Everything changes but nothing changes: gender stereotypes in the Italian population.

PURPOSE: Gender stereotypes refer to consensual or cultural shared beliefs about the attributes of men and women, influencing society behaviors, interpersonal relationships, education, and workplace. The literature has shown the existence of gender stereotypes on career choices, internalization of roles, and school and social experiences and demonstrates the impact of demographic factors on stereotypes. However, all the studies conducted in Italy available in scientific literature analyzed small sample sizes within specific schools of university settings, with a limited age range. METHODS: To assess the current state of gender stereotypes in Italy, we conducted an online survey from October 2022 to January 2023 on the general population residing in Italy. The questionnaire comprised sociodemographic factors and questions about gender stereotypes, investigating six fields: games, jobs, personality traits, home and family activities, sports, and moral judgments. RESULTS: The study involved 1854 participants, mostly women (70.1%) with an undergraduate or postgraduate degree (57.5%). The statistical and descriptive analyses revealed that gender stereotypes influenced respondents' beliefs, with statistically significant effects observed in most questions when stratifying by age, gender, and degree. Principal component analysis was performed to assess latent variables in different fields, revealing significant main stereotypes in each category. No statistically significant differences between men and women were found for the fields home and family activities, games, and moral judgments, confirming that stereotypes affect both men and women in the same way. CONCLUSIONS: Our results show the persistence of gender stereotypes in any fields investigated, although our cohort is predominantly composed of high educational level women living in the North of Italy. This demonstrates that the long-standing gender stereotypes are prevalent, pernicious, and, unfortunately, internalized at times even by successful women pushbacking and sabotaging them unconsciously.

Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Genetic determinants of circulating VEGF levels in major depressive disorder and electroconvulsive therapy response.

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome-wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome-wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy-one patients with treatment-resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR-corrected p = 2.4 × 10-5 ) and in patients with major depressive disorder (best SNP: FDR-corrected p = 2.6 × 10-3 ). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.

Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.

BDNF Genotype and Baseline Serum Levels in Relation to Electroconvulsive Therapy Effectiveness in Treatment-Resistant Depressed Patients.

OBJECTIVES: Electroconvulsive therapy (ECT) represents one of the most effective therapies for treatment-resistant depression (TRD). The brain-derived neurotrophic factor (BDNF) is a neurotrophin implicated in major depressive disorder and in the effects of different therapeutic approaches, including ECT. Both BDNF peripheral levels and Val66Met polymorphism have been suggested as biomarkers of treatment effectiveness. The objective of this study was to test the potential of serum BDNF levels and Val66Met polymorphism in predicting ECT outcome in TRD patients. METHODS: Seventy-four TRD patients scheduled to undergo ECT were included in the study. Illness severity was assessed through the Montgomery and Asberg Depression Rating Scale before beginning ECT (T0), the day after the end of ECT (T1), and 1 month after the end of ECT (T2). At T1, patients were classified as responders/nonresponders and remitters/nonremitters, whereas at T2, they were classified as sustained responders/nonresponders and sustained remitters/nonremitters. Serum concentrations of BDNF were measured at T0, and the BDNF Val66Met polymorphism was genotyped. RESULTS: No difference in BDNF concentrations was observed in responders versus nonresponders, in remitters versus nonremitters, in sustained responders versus sustained nonresponders, and in sustained remitters versus sustained nonremitters. No association of Val66Met polymorphism was detected with both the response and the remission status. CONCLUSIONS: Baseline serum BDNF levels and the BDNF Val66Met polymorphism showed no clinical utility in predicting ECT outcome in TRD patients.

Electroconvulsive Therapy in a Patient With Chronic Catatonia: Clinical Outcomes and Cerebral 18[F]Fludeoxyglucose Positron Emission Tomography Findings.

