To investigate the separate and combined impact of family major depression (MD) history and ten childhood adversities (CA) on the risk of adult MD.

All Danish citizens born 1977-2000 with known parental identity were followed from their 18th birthday until diagnosis of MD, migration, death, or December 31, 2022, in nationwide registers. Exposures were family MD history and ten selected CAs. Family MD history was operationalized using the ICD 8th Revision codes 296.09, 296.29, 298.09, and 300.49 or 10th Revision codes F32.0-F33.9. CAs were; relative family poverty, long-term parental unemployment, foster care, parental alcohol abuse, parental drug abuse, parental and sibling somatic illness, parental long-term unemployment, parental separation, and parental and sibling death. Multivariable Poisson regression was applied to estimate the incidence rate ratio (IRR) with 95 % CI of first-time MD.

The study included 1,461,034 individuals (Male: 51.5 %). During a mean follow-up of 14.5 years (SD ± 7.2), 50,231 (3.5 %) of cohort members were diagnosed with first-time MD in adulthood. Family MD history was associated with an IRR of 1.94 (95 % CI [1.88-2.00]) for MD. In all models, both CAs and family MD, separately and combined, were associated with an increased IRR for MD. The IRRs for individuals with a family MD history with or without CA, respectively, were generally relatively comparable.

Individuals exposed to family MD history and CAs are at increased risk of MD. However, the associations between family MD and onset of MD in adulthood remain largely unchanged regardless of the presence of any of the ten CAs.

Knowledge on how sunlight impacts SERT activity via SLC6A4 promoter methylation in Seasonal Affective Disorder (SAD) remains limited. This study aimed to investigate the effect of daily sunshine duration on SLC6A4 promoter methylation in 28 patients with SAD and 40 healthy controls (HC).

Daily sunlight data for Vienna, Austria (mean of 28 days before blood sampling), were obtained from ©GeoSphere Austria. A general linear model analysed SLC6A4 promoter methylation as the dependent variable, with sunlight hours as the independent variable, and group (SAD, HC), age, sex, and 5-HTTLPR/rs25531 as covariates. Exploratory analyses examined the effects of sunlight hours and methylation on Beck Depression Inventory (BDI) scores.

Sunlight had a significant effect on SLC6A4 promoter methylation (p = 0.03), with more sunlight hours resulting in lower methylation (r = -0.25). However, the interaction between sunlight and group was non-significant, suggesting a rather general effect across both groups. Sunlight also influenced BDI scores (p < 0.01), with fewer sunlight hours leading to higher scores (r = -0.25), which aligns with previous research. SLC6A4 promoter methylation had no significant effect on BDI scores.

Our findings suggest that sunlight influences SLC6A4 methylation without SAD specificity.

It is known that the effectiveness of drug treatment for depression, ammine deficit based, is largely unsatisfactory. In this review, we examine the proposal of a precision therapy has emerged and has received a strong push by the identification of the role of inflammation in depression. However, precision psychiatry risks being caught in the reductionist trap of searching for the molecular switch that resets the whole system and switches off the disease. This is an illusion since the human being is complex and depression is a systemic and variable disorder. In this study, we show the inadequacy of the reductionist paradigm, and, at the same time, illustrate the superiority of the systemic paradigm centered on psychoneuroendocrineimmunology (PNEI). According to the PNEI paradigm, depression is a disease of the whole human being, caused by different sources working together: psychological, biological, and behavioral. This means knowing the biological and psychological history of the subject, identifying relational and biological crisis factors, and building personalized treatments targeting those factors with the tools of medicine and psychology, which are not reducible to the combination of drugs and psychotherapy. Our proposal presents a paradigm shift that is both theoretical and practical, which enables clinicians to assess patients experiencing depression in a unified way and treat them in an integrated manner.

Considerable effort has been devoted to understanding how parents influence child development. Less attention has been given to the effects that children exert on their parents. This review aims to systematically survey the links between scientific articles exploring this question. Results of a document co-citation analysis reveal that research on this topic has been scarce and primarily concerned by how child and adolescent disruptive behaviour negatively impacts parents. Academic attention is directed to research that conceptualizes child effects as the outcome of genetic or temperamental predispositions. The implications of such a constrained view of child influence are discussed, highlighting the need for applied research on how children can actively contribute to positive behavioural change in parents and other adults.

Major depressive disorder represents a complex heterogeneous syndrome with significant public health impact. This pictorial review explores the multifaceted pathophysiology of depression through the case of an individual suffering from depression. Genetic vulnerability and environmental etiological factors, including early life adversity, and their interactions create a biological diathesis through alterations in stress response systems and neural circuitry. We review current evidence for several interconnected pathophysiological mechanisms underlying depression, including monoamine neurotransmission, hypothalamic-pituitary-adrenal axis dysfunction, chronic inflammation, and reduced neuroplasticity. Using the Research Domain Criteria framework, we connect these mechanisms across multiple levels of analysis-from genes, circuits to behavior. Neuroimaging findings highlight disruptions in key networks including the default mode, salience, and executive control circuits. The effectiveness of pharmacological, psychotherapeutic and other non-pharmacological interventions in depression underscores the importance of targeting multiple biological systems. This review emphasizes depression's complex etiology involving dynamic interactions between genetic predisposition, environmental stressors, and neurobiological alterations, suggesting the need for personalized, multimodal therapeutic approaches.

Because early-life stress is common and constitutes a strong risk factor for cognitive and mental health disorders, it has been the focus of a multitude of studies in humans and experimental models. Yet, we have an incomplete understanding of what is perceived as stressful by the developing brain, what aspects of stress influence brain maturation, what developmental ages are particularly vulnerable to stress, which molecules mediate the effects of stress on brain operations, and how transient stressful experiences can lead to enduring emotional and cognitive dysfunctions. Here, we discuss these themes, highlight the challenges and progress in resolving them, and propose new concepts and avenues for future research.

The impact of maternal mental illness on children's neurodevelopment has been insufficiently investigated, particularly in large populations. In this study, we examined the association between maternal mental health history and child neurodevelopment during the first 3 years postpartum, using large-scale data from the Japan Environment and Children's Study (JECS).

