Dissecting the Long-Term Effect of Stress Early in Life on FKBP5: The Role of miR-20b-5p and miR-29c-3p.

Exposure to early-life stress (ELS) has been related to an increased susceptibility to psychiatric disorders later in life. Although the molecular mechanisms underlying this association are still under investigation, glucocorticoid signaling has been proposed to be a key mediator. Here, we used two preclinical models, the prenatal stress (PNS) animal model and an in vitro model of hippocampal progenitor cells, to assess the long-term effect of ELS on FKBP5, NR3C1, NR3C2, and FoxO1, four stress-responsive genes involved in the effects of glucocorticoids. In the hippocampus of male PNS rats sacrificed at different time points during neurodevelopment (PND 21, 40, 62), we found a statistically significant up-regulation of FKBP5 at PND 40 and PND 62 and a significant increase in FoxO1 at PND 62. Interestingly, all four genes were significantly up-regulated in differentiated cells treated with cortisol during cell proliferation. As FKBP5 was consistently modulated by PNS at adolescence (PND 40) and adulthood (PND 62) and by cortisol treatment after cell differentiation, we measured a panel of miRNAs targeting FKBP5 in the same samples where FKBP5 expression levels were available. Interestingly, both miR-20b-5p and miR-29c-3p were significantly reduced in PNS-exposed animals (both at PND40 and 62) and also in the in vitro model after cortisol exposure. Our results highlight the key role of miR-20b-5p and miR-29c-3p in sustaining the long-term effects of ELS on the stress response system, representing a mechanistic link possibly contributing to the enhanced stress-related vulnerability to mental disorders.

Disturbed sex hormone milieu in males and females with major depressive disorder and low-grade inflammation.

Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20-30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-ß-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (ß = -1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (ß = -0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation.

Molecular underpinnings of programming by early-life stress and the protective effects of early dietary ω6/ω3 ratio, basally and in response to LPS: Integrated mRNA-miRNAs approach.

Early-life stress (ELS) exposure increases the risk for mental disorders, including cognitive impairments later in life. We have previously demonstrated that an early diet with low ω6/ω3 polyunsaturated fatty acid (PUFA) ratio protects against ELS-induced cognitive impairments. Several studies have implicated the neuroimmune system in the ELS and diet mediated effects, but currently the molecular pathways via which ELS and early diet exert their long-term impact are not yet fully understood. Here we study the effects of ELS and dietary PUFA ratio on hippocampal mRNA and miRNA expression in adulthood, both under basal as well as inflammatory conditions. Male mice were exposed to chronic ELS by the limiting bedding and nesting material paradigm from postnatal day(P)2 to P9, and provided with a diet containing a standard (high (15:1.1)) or protective (low (1.1:1)) ω6 linoleic acid to ω3 alpha-linolenic acid ratio from P2 to P42. At P120, memory was assessed using the object location task. Subsequently, a single lipopolysaccharide (LPS) injection was given and 24 h later hippocampal genome-wide mRNA and microRNA (miRNA) expression was measured using microarray. Spatial learning deficits induced by ELS in mice fed the standard (high ω6/ω3) diet were reversed by the early-life protective (low ω6/ω3) diet. An integrated miRNA - mRNA analysis revealed that ELS and early diet induced miRNA driven mRNA expression changes into adulthood. Under basal conditions both ELS and the diet affected molecular pathways related to hippocampal plasticity, with the protective (low ω6/ω3 ratio) diet leading to activation of molecular pathways associated with improved hippocampal plasticity and learning and memory in mice previously exposed to ELS (e.g., CREB signaling and endocannabinoid neuronal synapse pathway). LPS induced miRNA and mRNA expression was strongly dependent on both ELS and early diet. In mice fed the standard (high ω6/ω3) diet, LPS increased miRNA expression leading to activation of inflammatory pathways. In contrast, in mice fed the protective diet, LPS reduced miRNA expression and altered target mRNA expression inhibiting inflammatory signaling pathways and pathways associated with hippocampal plasticity, which was especially apparent in mice previously exposed to ELS. This data provides molecular insights into how the protective (low ω6/ω3) diet during development could exert its long-lasting beneficial effects on hippocampal plasticity and learning and memory especially in a vulnerable population exposed to stress early in life, providing the basis for the development of intervention strategies.

