Impulsivity, aggressivity and mood disorders: a narrative review

Aggressiveness and Impulsivity represent clinically significant elements in the context of coexisting mental disorders and have been extensively studied in the context of mood disorders. Considering their significant impact on prognostic trajectories, accruing evidence suggests the need to consider these elements in the development of specific treatment strategies tailored to the specific requirements at the individual patient level and in the specific context where care is delivered. In the present narrative review, we propose to the reader a selection of study articles deemed relevant to the discussion of this complex subject, with a critical analysis of the available evidence regarding empiric evidence for the association of aggressiveness and impulsivity with a focus on bipolar disorder and major depressive disorder. A brief overview of reports deemed relevant to the discussion for some of the possible biological basis for this phenomena is also outlined, offering a selection of studies based on the study authors' judgement

Leukocytosis associated with clozapine treatment: A case series and systematic review of the literature

Background and Objectives: Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia. Despite its superior efficacy profile as compared with other antipsychotics, clozapine remains underutilized. Clozapine monitoring systems clearly describe the proposed management of clozapine-induced neutropenia; however, no specific mention is made of how to interpret neutrophilic leukocytosis, despite that being a relatively frequent finding. Prescribers unfamiliar with this molecule may misjudge its clinical significance, potentially leading to untimely treatment interruption. Here, we systematically review the literature on the risk of neutrophilic leukocytosis during clozapine treatment, and describe eight additional cases among our patient cohort. Materials and Methods: We performed a systematic review of the literature on PubMed and Embase using the PRISMA 2020 guidelines, and selected all original reports describing either (1) the prevalence of neutrophilic leukocytosis during clozapine treatment, or (2) the clinical significance of neutrophilic leukocytosis. We described eight additional cases of neutrophilic leukocytosis during clozapine treatment while attending an outpatient psychiatric clinic. Results: Our research ultimately yielded the selection of 13 articles included in this systematic review. The case series highlighted the presence of stable and clinically unremarkable neutrophilia during a follow-up ranging from one to ten years. Conclusions: Existing evidence indicates that leukocytosis associated with clozapine treatment can be considered as an asymptomatic and benign condition, suggesting that no change in clozapine treatment is needed upon its detection

The role of gut microbiota in the high-risk construct of severe mental disorders: A mini review

Severe mental disorders (SMD) are highly prevalent psychiatric conditions exerting an enormous toll on society. Therefore, prevention of SMD has received enormous attention in the last two decades. Preventative approaches are based on the knowledge and detailed characterization of the developmental stages of SMD and on risk prediction. One relevant biological component, so far neglected in high risk research, is microbiota. The human microbiota consists in the ensemble of microbes, including viruses, bacteria, and eukaryotes, that inhabit several ecological niches of the organism. Due to its demonstrated role in modulating illness and health, as well in influencing behavior, much interest has focused on the characterization of the microbiota inhabiting the gut. Several studies in animal models have shown the early modifications in the gut microbiota might impact on neurodevelopment and the onset of deficits in social behavior corresponding to distinct neurosignaling alterations. However, despite this evidence, only one study investigated the effect of altered microbiome and risk of developing mental disorders in humans, showing that individuals at risk for SMD had significantly different global microbiome composition than healthy controls. We then offer a developmental perspective and provided mechanistic insights on how changes in the microbiota could influence the risk of SMD. We suggest that the analysis of microbiota should be included in the comprehensive assessment generally performed in populations at high risk for SMD as it can inform predictive models and ultimately preventative strategies

Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets

Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate method to detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (rg = −0.14, p = 6.5E−10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds

The role of affective temperaments in self-care and medication adherence among individuals with bipolar disorder: a moderation analysis

Background Affective 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.Objectives This 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.Methods A 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.Results The 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.Conclusions Affective 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

The Role of Magnesium in Pregnancy and in Fetal Programming of Adult Diseases

Magnesium is an essential trace metal and a necessary factor for multiple biochemical functions in humans. Its role in biology is fundamental in over 600 enzymatic reactions implicated in protein synthesis, mitochondrial functions, neuromuscular activity, bone formation, and immune system competence. Magnesium status is relevant in fetal development during gestation and in the newborn growth during the perinatal period. Moreover, magnesium is able to influence fetal programming and disease presentation in childhood or adulthood. The aim of this review is to focus on this metal homeostasis, analyzing its normal values, the causes of hypomagnesemia, the interaction with drugs and other conditions, and the diseases associated with magnesium value alteration during pregnancy, in order to study its role in fetal programming of adult diseases. The data here reported clearly indicated the existence of a connection between magnesium status and human pathology starting from intrauterine life and extending into childhood and adulthood

Increased C-reactive protein concentration and suicidal behavior in people with psychiatric disorders: A systematic review and meta-analysis