We analyzed data from 64,389 mother-offspring pairs enrolled in JECS. Maternal history of mental illness was assessed using questionnaires administered during early pregnancy. Child neurodevelopment was assessed at ages 1, 2, and 3 years by mothers or guardians using the Japanese version of the Ages and Stages Questionnaires, 3rd Edition (J-ASQ-3), across five domains. In this study, we employed multivariate logistic regression analysis.

Children whose mothers have a history of mental illness exhibited significantly higher risks of developmental delays in gross motor skills and problem-solving domains at age 1, and across all J-ASQ-3 domains at ages 2 and 3, compared to those whose mothers do not have such a history.

Our findings indicate that children born to mothers with a history of mental illness may exhibit early neurodevelopmental delays in gross motor skills and problem-solving as early as age 1 year, potentially leading to broader neurodevelopmental impairments observed in later childhood. Additionally, childcare support aimed at enhancing neurodevelopment may be essential for mothers with a history of mental illness within the first year postpartum.

The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined.

To this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP.

A meta-analysis comprising 26 case-control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP.

Our meta-analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (rG = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein-protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations (p value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained.

With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.

Anxiety disorders and depression often co-occur and lack broadly available treatments. Gardenia extract significantly associated with treatment of anxiety-like depression. Based on the dose effect hypothesis and previous studies, it is speculated that crocin I, the main component of gardenia, is significantly related to the treatment of anxiety-like depression. The present study aimed to verify the reversal effect of crocin I on chronic corticosterone-induced anxiety-like depression, and to further explore its metabolic process in vivo. Ultimately, a new method for rapid and sensitive detection of trace substances was established. In this study, the rat model of anxiety-like depression was induced by chronic corticosterone. The effects of crocin I were explored by combining behavioral, pathological sections and ELASA data. It is the first time that crocin I can reverse the morphological changes of hippocampus induced by corticosterone in rats. In terms of behavior, crocin Ⅰ can significantly improve the anxiety-like depressive behavior exhibited by model rats in water maze and sugar water preference experiments. It can also repair neuronal cell damage in the Dentate gyrus, CA1, and CA3 areas of the hippocampus. It also regulates the expression levels of monoamine neurotransmitters in the rat brain, thereby exerting an anti-anxiety-like depression effect. Pharmacokinetic analysis was performed to determine the metabolic process in vivo. Further integrating Surface-Enhanced Raman Scattering (SERS) technology, a highly sensitive and rapid detection method for trace substances had been established. It was first discovered that crocin I can reverse the changes in rat hippocampal morphology caused by corticosterone. It was determined that crocin Ⅰ can reverse the anxiety-like depression induced by chronic corticosterone and exert its therapeutic effect by regulating the levels of neurotransmitters in the brain. In vivo pharmacokinetic experiments revealed that crocin Ⅰ could not pass through the intestinal barrier into the blood, but its metabolite crocetin could pass through the intestinal barrier into the blood. Finally, by synthesizing silver nanoparticles, a detection method for trace amounts of the metabolite crocetin in blood samples was established for the first time.The calculated enhancement factor is 4.49 × 1011. The method was stable and reproducible over a week. This series of studies revealed the great potential of crocin I in treating comorbid anxiety and depression. It shortens the distance from theoretical research to clinical application.

One of the most frequent forms of maternal morbidity following childbirth is postpartum depression. Postpartum depression (PPD), a disabling condition as a major public health concern, has a significant negative impact on the child's emotional, mental as well as intellectual development if left undiagnosed and untreated, which can later have long-term complications. The oxytocin system is an excellent candidate gene system in the maternal context. Differences in vulnerability of mothers for the onset of postpartum psychiatric disorders could be influenced by individual differences in the genetic profile of each one. In this original research, we aimed to explore if there are any possible contributions of genetic variation on both the oxytocin receptor gene (OXTR) and the oxytocin gene (OXT) to the occurrence of postpartum depression, aiming to provide the latest evidence and determine which genetic polymorphisms significantly create a susceptibility for this condition. A total of 100 mothers were preliminarily genotyped before they completed the Edinburgh Postnatal Depression Scale Questionnaire (EPDS) at 6 weeks postpartum. DNA was extracted from peripheral blood samples of the participants (N = 100) and evaluated for the oxytocin gene (OXT_rs2740210; OXT_rs4813627) and oxytocin receptor gene (OXTR_ rs237885) single nucleotide polymorphisms. The results highlighted a significant interaction between the oxytocin OXT_rs2740210 genotype and maternal postpartum depression in mothers with the CC genotype but not in those with AA/AC genotypes. This reveals that an interaction of vulnerable genotypes (CC genotype of OXT_rs2740210, C allele in genotype of OXT_rs2740210, G allele in genotype of OXT_rs4813627) with an environmental burden or other risk factors would predispose the mothers to develop postpartum depression. We found no significant association between the interaction effect of the oxytocin receptor gene OXTR_rs237885 genotype depending on the occurrence of maternal postpartum depression. These findings prove the implication of the oxytocinergic system gene variants in vulnerability for postpartum depression and indicate the need for future studies adopting a multilevel approach in order to increase understanding.

As global gene discovery efforts turn away from a historic Eurocentric focus and advance towards embracing more diverse populations, consideration of sociocultural aspects of bipolar disorder become critical to their success. Diversity can be leveraged to accelerate gene discovery, via different patterns of linkage disequilibrium that lead to greater resolution of mapping association signals, and convergence of genes and pathways implicated within and across diverse ancestral groups improving our understanding of the molecular underpinnings of disease. However it is not just the differences in linkage disequilibrium structure and allele frequency that drive differences in genomic signals between populations. This review focuses on the role of social, cultural and societal factors on bipolar disorder, and their potential impact on disease prevalence, clinical course and outcome, and disease burden. Social, cultural, and geographical differences in expression of symptoms, and frequency of clinical subtypes in bipolar disorder present both opportunities and challenges to the field. In this era of global multi-ancestry research, resources that facilitate the collection and harmonization of data from culturally and ancestrally-diverse population groups will enhance our ability to gain true biological understanding. Such resources are essential to disambiguate the genetic and environmental components of disease risk, as well as inform effective lifestyle interventions to improve outcome for global citizens living with bipolar disorder.