Catatonia is a psychomotor syndrome that can be associated with both psychiatric diseases (mainly mood disorders, but also psychotic disorders) and medical conditions. Lorazepam (6-21 mg/day, occasionally up to 30 md/day) is the first choice treatment and electroconvulsive therapy (ECT) is the second line, regardless of the underlying clinical condition. There are some evidences also for effectiveness of other medications. Patients treated acutely usually show rapid and full therapeutic response but even longstanding catatonia can improve. However, some authors suggested that chronic catatonia in the context of schizophrenia is phenomenologically different and less responsive to lorazepam and ECT, especially if associated with echophenomena. We present here the case of a patient with longstanding catatonic schizophrenia treated with antipsychotics who significantly improved after ECT. Improvement regarded mainly catatonia, but also negative symptoms, cognition and psychosocial functioning. A slight amelioration in prefrontal metabolism (Brain[F]FDG PET) one month following the ECT course was also noted.

Seizure Adequacy Markers and the Prediction of Electroconvulsive Therapy Response.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective therapy for patients with treatment-resistant depression; however, some patients do not respond or relapse in a short time. Electroconvulsive therapy stimulus parameters may be related to the outcome. We carried out a retrospective study review to investigate various ECT parameters in relation to the outcome, clinical variables, and pharmacological treatments. Our aim was to understand which factors could be considered putative seizure quality markers and which are relevant to clinical practice. METHODS: Two physicians evaluated the seizure length, the postictal suppression index, the wave amplitude, tachycardia, and hemispheric brain wave synchronicity in a double-blind manner for 45 treatment-resistant depression patients receiving ECT. RESULTS: The analysis showed a significant association between the outcome and the ECT seizure quality measured by the parameters (P = 9.9 × 10). Among patients with poor-quality seizures, 61.5% relapsed after approximately 1 month from the last ECT session. Particularly, there was an association between higher symptomatology decrease and higher quality of hemispheric brain wave synchronicity (P = 5.0 × 10), as well as a higher wave amplitude (P = 0.01). CONCLUSIONS: Our results confirm that ECT seizure quality was strongly correlated with the decrease of depressive symptomatology.

The role of GRIK4 gene in treatment-resistant depression.

Several lines of evidence implicate abnormalities in glutamatergic neural transmission in major depressive disorder (MDD) and treatment response. A high percentage of MDD patients do not respond adequately to antidepressants and are classified as having treatment-resistant depression (TRD). In this study we investigated five GRIK4 variants, previously associated with antidepressants response, in an Italian cohort of 247 MDD no-TRD and 380 TRD patients. We found an association between rs11218030 G allele and TRD. Moreover, significant associations between rs11218030 and rs1954787 and the presence of psychotic symptoms were observed. In conclusion, our data support the involvement of GRIK4 in TRD and in the risk of developing psychotic symptoms during depressive episodes.

Childhood neglect, the neglected trauma. A systematic review and meta-analysis of its prevalence in psychiatric disorders.

Traumatic events increase risk of mental illnesses, but childhood neglect prevalence in psychiatric disorders is understudied. This systematic review and meta-analysis assessed neglect prevalence, including emotional neglect (EN) and physical neglect (PN), among adults with psychiatric disorders. We conducted a systematic search and meta-analysis in 122 studies assessing different psychiatric disorders. Prevalence was 46.6% (95%CI[34.5-59.0]) for unspecified neglect (Ne), 43.1% (95%CI[39.0-47.4]) for EN, and 34.8% (95%CI[30.6-39.2]) for PN. Although a moderating effect of the psychiatric diagnostic category was not confirmed, some clinical diagnoses had significantly lower prevalence rates than others. Patients with bipolar disorder and major depressive disorder showed lower prevalence rates of EN and PN, whereas lower prevalence was found in psychotic disorders and eating disorders for PN only. Neglect assessment was a significant moderator for Ne and PN. No moderating effect of age and sex on neglect prevalence was found. Heterogeneity levels within and between psychiatric diagnostic categories remained high. This is the first meta-analysis examining diverse types of neglect prevalence considering different psychiatric diagnoses. Our results explore the prevalence of childhood neglect and its subtypes among adults with psychiatric disorders, contributing to understanding the nuanced interplay between neglect and specific psychiatric conditions, and guiding interventions for affected individuals.

