Research was restricted to articles concerning humans and published between 1975 and 2020 in English. RESULTS: Out of 905 articles retrieved, nine were included for the analyses allowing the comparisons between 242 compulsorily and 738 voluntarily treated patients. Mean body mass index (BMI) was slightly lower in patients compelled to treatments. Mean illness duration, BMI at discharge and BMI variation showed no significant differences between the two groups. Average length of hospitalization was 3 weeks longer among compulsory-treated patients, but this did not result in a higher increase in BMI. No significant risk difference on mortality was estimated (three studies). CONCLUSIONS: Compulsory treatments are usually intended for patients having worse baseline conditions than voluntary ones. Those patients are unlikely to engage in treatments without being compelled but, after the treatments, albeit with longer hospitalisations, they do achieve similar outcomes. Therefore, we can conclude that forcing patients to treatment is a conceivable option. LEVEL OF EVIDENCE: Level I, systematic review and meta-analysis.

How Does SARS-CoV-2 Affect the Central Nervous System? A Working Hypothesis.

Interstitial pneumonia was the first manifestation to be recognized as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, in just a few weeks, it became clear that the coronavirus disease-2019 (COVID-19) overrun tissues and more body organs than just the lungs, so much so that it could be considered a systemic pathology. Several studies reported the involvement of the conjunctiva, the gut, the heart and its pace, and vascular injuries such as thromboembolic complications and Kawasaki disease in children and toddlers were also described. More recently, it was reported that in a sample of 214 SARS-CoV-2 positive patients, 36.4% complained of neurological symptoms ranging from non-specific manifestations (dizziness, headache, and seizures), to more specific symptoms such hyposmia or hypogeusia, and stroke. Older individuals, especially males with comorbidities, appear to be at the highest risk of developing such severe complications related to the Central Nervous System (CNS) involvement. Neuropsychiatric manifestations in COVID-19 appear to develop in patients with and without pre-existing neurological disorders. Growing evidence suggests that SARS-CoV-2 binds to the human Angiotensin-Converting Enzyme 2 (ACE2) for the attachment and entrance inside host cells. By describing ACE2 and the whole Renin Angiotensin Aldosterone System (RAAS) we may better understand whether specific cell types may be affected by SARS-CoV-2 and whether their functioning can be disrupted in case of an infection. Since clear evidences of neurological interest have already been shown, by clarifying the topographical distribution and density of ACE2, we will be able to speculate how SARS-CoV-2 may affect the CNS and what is the pathogenetic mechanism by which it contributes to the specific clinical manifestations of the disease. Based on such evidences, we finally hypothesize the process of SARS-CoV-2 invasion of the CNS and provide a possible explanation for the onset or the exacerbation of some common neuropsychiatric disorders in the elderly including cognitive impairment and Alzheimer disease.

The role of leptin in antipsychotic-induced weight gain: genetic and non-genetic factors.

Schizophrenia is a chronic and disabling mental illness affecting millions of people worldwide. A greater proportion of people with schizophrenia tends to be overweight. Antipsychotic medications have been considered the primary risk factor for obesity in schizophrenia, although the mechanisms by which they increase weight and produce metabolic disturbances are unclear. Several lines of research indicate that leptin could be a good candidate involved in pathways linking antipsychotic treatment and weight gain. Leptin is a circulating hormone released by adipocytes in response to increased fat deposition to regulate body weight, acting through receptors in the hypothalamus. In this work, we reviewed preclinical, clinical, and genetic data in order to infer the potential role played by leptin in antipsychotic-induced weight gain considering two main hypotheses: (1) leptin is an epiphenomenon of weight gain; (2) leptin is a consequence of antipsychotic-induced "leptin-resistance status," causing weight gain.

Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance.

Clinical and experimental evidence indicates that atypical antipsychotics impair glucose metabolism. We investigated whether clozapine may directly affect insulin action by analyzing insulin signaling in vitro and in vivo. Clozapine reduced insulin-stimulated glucose uptake in PC12 and in L6 cells, representative models of neuron and skeletal muscle, respectively. Consistently, clozapine reduced insulin effect on insulin receptor (IR) by 40% and on IR substrate-1 (IRS1) tyrosine phosphorylation by 60%. Insulin-stimulated Akt phosphorylation was also reduced by about 40%. Moreover, insulin-dependent phosphorylation of protein kinase C-ζ (PKC-ζ) was completely blunted in clozapine-treated cells. Interestingly, clozapine treatment was accompanied by an insulin-independent increase of Akt phosphorylation, with no change of IR, IRS1, and PKC-ζ basal phosphorylation. The cellular abundance of Ped/Pea-15, an Akt substrate and inducer of insulin resistance, was also increased following clozapine exposure, both in the absence and in the presence of cyclohexymide, a protein synthesis inhibitor. Similar as in cellular models, in the caudate-putamen and in the tibialis muscle of clozapine-treated C57/BL/KsJ mice, Akt phosphorylation and Ped/Pea-15 protein levels were increased and PKC-ζ phosphorylation was decreased. Thus, in these experimental models, clozapine deranged Akt function and up-regulated Ped/Pea-15, thereby inhibiting insulin stimulation of PKC-ζ and of glucose uptake.