Recent theories suggest that reduced serotonin transporter (5-HTT) function, which increases serotonin (5-HT) levels at the synapse, enhances neural plasticity and affects sensitivity to environmental cues. This may promote learning about emotionally relevant events. However, the boundaries that define such emotional learning remain to be established. This was investigated using 5-HTT knockout (5-HTTKO) mice which provide a model of long-term elevated 5-HT transmission and are associated with increased anxiety. Compared to wild-type controls, 5-HTTKO mice were faster to discriminate between an auditory cue that predicted footshock (CS+) and a cue predicting no footshock (CS-). Notably, this enhanced discrimination performance was driven not by faster learning that the CS+ predicted footshock, but rather by faster learning that the CS- cue signals the absence of footshock and thus provides temporary relief from fear/anxiety. Similarly, 5-HTTKO mice were also faster to reduce their fear of the CS+ cue during subsequent extinction. These findings are consistent with facilitated inhibitory learning that predicts the absence of potential threats in 5-HTTKO mice. However, 5-HTTKO mice also exhibited increased generalisation of fear learning about ambiguous aversive cues in a novel context, different from the training context. Thus, 5-HTTKO mice can exhibit both more and less fear compared to wild-type controls. Taken together, our results support the idea that loss of 5-HTT function, and corresponding increases in synaptic 5-HT availability, may facilitate learning by priming of aversive memories. This both facilitates inhibitory learning for fear memories but also enhances generalisation of fear.

Brain development may be influenced by both genetic and environmental factors, with potential consequences that may last through the lifespan. Alterations during neurogenesis are linked to neurodevelopmental cognitive disorders. Many neurotransmitters and their systems play a vital role in brain development, as most are present prior to synaptogenesis, and they are involved in the aetiology of many neurodevelopmental disorders. For instance, dopamine (DA) receptor expression begins at the early stages of development and matures at adolescence. The long maturation period suggests how important it is for the stabilisation and integration of neural circuits. DA and dopaminergic (DAergic) system perturbations have been implicated in the pathogenesis of several neurological and neuropsychiatric disorders. The DAergic system controls key cognitive and behavioural skills including emotional and motivated behaviour through DA as a neurotransmitter and through the DA neuron projections to major parts of the brain. In this review, we summarise the current understanding of the DAergic system's influence on neurodevelopment and its involvement in the aetiology and progression of major disorders of the developing brain including autism, schizophrenia, attention deficit hyperactivity disorder, down syndrome, and fragile X syndrome.

Framed by attachment and cognitive theories, the current meta-analysis tested the direct and indirect links among parenting dimensions (parental support, authoritative control, psychological control, and behavioral control), self-esteem, and depressive symptoms for children and adolescents.

Based on 53 studies, and 74 independent samples, the present study used One-Stage Meta-analytic Structural Equation Modeling (OSMASEM) to investigate these links, including testing a mediation effect by self-esteem between parental support-, authoritative control-, psychological control-, behavioral control-, and depressive symptoms. It also tested for potential moderation effects by several variables.

The evidence indicated that parental support (β = .29), authoritative control (β = .23), and behavioral control (β = .07) are positive correlates of self-esteem, while psychological control (β = -.26) is a negative one. It also found that self-esteem was negatively associated with depressive symptoms (β range: -.49 to -.53). Furthermore, parental support (β = -0.14), authoritative control (β = -0.10), and behavioral control (β = -0.05) are negative correlates of depressive symptoms, while psychological control is a positive correlate (β = .11). OSMASEM also provided evidence that parental support, authoritative control, psychological control, and behavioral control are indirectly associated with depressive symptoms, via self-esteem.

Parenting dimensions are associated with depressive symptoms both directly and indirectly. That is, self-esteem partially mediates the relationships between parental support, authoritative control, psychological control, and behavioral control with depressive symptoms. Furthermore, OSMASEM moderator tests provided evidence of several significant moderators, including age, sex, parenting measurement, and self-esteem measurement.

Regular participation in physical activity (PA) reduces all-cause mortality (ACM) in the general population. However, the effects of PA on depressed patients and potential gender-specific responses have not been fully elucidated. In this study, we aimed to investigate the role of PA on new-onset depression and ACM in Chinese adults aged 45 year and older, with particular emphasis on gender differences.

This was a longitudinal cohort study that took place over a nine-year period and featured 2,264 participants drawn from the China Health and Retirement Longitudinal Study (CHARLS). PA levels were categorized into quartiles using metabolic equivalents (MET; minutes/week), and depression was evaluated according to the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) scale. Specific relationships between PA, depression, and mortality were then investigated by applying multivariate logistic regression and Cox proportional hazards models.

Highest quantile levels of PA were correlated with a 37% increase in the risk of new-onset depression in middle-aged (45-59 years) and older adults (>60 years). This association was predominantly influenced by a significant increase in the risk of mild depression (a score of 10-14 on the CESD-10) (odds ratio [OR]: 1.76; 95% confidence interval [CI]: 1.29-2.42, p < 0.001), with a more pronounced effect observed in women (OR: 1.83; 95% CI: 1.26-2.66, p = 0.002). A critical threshold for PA was identified at 4536 MET-minutes/week, beyond which the risk of depression increased significantly (p < 0.05). Conversely, higher levels of PA were linked to a 90% reduction in ACM (HR: 0.10; 95% CI: 0.02-0.44, p = 0.002), with the effect being more pronounced in men.

While PA reduces mortality, excessive activity may increase the risk of mild depression, particularly in women. These findings highlight the need for gender-specific PA guidelines that balance physical and mental health outcomes.

Limited research has examined the association between the number of live births and bipolar disorder and major depression (BDMD). This study aims to investigate the relationship between the number of live births and BDMD among women in the UK, providing a theoretical basis for reproductive decision-making.

This cross-sectional study utilized data from >55,000 women in the UK Biobank. Inverse probability treatment weighting (IPTW) logistic regression models were employed to reduce bias and confounding. Multivariate logistic regression was applied to examine the relationship between live births and BDMD, while restricted cubic spline regression was utilized to analyze the nonlinear association between the number of live births and BDMD. Subgroup analyses were conducted, stratifying by age, BMI, spontaneous abortion, induced abortion, and spontaneous abortion.