Objective: Suicide is a leading cause of death worldwide. Identifying factors associated with suicidality (suicidal ideation [SI]/suicidal behavior) could increase our understanding of the pathophysiological underpinnings of suicide and improve its prevention. Methods: We conducted a systematic review (PubMed/PsycInfo/Cochrane databases, up to September 2020) and random-effect meta-analysis including observational studies comparing peripheral C-reactive protein (CRP) levels in suicidal versus non-suicidal patients affected by any psychiatric disorder and healthy controls (HC). Primary outcome was the CRP standardized mean difference (SMD) between patients with high suicidality versus those with absent or low suicidality. Secondary outcomes were SMD of CRP levels between those with suicide attempt versus no suicide attempt, as well as between those with (high) versus low or absent SI. Quality of included studies was measured with Newcastle-Ottawa scale. Results: Out of initial 550 references, 21 observational studies involving 7682 subjects (7445 with mood disorders or first-episode psychosis, 237 HC) were included. A significant association of CRP levels with suicidality (SMD 0.688, 95% CI 0.476–0.9, p < 0.001) emerged. CRP levels were higher in individuals with high SI (SMD 1.145, 95% CI 0.273–2.018, p = 0.010) and in those with suicide attempt (SMD 0.549, 95%CI 0.363–0.735, p < 0.001) than non-suicidal individuals (either patients or HC). Main analyses were confirmed in sensitivity analysis (removing HC), and after adjusting for publication bias. The cross-sectional design of included studies, and the high heterogeneity of diagnosis and treatment limit the generalizability of these results. Median quality of included studies was high. Conclusion: CRP is associated with higher suicidality in patients with mental disorders. Large cohort studies longitudinally monitoring CRP levels are needed to explore its longitudinal association with suicidality

Cost–utility analysis of pharmacogenetic testing based on CYP2C19 or CYP2D6 in major depressive disorder: assessing the drivers of different cost-effectiveness levels from an Italian societal perspective

Background and Objectives Major depressive disorder (MDD) is a common and severe psychiatric disorder that has enor- mous economical and societal costs. As pharmacogenetics is one of the key tools of precision psychiatry, we analyze the cost–utility of test screening of CYP2C19 and CYP2D6 for patients suffering from major depressive disorder (MDD) and try to understand the main drivers that influence the cost–utility. Methods We developed two pharmacoeconomic nonhomogeneous Markov models to test the cost–utility, from an Ital- ian societal perspective, of pharmacogenetic testing genetic to characterize the metabolizing profiles of cytochrome P450 (CYP) 2C19 and CYP2D6 in a hypothetical case study of patients suffering from major depressive disorder (MDD). The model considers different scenarios of adjustment of antidepressant treatment according to the patient’s metabolizing profile or treatment over a period of 18 weeks. The uncertainty of model parameters is tested through both a probabilistic sensitivity analysis and a one-way deterministic sensitivity analysis, and these results are used in a post-hoc analysis to understand the main drivers of three alternative cost-effectiveness levels (“poor,” “standard,” and “high”). These drivers are first evaluated from an exploratory multidimensional perspective and next from a predictive perspective as the probability that a patient belongs to a specific cost-effectiveness level is estimated on the basis of a restricted set of parameters used in the original pharmacoeconomic model. Results The models for CYP2C19 and CYP2D6 indicate that screening has an incremental cost-effectiveness ratio of 60,000€ and 47,000€ per quality-adjusted life year (QALY), respectively. The probabilistic sensitivity analysis shows that the treat- ments are cost-effective for a 75,000€ willingness to pay (WTP) threshold in 58% and 63% of the Monte Carlo replications, respectively. The post-hoc analysis highlights the factors that allow us to clearly discriminates poor cost-effectiveness from high cost-effectiveness scenarios and demonstrates that it is possible to predict with reasonable accuracy the cost-effectiveness of a genetic test and the associated therapeutic pattern. Conclusions Our findings suggest that screenings for both CYP2C19 and CYP2D6 enzymes for patients with MDD are cost-effective for a WTP threshold of 75,000€ per QALY, and provide relevant suggestions about the most important aspects to be further explored in clinical studies aimed at addressing the cost-effectiveness of genetic testing for patients diagnosed with MDD

Sex differences in shared genetic determinants between severe mental disorders and metabolic traits

High rates of metabolic risk factors contribute to premature mortality in patients with severe mental disorders, but the molecular underpinnings of this association are largely unknown. We performed the first analysis on shared genetic factors between severe mental disorders and metabolic traits considering the effect of sex. We applied an integrated analytical pipeline on the largest sex-stratified genome-wide association datasets available for bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and for body mass index (BMI) and waist-to-hip ratio (WHR) (all including participants of European origin). We observed extensive genetic overlap between all severe mental disorders and variants associated with BMI in women or men and identified several genetic loci shared between BD, or SZ and BMI in women (24 and 91, respectively) or men (13 and 208, respectively), with mixed directions of effect. A large part of the identified genetic variants showed sex differences in terms of location, genes modulated in adipose tissue and/or brain regions, and druggable targets. By providing a complete picture of disorder specific and cross-disorder shared genetic determinants, our results highlight potential sex differences in the genetic liability to metabolic comorbidities in patients with severe mental disorders

Has VZV epidemiology changed in Italy? Results of a seroprevalence study

The aim of the study was to evaluate if and how varicella prevalence has changed in Italy. In particular a seroprevalence study was performed, comparing it to similar surveys conducted in pre-immunization era. During 2013–2014, sera obtained from blood samples taken for diagnostic purposes or routine investigations were collected in collaboration with at least one laboratory/center for each region, following the approval of the Ethics Committee. Data were stratified by sex and age. All samples were processed in a national reference laboratory by an immunoassay with high sensitivity and specificity. Statutory notifications, national hospital discharge database and mortality data related to VZV infection were analyzed as well. A total of 3707 sera were collected and tested. In the studied period both incidence and hospitalization rates decreased and about 5 deaths per year have been registered. The seroprevalence decreased in the first year of life in subjects passively protected by their mother, followed by an increase in the following age classes. The overall antibody prevalence was 84%. The comparison with surveys conducted with the same methodology in 1996–1997 and 2003–2004 showed significant differences in age groups 1–19 y. The study confirms that in Italy VZV infection typically occurs in children. The impact of varicella on Italian population is changing. The comparison between studies performed in different periods shows a significant increase of seropositivity in age class 1–4 years, expression of vaccine interventions already adopted in some regions