Pattern of acute induction of Homer1a gene is preserved after chronic treatment with first- and second-generation antipsychotics: effect of short-term drug discontinuation and comparison with Homer1a-interacting genes.

Homer1a is a glutamate-related gene whose expression is induced by antipsychotics acutely (i.e. 90 min after treatment). Acute Homer1a expression is preserved after prolonged antipsychotic treatments, while the effects of short-term discontinuation after chronic antipsychotic treatment have not yet been assessed. Here, we studied early and long-term effects on gene expression by antipsychotics for Homer1a and other components of glutamatergic synapses. In the first paradigm, we evaluated Homer1a acute expression by single administration of antipsychotics (haloperidol 0.8 mg/kg, ziprasidone 10 and 4 mg/kg, clozapine 15 mg/kg). Haloperidol and ziprasidone induced Homer1a in the striatum. Induction by ziprasidone was dose-dependent. These results suggest that acute Homer1a expression correlates with dopaminergic affinity and motor side effects of antipsychotics. In the second paradigm, we studied antipsychotic-mediated long-term changes in Homer1a and glutamate-related genes. Rats were treated (21 days) with haloperidol 0.8 mg/kg, ziprasidone 4 mg/kg, or vehicle, and then sacrificed at 90 min (early time-point) or 24 h (delayed time-point) after last injection. Gene expression at these two time-points was compared. Homer1a preserved its pattern of expression at the early but not at the delayed time-point. Significant changes were also observed for PSD-95. The results suggest that Homer1a preserves its expression profile after chronic antipsychotics.

Parent of origin effect and differential allelic expression of BDNF Val66Met in suicidal behaviour.

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since BDNF levels are decreased in brain and plasma of suicide victims. Because the differential allelic expression of Val66Met BDNF gene on suicidal behaviour has not been investigated, we analyzed the parent-of-origin effect (POE) in suicide attempters and the differential expression of BDNF Val66Met alleles in suicide victims. METHODS: We performed a family-based association study and ETDT analyses of the Val66Met polymorphism in nuclear families with at least one subject affected by major psychosis with suicidal behaviour, and compared allele-specific mRNA levels in post-mortem brain samples from suicide and non-suicide victims. The subjects included in this study have diagnosis of schizophrenia, bipolar disorder type I and type II. RESULTS: Allele 3 in the GT repeat polymorphism was transmitted significantly more often to patients who attempted suicide (maternal transmissions: 46/22, P = 0.003; paternal transmissions: 55/30, P = 0.006). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of Val/Met-specific mRNA expression between suicide victims and controls. CONCLUSIONS: These data do not support a role for allelic imbalance or POE of BDNF for suicidal behaviour in major psychoses.

Weight gain, schizophrenia and antipsychotics: new findings from animal model and pharmacogenomic studies.

Excess body weight is one of the most common physical health problems among patients with schizophrenia that increases the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, and hypertension, and accounts in part for 20% shorter life expectancy than in general population. Among patients with severe mental illness, obesity can be attributed to an unhealthy lifestyle, personal genetic profile, as well as the effects of psychotropic medications, above all antipsychotic drugs. Novel "atypical" antipsychotic drugs represent a substantial improvement on older "typical" drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. Animal models of antipsychotic-related weight gain and animal transgenic models of knockout or overexpressed genes of antipsychotic receptors have been largely evaluated by scientific community for changes in obesity-related gene expression or phenotypes. Moreover, pharmacogenomic approaches have allowed to detect more than 300 possible candidate genes for antipsychotics-induced body weight gain. In this paper, we summarize current thinking on: (1) the role of polymorphisms in several candidate genes, (2) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction, and (3) the state of development of animal models in this matter. We also outline major areas for future research.

Differential expression of Homer 1 gene by acute and chronic administration of antipsychotics and dopamine transporter inhibitors in the rat forebrain.

Neuronal expression of immediate-early genes in response to a drug is a powerful screening tool for dissecting anatomical and functional brain circuitry affected by psychoactive compounds. We examined the effect of dopaminergic perturbation on two Homer 1 gene splice variants, Homer 1a and ania-3, in rat forebrain. Rats were treated with the "typical" antipsychotic haloperidol, the "atypical" quetiapine, or the selective dopamine transporter (DAT) inhibitor GBR 12909 in acute and chronic paradigms. Our results show that the high affinity dopamine D(2) receptor antagonist haloperidol strongly induces Homer 1 gene expression in the caudate-putamen, whereas quetiapine, a fast D2R dissociating antagonist, does not. This confirms that Homer 1 may be considered a predictor of "atypicality" of antipsychotic compounds in acute and also chronic regimens. Chronic treatment with GBR 12909 showed a strong induction in the parietal cortex, resembling the activation of "sensitization" circuitry by stimulants. Finally, we describe a differential spatial induction pattern of Homer 1 gene within the caudate-putamen by typical antipsychotics and DAT blockers, and propose a novel method to quantitate it.