The IPTW-multivariate logistic regression analysis indicated that live births serve as an independent protective factor against BDMD. In IPTW-multivariate Model 4, the odds ratio (OR) for the live births group was 0.71 (95 % CI 0.69-0.73, P < 0.001). A significant nonlinear relationship was identified between the number of live births and the risk of BDMD. Additionally, it was found that women with two live births exhibited the lowest risk of BDMD.

Our study demonstrated that live births are an independent protective factor against BDMD. This research holds particular significance in the context of globally declining fertility rates and the increasing prevalence of mental disorders. It provides guidance for women on fertility decisions amid declining global fertility rates and increasing mental health issues.

Associations between thyroid diseases and psychiatric disorders have been mainly described before. However, the genetic mechanism behind hypothyroidism and psychiatric disorders remains unexplained.

We examined the genetic architecture of hypothyroidism and 8 psychiatric disorders. Firstly, the global and local genetic relationship between the paired traits was explored. Secondly, cross-trait analysis was performed to investigate the genomic loci and genes between psychiatric disorders and hypothyroidism. Thirdly, the significant expression of these genes and the causal relationships were investigated. Lastly, enrichment analysis was conducted on these genes to explore their biological mechanisms.

We observed significant positive genetic correlations between psychiatric disorders and hypothyroidism. The cross-trait meta-analysis identified 62 shared genetic loci between hypothyroidism and psychiatric disorders. The colocalization analysis additionally revealed 15 potential pleiotropic loci with a posterior probabilities.H4 (PP·H4) value >0.7. We also found 2308 genes shared between both traits, which were highly enriched in biological pathways such as immune cell differentiation and autoimmune diseases, as well as in tissue structures like the frontal cortex and cerebral cortex. Especially, many pleiotropic genes were significantly expressed for multiple pairwise traits, such as BCL11B, RERE, and SUOX. Lastly, the Latent causal variable model (LCV) analysis did not find any causal components in the genetic structure between them.

The limitations of this study include that the conclusions were drawn from a European population.

These findings not only deepens our understanding of their biological mechanisms but also has significant implications for the intervention and treatment of these diseases.

Depression is presented as a multi-factorial bio-psycho-social expression that has evolved primarily as an effect of stressors related to the motivational/emotional systems that regulate the BrainMind in our relationship with conspecifics. These stressors may be caused by two sources of threat, firstly, the loss of bonding with the caregiver and later with a partner and/or group which relates to the SEPARATION (PANIC/GRIEF) system, secondly, social defeat as an expression of the social competition and social dominance. The sexual maturity drives the individual to social competition and social dominance, even if the latter often occurs before sexual maturity, e.g., chickens, dogs, non-human primates, and humans. Depression is an evolutionarily conserved mechanism in mammals to terminate both separation anxiety, so as to protect the vulnerable social brain from the consequences of prolonged separation anxiety, and the stress of social competition when social defeat is predictable. Adolescence and Young adulthood are particularly susceptible to these two types of threat because of human developmental characteristics that are summarized by the term neoteny. This refers to the slowing down of growth and development, resulting in both a prolonged period of dependence on a caring/protective adult and the persistence of juvenile characteristics throughout life. Therefore, neoteny makes the transition from childhood to sexual maturity more dramatic, making the integration of the SEPARATION (PANIC/GRIEF) system with the dynamics of social competition and dominance more stressful and a source of depression. Stress is an expression of the HPA-Hypothalamic-Pituitary-Adrenal axis that articulates with other systems, mainly the autonomic nervous system and the immune-inflammatory system. The latter is believed to be one of the most significant components in the dynamics of depressive processes, connected to the prodromes of its activation in childhood, under the pressure of environmental and relational stressors which can lead to learned helplessness. The recurrence of stressors makes it easier for the immune-inflammatory system to be activated in later life, which could make a significant contribution to the establishment of a depressive disease. The possible contribution of children's identification processes with their parents' depressive personalities through observational learning is considered.

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of drugs that increase serotonin signaling is associated with decreased social interactions. However, in primates, the direct involvement of serotonin signaling in the amygdala, particularly in affiliative social interaction, remains unexplored. Here, we examined the effects of serotonin manipulations within the amygdala on social behavior in eight pairs of familiar male macaques. We microinfused drugs targeting the serotonin system into either the basolateral (BLA) or central (CeA) amygdala and measured changes in social behavior. Surprisingly, the results demonstrated no significant differences in social behavior following the infusion of a selective serotonin reuptake inhibitor, 5-HT1A agonist or antagonist, 5-HT2A agonist or antagonist, or 5-HT3 agonist or antagonist into either the BLA or CeA. These findings suggest that serotonin signaling in the amygdala does not directly contribute to the regulation of social behavior between familiar conspecifics. Future research should explore alternative mechanisms and potential interactions with other brain regions to gain a comprehensive understanding of the complex neural circuitry governing social behavior.

Previous cross-sectional studies have utilized scales to explore potential indications of the moderating effect of resilience on the relationship between stressful life events (SLEs) and mental health. However, there remains a notable dearth of psychometrically driven models in longitudinal resilience research, especially concerning the prognosis of individuals with affective disorders and/or anxiety. This study aimed to investigate whether baseline resilience capacity, measured by the Connor-Davidson Resilience Scale, could mitigate the impact of SLEs on depressive symptoms assessed using the Beck Depression Inventory-II among 66 outpatients with depression and/or anxiety disorders during a follow-up period ranging from 4-8 years. Hierarchical linear regression analysis revealed that baseline resilience capacity significantly moderated the effect of SLEs on depressive symptoms at the end point, but neither SLEs nor baseline resilience capacity was significantly correlated with depressive symptoms at the end point after controlling for potential confounders. Patients with higher levels of baseline resilience capacity showed fewer depressive symptoms in response to SLEs. These findings underscore the potential of resilience capacity as a promising target for therapeutic interventions.

