Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study.

BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses. METHOD: We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications. RESULTS: Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

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.

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.

Lower Plasma Levels of Selective VGF (Non-Acronymic) Peptides in Bipolar Disorder: Comparative Analysis Reveals Distinct Patterns across Mood Disorders and Healthy Controls.

INTRODUCTION: Discriminating bipolar disorder (BD) from major depressive disorder (MDD) remains a challenging clinical task. Identifying specific peripheral biosignatures that can differentiate between BD and MDD would significantly increase diagnostic accuracy. Dysregulated neuroplasticity is implicated in BD and MDD, and psychotropic medications restore specific disrupted processes by increasing neurotrophic signalling. The nerve growth factor inducible vgf gene (non-acronymic) encodes a precursor protein named proVGF, which undergoes proteolytic processing to produce several VGF peptides, some of which were suggested to be implicated in mood disorders and have antidepressant effects. Since the presence of VGF peptides in humans has been exclusively investigated in brain and cerebrospinal fluid, we aimed to identify which VGF peptides are present in the plasma and to investigate whether their levels could differentiate BD from MDD as well as responders from non-responders to pharmacological interventions. METHODS: VGF peptides were investigated in plasma from patients diagnosed with MDD (n = 37) or BD (n = 40 under lithium plus n = 29 never exposed to lithium), as well as healthy controls (HC; n = 36). RESULTS: Three VGF peptides (TLQP-11, AQEE-14, and NAPP-19) were identified using spectrometry analysis of plasma from HC. These peptides were then measured in the entire sample using ELISA, which showed significantly lower levels of AQEE and NAPP in BD than in HC and MDD (p = 5.0 × 10-5, p = 0.001, respectively). CONCLUSION: Our findings suggest that lower plasma levels of NAPP and AQEE are specifically associated with BD, thus possibly representing a diagnostic biomarker in mood disorders.

Leukocyte Telomere Length and Mitochondrial DNA Copy Number in Treatment-Resistant Depression and Response to Electroconvulsive Therapy: A Pilot Longitudinal Study.

OBJECTIVES: In this study, we investigated if changes in leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-cn), 2 markers of cellular aging, are associated with treatment-resistant depression (TRD) and with response to electroconvulsive therapy (ECT). METHODS: LTL and mtDNA-cn were measured in 31 TRD patients before (T0), 1 week (T1), and 4 weeks (T2) after the ECT course, as well as in a sample of 65 healthy controls. RESULTS: TRD patients had significantly shorter LTL and higher mtDNA-cn compared with healthy controls at baseline. In the TRD sample, LTL was inversely correlated with Montgomery-Åsberg Depression Rating Scale scores at baseline. Baseline levels of LTL or mtDNA-cn were not correlated with response to ECT. Similarly, changes in LTL or mtDNA-cn were not associated with response to ECT either when considered as a dichotomous trait (responders vs nonresponders) or as a percentage change in symptoms improvements. CONCLUSIONS: Ours is the first longitudinal study exploring the role of LTL and mtDNA-cn in response to ECT. Findings of this pilot investigation suggest that LTL and mtDNA-cn may constitute disease biomarkers for TRD but are not involved in response to ECT.

A Secondary Analysis of the Complex Interplay between Psychopathology, Cognitive Functions, Brain Derived Neurotrophic Factor Levels, and Suicide in Psychotic Disorders: Data from a 2-Year Longitudinal Study.

Identifying phenotypes at high risk of suicidal behaviour is a relevant objective of clinical and translational research and can facilitate the identification of possible candidate biomarkers. We probed the potential association and eventual stability of neuropsychological profiles and serum BDNF concentrations with lifetime suicide ideation and attempts (LSI and LSA, respectively) in individuals with schizophrenia (SCZ) and schizoaffective disorder (SCA) in a 2-year follow-up study. A secondary analysis was conducted on a convenience sample of previously recruited subjects from a single outpatient clinic. Retrospectively assessed LSI and LSA were recorded by analysing the available longitudinal clinical health records. LSI + LSA subjects consistently exhibited lower PANSS-defined negative symptoms and better performance in the BACS-letter fluency subtask. There was no significant association between BDNF levels and either LSI or LSA. We found a relatively stable pattern of lower negative symptoms over two years among patients with LSI and LSA. No significant difference in serum BDNF concentrations was detected. The translational viability of using neuropsychological profiles as a possible avenue for the identification of populations at risk for suicide behaviours rather than the categorical diagnosis represents a promising option but requires further confirmation.

The Role of Copper Overload in Modulating Neuropsychiatric Symptoms.