Depression in Women: Potential Biological and Sociocultural Factors Driving the Sex Effect.

Important sex-related differences have been observed in the onset, prevalence, and clinical phenotype of depression, based on several epidemiological studies. Social, behavioural, and educational factors have a great role in underlying this bias; however, also several biological factors are extensively involved. Indeed, sexually dimorphic biological systems might represent the underlying ground for these disparities, including cerebral structures and neural correlates, reproductive hormones, stress response pathways, the immune system and inflammatory reaction, metabolism, and fat distribution. Furthermore, in this perspective, it is also important to consider and focus the attention on specific ages and life stages of individuals: indeed, women experience during their life specific periods of reproductive transitional phases, which are not found in men, that represent windows of particular psychological vulnerability. In addition to these, other biologically related risk factors, including the occurrence of sleep disturbances and the exposure to childhood trauma, which are found to differentially affect men and women, are also putative underlying mechanisms of the clinical bias of depression. Overall, by taking into account major differences which characterize men and women it might be possible to improve the diagnostic process, as well as treat more efficiently depressed individuals, based on a more personalized medicine and research.

Transcriptomic analyses of rats exposed to chronic mild stress: Modulation by chronic treatment with the antipsychotic drug lurasidone.

Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.

Psychobiological effects of an eHealth psychoeducational intervention to informal caregivers of persons with dementia: a pilot study during the COVID-19 pandemic in Italy.

BACKGROUND: The workload associated with caring for a person with dementia (PwD) could negatively affect informal caregivers' physical and mental health. According to the recent literature, there is a need for studies testing the implementation of affordable and accessible interventions for improving caregivers' well-being. AIMS: This study aimed to explore the feasibility and effectiveness of an 8 week eHealth psychoeducation intervention held during the COVID-19 pandemic in Italy in reducing the psychological burden and neuroendocrine markers of stress in caregivers of PwD. METHODS: Forty-one informal caregivers of PwD completed the eHealth psychoeducation intervention. Self-reported (i.e., caregiver burden, anxiety symptoms, depressive symptoms, and caregiver self-efficacy) and cortisol measurements were collected before and after the intervention. RESULTS: Following the intervention, the caregivers' self-efficacy regarding the ability to respond to disruptive behaviours improved (t = - 2.817, p = 0.007), anxiety and burden levels decreased (state anxiety: t = 3.170, p = 0.003; trait anxiety: t = 2.327, p = 0.025; caregiver burden: t = 2.290, p = 0.027), while depressive symptoms and cortisol levels did not change significantly. Correlation analyses showed that the increase in self-efficacy was positively associated with the improvement of caregiver burden from pre- to post-intervention (r = 0.386, p = 0.014). The intervention had a low rate of dropout (n = 1, due to the patient's death) and high levels of appreciation. DISCUSSION: The positive evidence and participation rate support the feasibility and effectiveness of the proposed eHealth psychoeducational intervention to meet the need for knowledge of disease management and possibly reduce detrimental effects on caregivers' psychological well-being. CONCLUSION: Further placebo-controlled trials are needed to test the generalizability and specificity of our results.

Vulnerability and resilience to prenatal stress exposure: behavioral and molecular characterization in adolescent rats.

Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention.

Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

Association of childhood trauma with cognitive domains in adult patients with mental disorders and in non-clinical populations: a systematic review.