Serotonin-transporter-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the promoter region of serotonin transporter gene, is classified into short (S) and long (L) alleles. Initial case-control association studies claiming the risks of the S allele in depression and anxiety were not completely supported by recent studies. However, most studies, especially those on East Asian populations, have overlooked the complexity of 5-HTTLPR, which involves multiple different alleles with distinct functional properties. To address this issue, distinguishing multiple 5-HTTLPR alleles is essential. Here, using the 5-HTTLPR genotypes previously determined by exhaustive Sanger sequencing of approximately 1,500 Japanese subjects and their comprehensive SNP data, we constructed a method for 5-HTTLPR genotype imputation. We identified 28 tag SNPs for the imputation of four major 5-HTTLPR alleles, which collectively account for 97.6% of 5-HTTLPR alleles in the Japanese population. Our imputation method, achieved an accuracy of 0.872 in cross-validation, will contribute to association analysis of 5-HTTLPR in the Japanese subjects.

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotoninnoradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from genome-wide association studies with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease, schizophrenia (SCZ), major depressive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and autism spectrum disorder. Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian randomization to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" (p = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p = 0.0001), and "Acetylcholine binding and downstream events" pathways (p = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and SCZ, suggesting possible pathophysiologic commonalities. In this study, we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcomes. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiological overlap with other neuropsychiatric diseases.

Fluoxetine is widely used as a first-line antidepressant. However, the molecular mechanisms for its antidepressant effects are still not fully understood. Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a core pathogenic mechanism contributing to depression, and fluoxetine treatment prevents this dysfunction. The glucocorticoid receptor (GR) is a major negative feedback regulator of the HPA axis, while Fk506-binding protein 5 (Fkbp5) is a negative regulator of the GR signaling. Therefore, we examined the effects of fluoxetine on Fkbp5 and the GR signaling in the hypothalamic paraventricular nucleus (PVN) of depressed mice.

Mice were exposed to chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), or chronic restraint stress (CRS) with or without fluoxetine treatment (intraperitoneally injected, 20 mg/kg) and examined for changes in depression-like behaviors and HPA axis activity as well as Fkbp5 expression and GR phosphorylation in the PVN. We then examined if adeno-associated virus (AAV)-mediated Fkbp5 overexpression in the PVN affected the antidepressant actions of fluoxetine in mice.

Fluoxetine treatment significantly mitigated CSDS-, CUMS-, and CRS-induced depression-like behaviors and HPA axis hyperactivity in mice. Subsequent western blotting analyses showed that fluoxetine treatment fully reversed not only chronic stress-induced upregulation of Fkbp5 and CRH but also chronic stress-induced increase in Ser203 phosphorylation and decrease in Ser211 and Ser234 phosphorylation in GR in the PVN. Moreover, quantitative real-time reverse transcription PCR (qRT-PCR) analyses revealed that the enhanced mRNA levels of Fkbp5 and CRH in PVN neurons of mice subjected to CSDS/CUMS/CRS were also notably reversed by fluoxetine administration. Conversely, Fkbp5 overexpression in the PVN significantly eliminated the antidepressant effects of fluoxetine in mice without affecting their locomotor activity.

These results together suggest that fluoxetine treatment reverses chronic stress-induced promotion on Fkbp5 expression and multiple effects on GR phosphorylation in the PVN of mice.

The selective serotonin reuptake inhibitor fluoxetine (sold as Prozac) is a widely used treatment for depression, but the full spectrum of therapeutic mechanisms is still debated. Recent evidence suggests that these therapeutic mechanisms include suppression of chronic stress-activated hypothalamus-pituitary-adrenal (HPA) axis. The current study presents the first in vivo evidence showing that suppression of HPA axis hyperactivity by fluoxetine treatment involves reversal of glucocorticoid receptor (GR) phosphorylation via modulation of the GR negative regulator Fk506-binding protein 5 (Fkbp5) in the hypothalamic paraventricular nucleus (PVN). Fluoxetine treatment not only inhibited chronic stress-induced depression-like behaviors and HPA axis hyperactivity but also reversed Fkbp5 upregulation and GR phosphorylation changes in the PVN, while adeno-associated virus (AAV)-based Fkbp5 overexpression in the PVN eliminated the antidepressant effects of fluoxetine. These findings may expand our understanding of the pharmacological effects of fluoxetine, and further identify Fkbp5 as a possible target for novel antidepressants.

Depression is a major public health problem with a continued need to uncover its etiology. Current models of depression contend that gene-by-environment (G × E) interactions influence depression risk, and further, that depression is polygenic. Thus, recent models have emphasized two polygenic approaches: a hypothesis-driven multilocus genetic profile score (MGPS; "MGPS × E") and a polygenic risk score (PRS; "PRS × E") derived from genome-wide association studies (GWAS). This review for the first time synthesizes current knowledge on polygene by environment "P × E" interaction research predicting primarily depression-related outcomes, and in brief, neurobiological outcomes. The "environment" of focus in this project is stressful life events. It further discusses findings in the context of differential susceptibility and diathesis-stress theories-two major theories guiding G × E work. This synthesis indicates that, within the MGPS literature, polygenic scores based on the serotonin system, the HPA axis, or across multiple systems, interact with environmental stress exposure to predict outcomes at multiple levels of analyses and most consistently align with differential susceptibility theory. Depressive outcomes are the most studied, but neuroendocrine, and neuroimaging findings are observed as well. By contrast, vast methodological differences between GWAS-based PRS studies contribute to mixed findings that yield inconclusive results.

Depression is a chronic and recurrent psychiatric condition characterised by depressed mood, loss of interest or pleasure, poor sleep, low appetite, and poor concentration. Research has shown that both heritable and environmental risk factors are involved in the pathogenesis of depression. In addition, several studies have indicated that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the development of depression in adulthood. However, the mechanism underlying the activation of HPA axis-induced depression remains unclear. Arginine vasopressin (AVP), also known as vasopressin (VP), is a hormone synthesised in the hypothalamus that plays important roles in numerous biological functions in mammals, including the regulation of stress and anxiety, and has been implicated in the pathogenesis of many disorders. VP regulates pituitary corticotroph function by binding to the plasma membrane G-protein receptors of the V1B receptor (V1BR), which are coupled to calcium-phospholipid signalling. V1BR, a receptor subtype of VP, plays a pivotal role in HPA axis abnormalities observed in depression. In animals, V1BR antagonists reduce plasma stress hormone levels and have been shown to have antidepressant activity. However, the precise mechanism of V1BR in modulating HPA axis activity remains unclear. We therefore reviewed and integrated the clinical and preclinical literature pertinent to the role of V1BR in depression, while emphasising the effect of V1BR antagonists on attenuating the hyperactivity of the HPA axis. In addition, therapy for depression through the regulation of the HPA axis is briefly discussed. Although effective antidepressants are available, a large proportion of patients do not respond to initial treatment. Therefore, this review describes the exact mechanisms of V1BR in depression and contributes to the development of new therapeutic strategies for this disease.