DNA methylation changes in association with trauma-focused psychotherapy efficacy in treatment-resistant depression patients: a prospective longitudinal study.

Background: Stressful events increase the risk for treatment-resistant depression (TRD), and trauma-focused psychotherapy can be useful for TRD patients exposed to early life stress (ELS). Epigenetic processes are known to be related to depression and ELS, but there is no evidence of the effects of trauma-focused psychotherapy on methylation alterations.Objective: We performed the first epigenome-wide association study to investigate methylation changes related to trauma-focused psychotherapies effects in TRD patients.Method: Thirty TRD patients assessed for ELS underwent trauma-focused psychotherapy, of those, 12 received trauma-focused cognitive behavioural therapy, and 18 Eye Movement Desensitization and Reprocessing (EMDR). DNA methylation was profiled with Illumina Infinium EPIC array at T0 (baseline), after 8 weeks (T8, end of psychotherapy) and after 12 weeks (T12 - follow-up). We examined differentially methylated CpG sites and regions, as well as pathways analysis in association with the treatment.Results: Main results obtained have shown 110 differentially methylated regions (DMRs) with a significant adjusted p-value area associated with the effects of trauma-focused psychotherapies in the entire cohort. Several annotated genes are related to inflammatory processes and psychiatric disorders, such as LTA, GFI1, ARID5B, TNFSF13, and LST1. Gene enrichment analyses revealed statistically significant processes related to tumour necrosis factor (TNF) receptor and TNF signalling pathway. Stratified analyses by type of trauma-focused psychotherapy showed statistically significant adjusted p-value area in 141 DMRs only for the group of patients receiving EMDR, with annotated genes related to inflammation and psychiatric disorders, including LTA, GFI1, and S100A8. Gene set enrichment analyses in the EMDR group indicated biological processes related to inflammatory response, particularly the TNF signalling pathway.Conclusion: We provide preliminary valuable insights into global DNA methylation changes associated with trauma-focused psychotherapies effects, in particular with EMDR treatment.

Stressful events increase treatment-resistant depression, and trauma-focused psychotherapy can be useful for these patients.Epigenome-wide data shows changes associated with trauma-focused psychotherapies, especially eye movement desensitization and reprocessing therapy, in treatment-resistant depression patients.Genes and biological pathways related to inflammatory and immune systems are among the most statistically significant results.

Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes.

BACKGROUND: Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results. METHODS: In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects. RESULTS: An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82).Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4, OR = 0.46, 95% CI: 0.30-0.70).In relation to diagnostic subtypes, the estimated/phased DAO GT diplotype and PPP3CC CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively. CONCLUSIONS: Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes (DAO, PPP3CC, DTNBP1) might be involved in schizophrenia pathogenic mechanisms related to gender.

Role of allelic variants of FK506-binding protein 51 (FKBP5) gene in the development of anxiety disorders.

BACKGROUND: Anxiety disorders exhibit remarkably high rates of comorbidity with major depressive disorder (MDD). Mood and anxiety disorders are considered stress-related diseases. Genetic variations in the co-chaperone FK506-binding protein 51, FKBP5, which modulates the function of glucocorticoid receptors, have been associated with an increased risk for the development of posttraumatic stress disorder, but data regarding its role in MDD are controversial. The aims of this study were to clarify the role of the FKBP5 gene in depression and anxiety disorders through a case-control study and an association study with personality traits using the Temperament and Character Inventory (TCI) in healthy subjects. METHODS: Six hundred fifty-seven MDD patients, with or without an anxiety disorder in comorbidity, and 462 healthy volunteers were enrolled in the study. Two hundred fifty-six controls agreed to fill out the TCI. RESULTS: The results showed that the T allele of rs1360780 was more frequent among the patients affected by MDD with a comorbidity of anxiety disorders, compared to those without (P < .001). Among the controls, we found that the T allele more often exhibited personality traits associated with an increased vulnerability to anxiety. CONCLUSIONS: These results support the hypothesis that allelic variants of FKBP5 are a risk factor for anxiety disorders. The identification of genetic variants involved in anxiety may have implications for the optimization of therapeutic interventions.