Copper is a transition metal essential for growth and development and indispensable for eukaryotic life. This metal is essential to neuronal function: its deficiency, as well as its overload have been associated with multiple neurodegenerative disorders such as Alzheimer's disease and Wilson's disease and psychiatric conditions such as schizophrenia, bipolar disorder, and major depressive disorders. Copper plays a fundamental role in the development and function of the human Central Nervous System (CNS), being a cofactor of multiple enzymes that play a key role in physiology during development. In this context, we thought it would be timely to summarize data on alterations in the metabolism of copper at the CNS level that might influence the development of neuropsychiatric symptoms. We present a non-systematic review with the study selection based on the authors' judgement to offer the reader a perspective on the most significant elements of neuropsychiatric symptoms in Wilson's disease. We highlight that Wilson's disease is characterized by marked heterogeneity in clinical presentation among patients with the same mutation. This should motivate more research efforts to disentangle the role of environmental factors in modulating the expression of genetic predisposition to this disorder.

Lithium and its effects: does dose matter?

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.

Symptomatic remission and recovery in major psychosis: Is there a role for BDNF? A secondary analysis of the LABSP cohort data.

Remission, relapse prevention, and clinical recovery are crucial areas of interest in schizophrenia (SCZ) research. Although SCZ is a chronic disorder with poor overall outcomes, years of research demonstrated that recovery is possible. There are considerable data linking brain-derived neurotrophic factor (BDNF) to SCZ, however, evidence on the role of BDNF in remission in SCZ is scarce. This secondary analysis of the Longitudinal Assessment of BDNF in Sardinian patients (LABSP) data aimed to investigate the relationship between serum BDNF levels and symptomatic remission, simultaneous clinical and functional remission, and recovery in patients with SCZ. A total of 105 patients with SCZ or schizoaffective disorder were recruited for a longitudinal assessment of BDNF levels over 24 months. Longitudinal data were analyzed using mixed-effects linear regression models. The study found significant associations between use of long acting injectables (χ2 = 7.075, df = 1, p = 0.008), baseline serum BDNF levels (U = 701, z = -2.543, p = 0.011), and "childhood" (U = 475, z = -2.124, p = 0.034) and "general" (U = 55, z = -2.014, p = 0.044) subscales of the Premorbid Adjustment Scale (PAS) with patients maintaining remission and recovery. The diagnosis of SCZ was significantly associated with lower BDNF levels for patients with simultaneous clinical and functional remission (Z = 2.035, p = 0.0419) and recovery (Z = 2.009, p = 0.0445) compared to those without. There were no significant associations between remission in the entire sample and longitudinal serum BDNF levels or genetic variants within the BDNF gene. These findings provide further insight into the complex relationship between BDNF and SCZ.

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.

Food and Alcohol Disturbance in High School Adolescents: Prevalence, Characteristics and Association with Problem Drinking and Eating Disorders.

Food and alcohol disturbance (FAD) is characterized by the association of alcohol use with compensatory behaviors such as restricting calories, physical activity and purging. Despite not being part of the current nosography, research has grown in the past 10 years, mostly on college students' samples. In this study, we aim to describe the prevalence, characteristics and association of FAD with problem drinking (PD) and eating disorder risk (EDR) in a sample of Italian high school students. Participants were 900 high school students (53.6% males; mean age = 16.22) that were administered standardized questionnaires. Students who screened positive for PD, EDR and both were, respectively, 17.3%, 5.9% and 1.3%. Approximately one out four students reported FAD behaviors, mostly to control weight and by restricting calories, with higher prevalence and severity among those who screened positive for PD. Purging behaviors were rare overall (15.5%), but significantly more frequent in participants who screened positive for both PD and EDR (41.7%). FAD was more strongly associated with alcohol use severity than with ED symptom severity across all subgroups. FAD behaviors appear to be common in the Italian high school population and more strongly associated with PD. Future studies should investigate FAD's impact on adolescents' functioning and possible early interventions.

A Pilot Interaction Analysis of Gut Microbiota and Peripheral Markers of Aging in Severe Psychiatric Disorders: A Role for Lachnoclostridium?

Excessive predominance of pathological species in the gut microbiota could increase the production of inflammatory mediators at the gut level and, via modification of the gut-blood barrier, at the systemic level. This pro-inflammatory state could, in turn, increase biological aging that is generally proxied by telomere shortening. In this study, we present findings from a secondary interaction analysis of gut microbiota, aging, and inflammatory marker data from a cohort of patients with different diagnoses of severe mental disorders. We analyzed 15 controls, 35 patients with schizophrenia (SCZ), and 31 patients with major depressive disorder (MDD) recruited among those attending a community mental health center (50 males and 31 females, mean and median age 46.8 and 46.3 years, respectively). We performed 16S rRNA sequencing as well as measurement of telomere length via quantitative fluorescence in situ hybridization and high-sensitivity C-reactive protein. We applied statistical modeling with logistic regression to test for interaction between gut microbiota and these markers. Our results showed statistically significant interactions between telomere length and gut microbiota pointing to the genus Lachnostridium, which remained significantly associated with a reduced likelihood of MDD even after adjustment for a series of covariates. Although exploratory, these findings show that specific gut microbiota signatures overexpressing Lachnoclostridium and interacting with biological aging could modulate the liability for MDD.