Leveraging real-world clinical biobanks to investigate the associations between genetic and environmental risk factors for mental illness may help direct clinical screening efforts and evaluate the portability of polygenic scores across environmental contexts.

To examine the associations between sexual trauma, polygenic liability to mental health outcomes, and clinical diagnoses of schizophrenia, bipolar disorder, and major depressive disorder in a clinical biobank setting.

This genetic association study was conducted using clinical and genotyping data from 96 002 participants across hospital-linked biobanks located at Vanderbilt University Medical Center (VUMC), Nashville, Tennessee (including 58 262 individuals with high genetic similarity to the 1000 Genomes Project [1KG] Northern European from Utah reference population [1KG-EU-clustered] and 11 047 with high genetic similarity to the 1KG African-ancestry reference population of Yoruba in Ibadan, Nigeria [1KG-YRI-clustered]), and Mass General Brigham (MGB), Boston, Massachusetts (26 693 individuals with high genetic similarity to the combined European-ancestry superpopulation [1KG-EU-clustered]). Clinical data analyzed included diagnostic billing codes and clinical notes spanning from 1976 to 2023. Data analysis was performed from 2022 to 2024.

Clinically documented sexual trauma disclosures and polygenic scores for schizophrenia, bipolar disorder, and major depressive disorder.

Diagnoses of schizophrenia, bipolar disorder, and major depressive disorder, determined by aggregating related diagnostic billing codes, were the dependent variables in logistic regression models including sexual trauma disclosure status, polygenic scores, and their interactions as the independent variables.

Across the VUMC and MGB biobanks, 96 002 individuals were included in analyses (VUMC 1KG-EU-clustered: 33 011 [56.7%] female; median [range] age, 56.8 [10.0 to >89] years; MGB 1KG-EU-clustered: 14 647 [54.9%] female; median [range] age, 58.0 [10.0 to >89] years; VUMC 1KG-YRI-clustered: 6961 [63.0%] female; median [range] age, 44.6 [10.1 to >89] years). Sexual trauma history was associated with all mental health conditions across institutions (ORs ranged from 8.83 [95% CI, 5.50-14.18] for schizophrenia in the VUMC 1KG-YRI-clustered cohort to 17.65 [95% CI, 12.77-24.40] for schizophrenia in the VUMC 1KG-EU-clustered cohort). Sexual trauma history and polygenic scores jointly explained 3.8% to 8.8% of mental health phenotypic variance. Schizophrenia and bipolar disorder polygenic scores had greater associations with mental health outcomes in individuals with no documented disclosures of sexual trauma (schizophrenia interaction: OR, 0.70 [95% CI, 0.56-0.88]; bipolar disorder interaction: OR, 0.83 [95% CI, 0.74-0.94]).

Sexual trauma and mental health polygenic scores, while correlated with one another, were independent and joint risk factors for severe mental illness in a large, diverse hospital biobank population. Furthermore, associations of schizophrenia and bipolar disorder polygenic scores with respective diagnoses were greater in those without disclosures, suggesting that genetic predisposition to mental illness as measured by polygenic scores may be less impactful in the presence of this severe environmental risk factor.

To produce a theoretical approach about the relations between neuroscience and psychopathology that expands beyond the biomedical model to include a non-reductionist, enactive, and biocultural perspective. An integrative review, drawing from the biocultural approach from Anthropology, is used to produce examples from epigenetics, neuroplasticity, and functional neuroanatomy. A biocultural approach points to a brain that is highly plastic, reinforcing a much more complex model in which biological vulnerabilities and the historical-cultural environment co-construct each other. The examples given seem to point to the pressing need for a critical expansion of reductionist models of psychopathology. Importantly, the cultural-historical environment to which we refer is not a set of neutral social relations to which individuals are homogeneously exposed, such that aspects that are usually studied under the social determinants of health and disease (poverty, discrimination, violence, and other factors that represent sources of control, production, and distribution of material resources, ideology, and power) need to be incorporated in adequate biopsychosocial models of mental distress.

Early life stress (ELS) can negatively impact health, increasing the risk of stress-related disorders, such as post-traumatic stress disorder (PTSD). Importantly, PTSD disproportionately affects women, emphasizing the critical need to explore how sex differences influence the genetic and metabolic neurobiological pathways underlying trauma-related behaviors. This study uses the limited bedding and nesting (LBN) paradigm to model ELS and investigate its sex-specific effects on fear memory formation. Employing innovative unsupervised behavioral classification, the current study reveals distinct behavioral patterns associated with fear acquisition and retrieval in male and female mice following ELS. Females exposed to LBN display heightened active fear responses, contrasting with males. Furthermore, the study examined the crucial link between behavioral regulation and cellular metabolism in key brain regions involved in fear and stress processing. Sex-specific and stress-dependent alterations were observed in purine, pyrimidine, and glutamate metabolism within the basolateral amygdala, the dorsal hippocampus, and the ventral hippocampus. These findings provide crucial insights into the complex interplay between metabolic pathways, the neurobiological underpinnings of fear memory, and stress responses. Importantly, they emphasize the significance of considering sex-specific metabolic alterations when investigating stress-related disorders, opening potential avenues for the development of targeted interventions.

Various risk factors, such as childhood nurturing experiences and subjective social status, have been identified to be involved in the onset of depression. However, the mechanism of depression is not yet fully understood. In this study, we hypothesized that nurturing experienced in childhood affects subjective social status and current personality traits, which in turn influence depressive symptoms in adulthood, and verified this hypothesis through structural equation modeling.

A questionnaire survey was conducted on 404 adults. Multiple regression analysis and structural equation modeling were conducted using demographic information and scores for the Patient Health Questionnaire-9, Parental Bonding Instrument, and NEO Five-Factor Inventory.