Although the association between cognitive performances and the onset of psychiatric disorders has been widely investigated, limited research on the role of childhood trauma or early life stress (CT/ELS), and whether this role differs between clinical and non-clinical cohorts is available. This systematic review aims at filling this gap, testing whether the occurrence of CT/ELS and its subtypes are associated with cognitive domains (general cognitive ability, executive functions, working memory, attention, processing speed, verbal/visual memory) in patients with psychiatric disorders and in non-clinical populations. This study followed the PRISMA 2020 guidelines and the Newcastle-Ottawa scale for quality assessment. The search was performed until May 2022. Seventy-four studies were classified as eligible. The graphical representations of the results reported an association between exposure to CT/ELS and worse general cognitive ability, verbal/visual memory, processing speed and attention in patients affected by anxiety, mood and psychotic disorders, and that specific CT/ELS subtypes (physical neglect, physical/sexual abuse) can differentially influence specific cognitive abilities (executive functions, attention, working memory, verbal/visual memory). In non-clinical cohorts we found associations between CT/ELS exposure and impairments in executive functions, processing speed and working memory, while physical neglect was related to general cognitive ability and working memory. Concerning the emotional abuse/neglect subtypes in both populations, the results indicated their involvement in cognitive functioning; however, the few studies conducted are not enough to reach definitive conclusions. These findings suggest an association of CT/ELS with specific cognitive deficits and psychopathology.

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation.

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I2=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study.

Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case-control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1-3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.

A peripheral signature of Alzheimer's disease featuring microbiota-gut-brain axis markers.

BACKGROUND: Increasing evidence links the gut microbiota (GM) to Alzheimer's disease (AD) but the mechanisms through which gut bacteria influence the brain are still unclear. This study tests the hypothesis that GM and mediators of the microbiota-gut-brain axis (MGBA) are associated with the amyloid cascade in sporadic AD. METHODS: We included 34 patients with cognitive impairment due to AD (CI-AD), 37 patients with cognitive impairment not due to AD (CI-NAD), and 13 cognitively unimpaired persons (CU). We studied the following systems: (1) fecal GM, with 16S rRNA sequencing; (2) a panel of putative MGBA mediators in the blood including immune and endothelial markers as bacterial products (i.e., lipopolysaccharide, LPS), cell adhesion molecules (CAMs) indicative of endothelial dysfunction (VCAM-1, PECAM-1), vascular changes (P-, E-Selectin), and upregulated after infections (NCAM, ICAM-1), as well as pro- (IL1ß, IL6, TNFα, IL18) and anti- (IL10) inflammatory cytokines; (3) the amyloid cascade with amyloid PET, plasma phosphorylated tau (pTau-181, for tau pathology), neurofilament light chain (NfL, for neurodegeneration), and global cognition measured using MMSE and ADAScog. We performed 3-group comparisons of markers in the 3 systems and calculated correlation matrices for the pooled group of CI-AD and CU as well as CI-NAD and CU. Patterns of associations based on Spearman's rho were used to validate the study hypothesis. RESULTS: CI-AD were characterized by (1) higher abundance of Clostridia_UCG-014 and decreased abundance of Moryella and Blautia (p < .04); (2) elevated levels of LPS (p < .03), upregulation of CAMs, Il1ß, IL6, and TNFα, and downregulation of IL10 (p < .05); (3) increased brain amyloid, plasma pTau-181, and NfL (p < 0.004) compared with the other groups. CI-NAD showed (1) higher abundance of [Eubacterium] coprostanoligenes group and Collinsella and decreased abundance of Lachnospiraceae_ND3007_group, [Ruminococcus]_gnavus_group and Oscillibacter (p < .03); (2) upregulation of PECAM-1 and TNFα (p < .03); (4) increased plasma levels of NfL (p < .02) compared with CU. Different GM genera were associated with immune and endothelial markers in both CI-NAD and CI-AD but these mediators were widely related to amyloid cascade markers only in CI-AD. CONCLUSIONS: Specific bacterial genera are associated with immune and endothelial MGBA mediators, and these are associated with amyloid cascade markers in sporadic AD. The physiological mechanisms linking the GM to the amyloid cascade should be further investigated to elucidate their potential therapeutic implications.

Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer.