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study.

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

A genome-wide association study of antidepressant-induced mania.

Antidepressant-induced mania (AIM) is a side effect of antidepressant treatment that is characterized by mania or hypomania after the start of medication. It is likely polygenic, but its genetic component remains largely unexplored. We aim to conduct the first genome-wide association study of AIM in 814 bipolar disorder patients of European ancestry. We report no significant findings from our single-marker or gene-based analyses. Our polygenic risk score analyses also did not yield significant results with bipolar disorder, antidepressant response, or lithium response. Our suggestive findings on the hypothalamic-pituitary-adrenal axis and the opioid system in AIM require independent replications.

Probing the Association between Cognition, Suicidal Behavior and Tryptophan Metabolism in a Sample of Individuals Living with Bipolar Disorder: A Secondary Analysis.

Background and Objectives: Alterations in hot cognition and in the tryptophan metabolism through serotonin (5-HT) and kynurenine (KYN) pathways have been associated with an increased risk of suicidal behavior. Here, we aim at probing the association between Stroop test performances and tryptophan pathway components in a sample of individuals with bipolar disorder (BD). Materials and Methods: We explored the association between the Emotion Inhibition Subtask (EIS) performances of the Brief Assessment of Cognition for Affective Disorders (BAC-A) and plasmatic levels of 5-hydroxytriptophan (5-HTP), 5-HT, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KYNA) among subjects reporting lifetime suicide ideation (LSI) vs. non-LSI and subjects reporting lifetime suicide attempts (LSA) vs. non-LSA. Results: In a sample of 45 subjects with BD, we found a statistically significant different performance for LSA vs. non-LSA in the color naming (CN) and neutral words (NW) EIS subtasks. There was a significant association between CN performances and plasma 5-HTP levels among LSI and LSA subjects but not among non-LSI or non-LSA. Conclusions: In our sample, patients with LSA and LSI presented lower performances on some EIS subtasks compared to non-LSA and non-LSI. Moreover, we found an inverse correlation between plasma 5-HTP concentration and some EIS performances in LSA and LSI but not among non-LSA or non-LSI. This may represent an interesting avenue for future studies probing this complex association.

Pharmacological Treatment of Bipolar Depression: A Review of Observational Studies.

The persistence of depressive morbidity is frequent in bipolar disorder, and the pharmacological management of this symptomatology often lacks effectiveness. This systematic review aimed to summarize the results of the naturalistic observational studies on the pharmacological treatment of bipolar depression published through April 2022. The certainty of evidence was evaluated according to the GRADE approach. In sum, 16 studies on anticonvulsants, 20 on atypical antipsychotics, 2 on lithium, 28 on antidepressants, and 9 on other compounds were found. Lamotrigine, quetiapine, aripiprazole, and ketamine were the most investigated compounds. Overall, the results support the recommendations regarding the effectiveness of lamotrigine and quetiapine. In contrast to the current recommendations, aripiprazole was shown to be effective and generally well tolerated. Additionally, SSRIs were shown to be effective, but, since they were associated with a possibly higher switch risk, they should be used as an adjunctive therapy to mood stabilizers. Lithium was only studied in two trials but was shown to be effective, although the serum concentrations levels were not associated with clinical response. Finally, ketamine showed divergent response rates with a low certainty of evidence and, so far, unclear long-term effects. Heterogeneity in diagnosis, sample sizes, study designs, reporting of bias, and side effects limited the possibility of a head-to-head comparison.

Pharmacokinetic Markers of Clinical Outcomes in Severe Mental Illness: A Systematic Review.

The term severe mental illness (SMI) encompasses those psychiatric disorders exerting the highest clinical burden and socio-economic impact on the affected individuals and their communities. Pharmacogenomic (PGx) approaches hold great promise in personalizing treatment selection and clinical outcomes, possibly reducing the burden of SMI. Here, we sought to review the literature in the field, focusing on PGx testing and particularly on pharmacokinetic markers. We performed a systematic review on PUBMED/Medline, Web of Science, and Scopus. The last search was performed on the 17 September 2022, and further augmented with a comprehensive pearl-growing strategy. In total, 1979 records were screened, and after duplicate removal, 587 unique records were screened by at least 2 independent reviewers. Ultimately, forty-two articles were included in the qualitative analysis, eleven randomized controlled trials and thirty-one nonrandomized studies. The observed lack of standardization in PGx tests, population selection, and tested outcomes limit the overall interpretation of the available evidence. A growing body of evidence suggests that PGx testing might be cost-effective in specific settings and may modestly improve clinical outcomes. More efforts need to be directed toward improving PGx standardization, knowledge for all stakeholders, and clinical practice guidelines for screening recommendations.

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.

Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders.

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.