Genome-wide association studies on Northern Italy isolated populations provide further support concerning genetic susceptibility for major depressive disorder.

OBJECTIVES: Major depressive disorder (MDD) is a psychiatric disorder with pathogenesis influenced by both genetic and environmental factors. To date, the molecular-level understanding of its aetiology remains unclear. Thus, we aimed to identify genetic variants and susceptibility genes for MDD with a genome-wide association study (GWAS) approach. METHODS: We performed a meta-analysis of GWASs and a gene-based analysis on two Northern Italy isolated populations (cases/controls n = 166/472 and 33/320), followed by replication and polygenic risk score (PRS) analyses in Italian independent samples (cases n = 464, controls n = 339). RESULTS: We identified two novel MDD-associated genes, KCNQ5 (lead SNP rs867262, p = 3.82 × 10-9) and CTNNA2 (rs6729523, p = 1.25 × 10-8). The gene-based analysis revealed another six genes (p < 2.703 × 10-6): GRM7, CTNT4, SNRK, SRGAP3, TRAPPC9, and FHIT. No replication of the genome-wide significant SNPs was found in the independent cohort, even if 14 SNPs around CTNNA2 showed association with MDD and related phenotypes at the nominal level of p (<0.05). Furthermore, the PRS model developed in the discovery cohort discriminated cases and controls in the replication cohort. CONCLUSIONS: Our work suggests new possible genes associated with MDD, and the PRS analysis confirms the polygenic nature of this disorder. Future studies are required to better understand the role of these findings in MDD.

Biological markers of sex-based differences in major depressive disorder and in antidepressant response.

Major depressive disorder (MDD) presents different clinical features in women and men, with women being more affected and responding differently to antidepressant treatment. Specific molecular mechanisms underlying these differences are not well studied and this narrative review aims at providing an overview of the neurobiological features underlying sex-differences in biological systems involved in MDD pathophysiology and response to antidepressant treatment, focusing on human studies. The majority of the reviewed studies were performed through candidate gene approaches, focusing on biological systems involved in MDD pathophysiology, including the stress response, inflammatory and immune, monoaminergic, neurotrophic, gamma-aminobutyric acid and glutamatergic, and oxytocin systems. The influence of the endocrine system and sex-specific hormone effects are also discussed. Genome, epigenome and transcriptome-wide approaches are less frequently performed and most of these studies do not focus on sex-specific alterations, revealing a paucity of omics studies directed to unravel sex-based differences in MDD. Few studies about sex-related differences in antidepressant treatment response have been conducted, mostly involving the inflammatory system, with less evidence on the monoaminergic system and sparse evidence in omics approaches. Our review covers the importance of accounting for sex-differences in research, optimizing patient stratification for a more precise diagnostic and individualized treatment for women and men.

Psychological impact of Covid-19 pandemic in mental healthcare workers: a cross-sectional study in an Italian Department of Mental Health.