Prostate cancer (PCa) is a leading cause of death in the male population commonly treated with androgen deprivation therapy that often relapses as androgen-independent and aggressive castration-resistant prostate cancer (CRPC). Ferroptosis is a recently described form of cell death that requires abundant cytosolic labile iron to promote membrane lipid peroxidation and which can be induced by agents that inhibit the glutathione peroxidase-4 activity such as RSL3. Exploiting in vitro and in vivo human and murine PCa models and the multistage transgenic TRAMP model of PCa we show that RSL3 induces ferroptosis in PCa cells and demonstrate for the first time that iron supplementation significantly increases the effect of RSL3 triggering lipid peroxidation, enhanced intracellular stress and leading to cancer cell death. Moreover, the combination with the second generation anti-androgen drug enzalutamide potentiates the effect of the RSL3 + iron combination leading to superior inhibition of PCa and preventing the onset of CRPC in the TRAMP mouse model. These data open new perspectives in the use of pro-ferroptotic approaches alone or in combination with enzalutamide for the treatment of PCa.

Transcriptomics and miRNomics data integration in lymphoblastoid cells highlights the key role of immune-related functions in lithium treatment response in Bipolar disorder.

BACKGROUND: Bipolar Disorder (BD) is a complex mental disease characterized by recurrent episodes of mania and depression. Lithium (Li) represents the mainstay of BD pharmacotherapy, despite the narrow therapeutic index and the high variability in treatment response. However, although several studies have been conducted, the molecular mechanisms underlying Li therapeutic effects remain unclear. METHODS: In order to identify molecular signatures and biological pathways associated with Li treatment response, we conducted transcriptome and miRNome microarray analyses on lymphoblastoid cell lines (LCLs) from 20 patients diagnosed with BD classified as Li responders (n = 11) or non-responders (n = 9). RESULTS: We found 335 mRNAs and 77 microRNAs (miRNAs) significantly modulated in BD responders versus non-responders. Interestingly, pathway and network analyses on these differentially expressed molecules suggested a modulatory effect of Li on several immune-related functions. Indeed, among the functional molecular nodes, we found NF-κB and TNF. Moreover, networks related to these molecules resulted overall inhibited in BD responder patients, suggesting anti-inflammatory properties of Li. From the integrative analysis between transcriptomics and miRNomics data carried out using miRComb R package on the same samples from patients diagnosed with BD, we found 97 significantly and negatively correlated mRNA-miRNA pairs, mainly involved in inflammatory/immune response. CONCLUSIONS: Our results highlight that Li exerts modulatory effects on immune-related functions and that epigenetic mechanisms, especially miRNAs, can influence the modulation of different genes and pathways involved in Li response. Moreover, our data suggest the potentiality to integrate data coming from different high-throughput approaches as a tool to prioritize genes and pathways.

Understanding treatment-resistant depression using "omics" techniques: A systematic review.

BACKGROUND: Treatment-resistant depression (TRD) results in huge healthcare costs and poor patient clinical outcomes. Most studies have adopted a "candidate mechanism" approach to investigate TRD pathogenesis, however this is made more challenging due to the complex and heterogeneous nature of this condition. High-throughput "omics" technologies can provide a more holistic view and further insight into the underlying mechanisms involved in TRD development, expanding knowledge beyond already-identified mechanisms. This systematic review assessed the information from studies that examined TRD using hypothesis-free omics techniques. METHODS: PubMed, MEDLINE, Embase, APA PsycInfo, Scopus and Web of Science databases were searched on July 2022. 37 human studies met the eligibility criteria, totalling 17,518 TRD patients, 571,402 healthy controls and 62,279 non-TRD depressed patients (including antidepressant responders and untreated MDD patients). RESULTS: Significant findings were reported that implicate the role in TRD of various molecules, including polymorphisms, genes, mRNAs and microRNAs. The pathways most commonly reported by the identified studies were involved in immune system and inflammation, neuroplasticity, calcium signalling and neurotransmitters. LIMITATIONS: Small sample sizes, variability in defining TRD, and heterogeneity in study design and methodology. CONCLUSIONS: These findings provide insight into TRD pathophysiology, proposing future research directions for novel drug targets and potential biomarkers for clinical staging and response to antidepressants (citalopram/escitalopram in particular) and electroconvulsive therapy (ECT). Further validation is warranted in large prospective studies using standardised TRD criteria. A multi-omics and systems biology strategy with a collaborative effort will likely deliver robust findings for translation into the clinic.