Subjective social status was found to mediate the association between nurturing experiences and neuroticism (0.029 for Overprotection and -0.034 for Care). On the other hand, neuroticism was found to mediate the association between subjective social status and depressive symptoms (-0.097 in Care model and -0.103 in Overprotection model), as well as the association between nurturing experiences and depressive symptoms (0.144 for Overprotection and -0.134 for Care). Furthermore, it was also shown that complex paths, in which the association of nurturing experiences with depressive symptoms was mediated by two factors, namely, subjective social status and neuroticism, were statistically significant as indirect effects (0.016 for Overprotection and -0.018 for Care).

In this study, we clarified that nurturing experienced in childhood affects neuroticism in adulthood, which is mediated by subjective social status, and furthermore, the effects of nurturing on neuroticism lead to varying levels of depressive symptoms in adulthood. The mediation effects demonstrated in the present study may contribute towards unraveling the causes of depression and developing effective treatments for depressive symptoms.

Stressful events, from daily stressors to traumatic experiences, are common and occur at any age. Despite the high prevalence of trauma, not everyone develops stress-related disorders like major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), a variation attributed to resilience, the ability to adapt and avoid negative consequences of significant stress. This review examines the locus coeruleus-norepinephrine (LC-NE) system, a critical component in the brain's stress response. It discusses the LC-NE system's anatomical and functional complexity and its role in individual variability in stress responses. How different etiological factors and stress modalities affect the LC-NE system, influencing both adaptive stress responses and psychopathologies, are discussed and supported by evidence from human and animal studies. It also explores molecular and cellular adaptations in the LC that contribute to resilience, including roles of neuropeptide, inflammatory cytokines, and genetic modulation, and addresses developmental and sex differences in stress vulnerability. The need for a multifaceted approach to understand stress-induced psychopathologies is emphasized and pave the way for more personalized interventions for stress-related disorders.

Beginning with the successful sequencing of the human genome two decades ago, the possibility of developing personalized health interventions based on one's biology has captured the imagination of researchers, medical providers, and individuals seeking health care services. However, the application of a personalized medicine approach to emotional and behavioral health has lagged behind the development of personalized approaches for physical health conditions. There is potential value in developing improved methods for integrating biological science with prevention science to identify risk and protective mechanisms that have biological underpinnings, and then applying that knowledge to inform prevention and intervention services for emotional and behavioral health. This report represents the work of a task force appointed by the Board of the Society for Prevention Research to explore challenges and recommendations for the integration of biological and prevention sciences. We present the state of the science and barriers to progress in integrating the two approaches, followed by recommended strategies that would promote the responsible integration of biological and prevention sciences. Recommendations are grounded in Community-Based Participatory Research approaches, with the goal of centering equity in future research aimed at integrating the two disciplines to ultimately improve the well-being of those who have disproportionately experienced or are at risk for experiencing emotional and behavioral problems.

Nomograms are superior to traditional multivariate regression models in the competence of quantifying an individual's personalized risk of having a given condition. To date, no literature has been found to report a quantified risk prediction model for prenatal depression. Therefore, this study was conducted to investigate the prevalence and associated factors of prenatal depression. Moreover, two novel nomograms were constructed for the quantitative risk prediction.

In this cross-sectional study, the participants were recruited using convenience sampling and administered with the research questionnaires. The prevalence of prenatal depression was calculated with a cutoff point of ≥ 10 in the 8-item Patient Health Questionnaire. Univariate and multivariate binomial logistic regression models were subsequently employed to identify the associated factors of prenatal depression. Two nomograms for the risk prediction were constructed and multiple diagnostic parameters were used to examine their performances.

The prevalence of prenatal depression was 9.5%. Multivariate binomial logistic regression model based on sociodemographic, health-related, and pregnancy-related variables (model I) suggested that unemployment, poor relationship with partners, antecedent history of gynecologic diseases, unplanned pregnancy, an earlier stage of pregnancy, and more severe vomiting symptoms were associated with increased risk of prenatal depression. In the regression model that further included psychosocial indicators (model II), unemployment, antecedent history of gynecologic diseases, unplanned pregnancy, an earlier stage of pregnancy, and a higher total score in the Pregnancy Stress Rating Scale were found to be associated with prenatal depression. The diagnostic parameters suggested that both nomograms for the risk prediction of prenatal depression have satisfactory discriminative and predictive efficiency and clinical utility. The nomogram based on model II tended to have superior performances and a broader estimating range and that based on model I could be advantageous in its ease of use.

The prevalence of prenatal depression was considerably high. Risk factors associated with prenatal depression included unemployment, poor relationship with partners, antecedent history of gynecologic diseases, unplanned pregnancy, an earlier stage of pregnancy, more severe vomiting symptoms, and prenatal stress. The risk prediction model I could be used for fasting screening, while model II could generate more precise risk estimations.

Adolescent non-suicidal self-injury (NSSI) has emerged as a progressively widespread and significant public health concern on a global scale. Research has increasingly documented a positive linkage between deviant peer affiliation and adolescent NSSI; however, there is little known about the underlying moderating or mediating mechanism of NSSI. According to the gene × environment interaction perspective, the current study investigated the intermediary function of depression in linking deviant peer affiliation to NSSI among adolescents, while also considering the moderating effect of the OXTR gene rs53576 polymorphism on this intermediary process.

A total of 469 adolescents (Meanage = 12.81 years; SD = 0.47 years) anonymously finished the study questionnaires. This study used structural equation modeling analysis to verify a moderated mediation model. Gender, age, and family financial difficulties were used as covariates.

Mediation analyses suggested that the positive connection between deviant peer affiliation and adolescent NSSI was mediated by depression. Moreover, the moderated mediation analyses revealed that deviant peer affiliation increased depression levels, which in turn contributed to increased NSSI among adolescents with the AA genotype. Nevertheless, the correlation failed to reach statistical significance among adolescents possessing the GA and GG genotypes.

These findings emphasize depression's potential as a bridge linking deviant peer affiliation to adolescent NSSI. The AA genotype of the OXTR gene rs53576 emerges as a critical risk factor in the enhancement of this indirect effect. This study provides valuable perspectives for designing intervention strategies aimed at reducing adolescent NSSI.