AIM: The Covid-19 pandemic is having a great impact on the lives of healthcare workers, but its psychological impact on Mental Healthcare Workers (MHWs) remains to be better explored. The aims of the present study were to assess the correlates and predictors of stress and adverse psychological effects in MHWs during the first waves of the Covid-19 pandemic. METHODS: A total of 124 MHWs (psychiatrist/psychiatry resident, nurse, psychologist/psychotherapist, psychiatric rehabilitation therapist/educator, other mental health professional) working in public facilities of the ASST Spedali Civili of Brescia, Italy, was assessed between June 28, 2020 and August 10, 2020 with an online questionnaire that included sociodemographic, professional and Covid-19 exposure information, the Impact of Event Scale - Revised and the Depression Anxiety Stress Scales 21. Multivariate linear regression models were designed to identify individual predictors of post-traumatic, depressive, anxiety and stress-symptoms. RESULTS: The professional role of nurse, having more years of professional experience and experiencing the death of a patient emerged as predictors of more severe post-traumatic symptoms. The professional role of nurse emerged as the only predictor of more severe depressive symptoms; the professional role of nurse and having more years of professional experience emerged as predictors of more severe anxiety symptoms; more years of professional experience, higher workloads, worse team relationships and experiencing the death of a loved one emerged as predictors of more severe stress symptoms. CONCLUSIONS: Alongside other stressful factors, the professional role of nurse and more years of professional experience emerged as predictors of adverse psychological events. Working as a MHW, particularly with high levels of contact with patients during the Covid-19 pandemic, may be considered strenuous work, requiring dedicated training and interventions to improve resilience. KEY WORDS: Anxiety, Covid-19, depression, mental healthcare workers, stress-related disorder, stressful life events.

The role of pharmacogenetics in the treatment of major depressive disorder: a critical review.

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

Multi-omics data integration methods and their applications in psychiatric disorders.

To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently. Technological advancements and decreasing costs of high throughput sequencing has led to an unprecedented increase in data generation. Furthermore, over the years it has become increasingly clear that these subsystems do not act in isolation but instead interact with each other to drive mental illness and health. Consequently, individual subsystems are now analysed jointly to promote a holistic understanding of the underlying biological complexity of health and disease. Complementing the increasing data availability, current research is geared towards developing novel methods that can efficiently combine the information rich multi-omics data to discover biologically meaningful biomarkers for diagnosis, treatment, and prognosis. However, clinical translation of the research is still challenging. In this review, we summarise conventional and state-of-the-art statistical and machine learning approaches for discovery of biomarker, diagnosis, as well as outcome and treatment response prediction through integrating multi-omics and clinical data. In addition, we describe the role of biological model systems and in silico multi-omics model designs in clinical translation of psychiatric research from bench to bedside. Finally, we discuss the current challenges and explore the application of multi-omics integration in future psychiatric research. The review provides a structured overview and latest updates in the field of multi-omics in psychiatry.

An integrated precision medicine approach in major depressive disorder: a study protocol to create a new algorithm for the prediction of treatment response.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients' empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance.

ErbB3 mRNA leukocyte levels as a biomarker for major depressive disorder.

BACKGROUND: In recent years, the identification of peripheral biomarkers that are associated with psychiatric diseases, such as Major Depressive Disorder (MDD), has become relevant because these biomarkers may improve the efficiency of the differential diagnosis process and indicate targets for new antidepressant drugs. Two recent candidate genes, ErbB3 and Fgfr1, are growth factors whose mRNA levels have been found to be altered in the leukocytes of patients that are affected by bipolar disorder in a depressive state. On this basis, the aim of the study was to determine if ErbB3 and Fgfr1 mRNA levels could be a biomarkers of MDD. METHODS: We measured by Real Time PCR ErbB3 and Fgfr1 mRNA expression levels in leukocytes of MDD patients compared with controls. Successively, to assess whether ErbB3 mRNA levels were influenced by previous antidepressant treatment we stratified our patients sample in two cohorts, comparing drug-naive versus drug-free patients. Moreover, we evaluated the levels of the transcript in MDD patients after 12 weeks of antidepressant treatment, and in prefrontal cortex of rats stressed and treated with an antidepressant drug of the same class. RESULTS: These results showed that ErbB3 but not Fgfr1 mRNA levels were reduced in leukocytes of MDD patients compared to healthy subjects. Furthermore, ErbB3 levels were not affected by antidepressant treatment in either human or animal models CONCLUSIONS: Our data suggest that ErbB3 might be considered as a biomarker for MDD and that its deficit may underlie the pathophysiology of the disease and is not a consequence of treatment. Moreover the study supports the usefulness of leukocytes as a peripheral system for identifying biomarkers in psychiatric diseases.