Identifying the Common Genetic Basis of Antidepressant Response.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Adolescents' mental health and maladaptive behaviors before the Covid-19 pandemic and 1-year after: analysis of trajectories over time and associated factors.

BACKGROUND: Adolescents have been deeply exposed to negative consequences of social distancing imposed by Covid-19. There is a lack of longitudinal studies regarding the impact on adolescents of this unfavorable condition, and their results are controversial. The aim of the present prospective study is to assess psychopathological symptoms in adolescent students over time and to evaluate what type of impact the Covid-19 pandemic had on adolescents. Moreover, the association between mental health indexes, potential risk and resilience factors is explored. METHODS: Psychopathological symptoms (i.e., anxiety, depression, stress, emotional dysregulation, maladaptive behaviours), and potential risk and resilience factors (i.e., childhood trauma, emotional regulation skills, family function, personality traits) were assessed among a sample of 153 students (72% female; mean age 16.1 ± 0.49), living in a medium-size city in the north of Italy, at two time points: before the outbreak of the Covid-19 pandemic (November 2019-January 2020) and 1 year later (April-May 2021). RESULTS: After 1 year, we found an increase in mean scores on anxiety, stress for future uncertainty, and higher frequency of maladaptive behaviours. By contrast, the level of stress related to social domains (i.e., school attendance, romantic relationships, peer pressure) decreased. Dysfunctional emotional regulation skills, childhood trauma, low family functioning, and specific personality traits were associated to higher psychopathological symptoms. Cluster analysis detected three groups of youths based on their change over time in psychopathological symptoms: those who worsened (N = 23; 15%), improved (N = 55; 34%), or remained stable (N = 75; 46%). After controlling for baseline mental health status, those adolescents reporting increase in self-harm (OR = 2.61; p < 0.001), binge-drinking (OR = 3.0; p = 0.007), aggressiveness (OR 1.92; p = 0.004), and binge-eating (OR 2.55; p = 0.003) were more likely to present a worsened mental health condition. CONCLUSION: The present results suggest that the Covid-19 pandemic seems to have had a different impact on subgroups of students. Indeed, we found a global worsening of psychological well-being only in a subgroup of adolescents, otherwise other students remained stable or improved. Increased frequency of maladaptive behaviors was found as a predictor of worsened mental health, therefore interventions to strengthen emotional regulation strategies are warranted. Finally, the decrease of stress in social domains could be due to reduction of potential triggering situations, thus indicating only a temporary beneficial effect that requires careful monitoring.

Cause or consequence? Understanding the role of cortisol in the increased inflammation observed in depression.

Glucocorticoids such as cortisol are a class of steroid hormones that play an important role in co-ordinating the body's response to stress. Elevated cortisol levels and increased inflammation have frequently been reported in patients with depression. The currently accepted "glucocorticoid resistance" model posits this increased inflammation as a consequence of reduced sensitivity to cortisol's putative anti-inflammatory action. However, opposing evidence has accumulated that supports a more recent model, which instead proposes that cortisol possesses immune potentiating properties and may thus directly cause the increased inflammation seen in depression. Despite all of this, a clear explanation of the neuroendocrine mechanism that contributes to the development of depression is still lacking and thus requires further investigation in improved future studies.

Neurotrophic factors, childhood trauma and psychiatric disorders: A systematic review of genetic, biochemical, cognitive and imaging studies to identify potential biomarkers.

BACKGROUND: Exposure to traumatic experience represents one of the key environmental factors influencing the risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric disorders. METHODS: A systematic review was conducted, considering genetic, biochemical and expression studies along with cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-Ottawa Scale). RESULTS: 103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor ß1 (TGF-ß1). LIMITATIONS: Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range and ethnicity of samples for BDNF studies; limited studies for other neurotrophins. CONCLUSIONS: Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive functions and specific brain region architecture.