The nucleus accumbens (NAc) plays an important role in various emotional and motivational behaviors that rely on heightened wakefulness. However, the neural mechanisms underlying the relationship between arousal and emotion regulation in NAc remain unclear. Here, we investigated the roles of a specific subset of inhibitory corticotropin-releasing hormone neurons in the NAc (NAcCRH) in regulating arousal and emotional behaviors in mice. We found an increased activity of NAcCRH neurons during wakefulness and rewarding stimulation. Activation of NAcCRH neurons converts NREM or REM sleep to wakefulness, while inhibition of these neurons attenuates wakefulness. Remarkably, activation of NAcCRH neurons induces a place preference response (PPR) and decreased basal anxiety level, whereas their inactivation induces a place aversion response and anxious state. NAcCRH neurons are identified as the major NAc projection neurons to the bed nucleus of the stria terminalis (BNST). Furthermore, activation of the NAcCRH-BNST pathway similarly induced wakefulness and positive emotional behaviors. Taken together, we identified a basal forebrain CRH pathway that promotes the arousal associated with positive affective states.

While a myriad of factors likely contribute to the development of mental illness in young people, the social environment (including early adverse experiences) in concert with neurodevelopmental alterations is undeniably important. A number of influential theories make predictions about how and why neurodevelopmental alterations may mediate or moderate the effects of the social environment on the emergence of mental illness. Here, we discuss current evidence supporting each of these theories. Although this area of research is rapidly growing, the body of evidence is still relatively limited. However, there exist some consistent findings, including increased striatal reactivity during positive affective processing and larger hippocampal volumes being associated with increased vulnerability or susceptibility to the effects of social environments on internalizing symptoms. Limited longitudinal work has investigated neurodevelopmental mechanisms linking the social environment with mental health. Drawing from human research and insights from animal studies, we propose an integrated mediation-moderation model and outline future research directions to advance the field.

Both acute and chronic stress have significant impact on brain functions. The amygdala is essential in mediating stress responses, but how its transcriptomic dynamics change under stress remains elusive. To overcome the difficulties in detecting subtle stress-induced changes by evaluating total RNA using classic RNA sequencing, we conducted thiol-labeled RNA sequencing (SLAM-seq). We injected 4-thiouridine (4sU) into mouse amygdala followed by SLAM-seq to detect nascent mRNA induced by acute and chronic restraint stress, and found that SLAM-seq could label actively transcribed genes in the major neuronal and glial subtypes. Using SLAM-seq, we found that chronic stress led to higher turnover of a group of genes associated with myelination, and this finding is confirmed by immunostaining which showed increased myelination in the chronically stressed amygdala. Additionally, genes detected by SLAM-seq and RNA-seq only partially overlapped, suggesting that SLAM-seq and RNA-seq are complementary in identifying stress-responsive genes. By applying SLAM-seq in vivo, we obtained a rich dataset of genes with higher turnover in the amygdala under stress.

Adversity that exhibits continuity across the life course has long-term detrimental effects on physical and mental health. Using 920 participants from the Dunedin Study, we tested the following hypotheses: (1) children (ages 3-15) who experienced adversity would also tend to experience adversity in adulthood (ages 32-45), and (2) interim personality traits in young adulthood (ages 18-26) would help account for this longitudinal association. Children who experienced more adversity tended to also experience more stressful life events as adults, β=.11, 95% CI [.04, .18], p=.002. Negative emotionality-particularly its sub-facet alienation, characterized by mistrust of others-helped explain this childhood-to-midlife association (indirect effect: β=.06, 95% CI [.04, .09], p<.001). Results were robust to adjustment for sex, socioeconomic origins, childhood IQ, preschool temperament, and other young-adult personality traits. Prevention of early-life adversity and treatment of young-adult negative emotionality may reduce vulnerability to later life stress and thereby promote the health of aging adults.

Major depressive disorder (MDD) is a common psychological condition, the consequences of which, such as suicide, can be severe. Escitalopram, a selective serotonin reuptake inhibitor, is a commonly used antidepressant in clinics. However, more than one-third of patients with MDD do not respond to this drug. Gene polymorphism may affect the efficacy of escitalopram, but the genetic architecture of the antidepressant response in patients with MDD remains unclear. We perform a genome-wide association study (GWAS) of the genetic effect on the outcome of escitalopram in patients with MDD. A total of 203 patients with MDD and 176 healthy control (HC) adults were recruited from Beijing Anding Hospital. Patients received 12 weeks of antidepressant treatment with escitalopram. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) or Hamilton depression scale (HAMD) were used to evaluate the severity of depression symptoms at the baseline and the end of 2 and 12 weeks of treatment. A total of 140 variants in MDD patients were identified by GWAS to have genome-wide significance (p < 5e - 8) compared with HCs. Similarly, 189 and 18 variants were identified to be associated with QIDS-SR and HAMD score changes in patients after antidepressant treatment (p < 1e - 5), including rs12602361, rs72799048, rs16842235, and rs2518256. In the two weeks QIDS-SR score study, the gene-level association for these variants and gene set enrichment analyses implicate the enrichment of genes involved in the synaptic plasticity process and nervous system development. Our results implicate the predictive capacity of the effect of escitalopram treatment, supporting a link between genetic basis and remission of depression.

One of the fundamental aspects of research in psychiatry, and what makes it such a complex area, is its methodological specificities [...].

Depression is a leading cause of disability in the United States. Previous research has shown that added sugar consumption and stress are both risk factors for depression. Despite evidence that stress predicts added sugar consumption, and both affect the HPA axis, no research has explored how stress, added sugar consumption and depression are related. In this study, we investigated the possible effects of total added sugar and sugar-sweetened beverage consumption on depression, as well as their potential interactions with chronic stress. Measures of sugar consumption, chronic stress and depression were taken in an adult community sample at two time points. We hypothesized that high sugar consumption would predict more depression even after stress was statistically adjusted for, but that stress would moderate the relationship between added sugar consumption and depressive symptoms, amplifying the effect. We found that both total sugar consumption and sugar-sweetened beverage consumption at baseline predicted depressive symptoms one month later. However, only sugar-sweetened beverage consumption was a significant predictor of depression after controlling for stress, possibly because stress is related to diet quality. Stress did not moderate the relationship between added sugar consumption and depressive symptoms. These results suggest that stress should be included in future research on sugar and depression.

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure.