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Background: Interactions between the serotonin (5-HT) and endocannabinoid (eCB) systems have been reported in the psychopathology of stress-related symptoms, while their interplay in regulating the relationship between childhood trauma and burnout remains unclear. In this study, we investigated the interaction of childhood trauma with genetic polymorphisms in these two systems in predicting burnout., Methods: Burnout, childhood trauma, and job stress were assessed using rating scales in 992 general occupational individuals. Genetic polymorphisms including HTR2A rs6313, 5-HTT rs6354 and FAAH rs324420, were genotyped. Linear hierarchical regression analysis and PROCESS macro in SPSS were used to examine two- and three-way interactions., Results: There were significant interactions of job stress × HTR2A rs6313 and childhood abuse × FAAH rs324420 on reduced personal accomplishment. Moreover, we found significant three-way interactions of childhood abuse × FAAH rs324420 × HTR2A rs6313 on cynicism and reduced personal accomplishment, childhood abuse × FAAH rs324420 × 5-HTT rs6354 on emotional exhaustion, and childhood neglect × FAAH rs324420 × 5-HTT rs6354 on reduced personal accomplishment. These results suggest that the FAAH rs324420 A allele carriers, when with some specific genetic polymorphisms of 5-HT system, would show more positive associations between childhood trauma and burnout., Conclusions: Genetic polymorphisms in the 5-HT and eCB systems may jointly moderate the impact of childhood trauma on burnout., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adverse childhood experiences (ACEs) are a well-known risk factor of schizophrenia. Moreover, individuals with schizophrenia are likely to use maladaptive stress coping strategies. Although it has been reported that a history of ACEs might be associated with a pro-inflammatory phenotype in patients with schizophrenia, the interacting effect of coping styles on this association has not been tested so far. In the present study, we aimed to investigate the levels of immune-inflammatory markers in patients with schizophrenia and healthy controls (HCs), taking into consideration a history of ACEs and coping strategies. Participants included 119 patients with schizophrenia and 120 HCs. Serum levels of 26 immune-inflammatory markers were determined. A history of any categories of ACEs was significantly more frequent in patients with schizophrenia. Moreover, patients with schizophrenia were significantly more likely to use emotion-focused coping and less likely to use active coping strategies compared to HCs. The levels of interleukin(IL)-6, RANTES, and tumor necrosis factor-α (TNF-α), appeared to be elevated in patients with schizophrenia after adjustment for potential confounding factors in all tested models. Participants reporting a history of any ACEs had significantly higher levels of TNF-α and IL-6. No significant main and interactive effects of active strategies as the predominant coping on immune-inflammatory markers with altered levels in patients with schizophrenia were found. Findings from the present study indicate that ACEs are associated with elevated TNF-α and IL-6 levels regardless of schizophrenia diagnosis and predominant coping styles., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Physicians face documented challenges to their mental and physical well-being, particularly in the forms of occupational burnout and cardiovascular disease. This study examined the previously under-researched intersection of early life stressors, prolonged occupational stress, and cardiovascular health in physicians., Methods: Participants were 60 practicing male physicians, 30 with clinical burnout, defined by the Maslach Burnout Inventory, and 30 non-burnout controls. They completed the Adverse Childhood Experiences (ACE) Questionnaire asking about abuse, neglect and household dysfunctions before the age of 18, and the Perceived Stress Scale to rate thoughts and feelings about stress in the past month. Endothelium-independent (adenosine challenge) coronary flow reserve (CFR) and endothelium-dependent CFR (cold pressor test) were assessed by positron emission tomography-computed tomography. The segment stenosis score was determined by coronary computed tomography angiography., Results: Twenty-six (43%) participants reported at least one ACE and five (8%) reported ≥4 ACEs. A higher ACEs sum score was associated with lower endothelium-independent CFR (r partial (r p ) = -0.347, p = .01) and endothelium-dependent CFR (r p  = -0.278, p = .04), adjusting for age, body mass index, perceived stress and segment stenosis score. In exploratory analyses, participants with ≥4 ACEs had lower endothelium-independent CFR (r p  = -0.419, p = .001) and endothelium-dependent CFR (r p  = -0.278, p = .04), than those with <4 ACEs. Endothelium-dependent CFR was higher in physicians with burnout than in controls (r p  = 0.277, p = .04). No significant interaction emerged between burnout and ACEs for CFR., Conclusion: The findings suggest an independent association between ACEs and CFR in male physicians and emphasize the nuanced relationship between early life stressors, professional stress, and cardiovascular health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study aimed to expand on previous findings that pre-treatment autonomic nervous system (ANS) functioning serves as a predictor of clinical outcome in adolescent borderline personality disorder (BPD), while examining whether the relationship between ANS functioning and treatment outcome may vary as a function of early life maltreatment (ELM). ANS stress response was examined considering changes in heart rate (HR) and vagally-mediated heart rate variability (vmHRV) over different conditions of the Montreal Imaging Stress Task (MIST) in a clinical sample of N = 27 adolescents across the spectrum of BPD severity. Participants received in- and/or outpatient treatment, while clinical data was assessed at routine follow-ups. Clinical outcome was defined by change in the number of fulfilled BPD criteria (as measured using the SCID-II), severity of psychopathology (CGI-S), and global level of functioning (GAF), measured 12 and 24 months after baseline assessments. Mixed-effects (random-intercept/random slope) linear regression models were calculated to examine markers of ANS function as potential predictors of clinical outcome. Irrespective of the presence of ELM exposure, both vmHRV resting-state and stress recovery measures were identified as significant predictors of clinical outcome over time. This study adds to the existing literature by replicating and expanding on preliminary findings, considering also physiological reactivity and recovery in addition to resting-state measures of ANS functioning. The present results further highlight the potential of markers of ANS functioning to serve as objective measures in the process of monitoring patient progress and to make predictions regarding treatment outcome in psychiatry research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD)., Methods: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters., Results: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation., Conclusions: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive impairment has been associated with both childhood adversity and abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function. An interaction exists between the functional polymorphism rs1360780 in the FKBP5 gene and childhood maltreatment, influencing a variety of clinical outcomes. Our goal was to study the relationship between different types of childhood trauma, HPA axis functionality, rs1360780 genotype and cognitive function in 198 healthy individuals who participated in the study. We obtained clinical data, childhood maltreatment scores and neurocognitive performance by clinical assessment; HPA negative feedback was analysed using the dexamethasone suppression test ratio (DSTR) after administration of 0.25 mg of dexamethasone; and the FKBP5 rs1360780 polymorphism was genotyped in DNA obtained from blood samples. The results showed a significant influence of physical neglect on measures of neurocognition as well as an interaction between the DSTR and physical and emotional neglect. Regarding social cognition, a significant association was found with sexual and physical abuse as well as with rs1360780 risk-allele carrier status. Moreover, an interaction between the rs1360780 genotype and the presence of physical abuse was significantly associated with social cognition results. Our results suggest a specific impact of different kinds of childhood maltreatment on measures of neurocognition and social cognition, which might be influenced by HPA axis reactivity and genetic variants in HPA axis-related genes such as FKBP5. Disentangling the relationship between these elements and their influence on cognitive performance might help identify susceptible individuals with higher stress vulnerability and develop preventive interventions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: During this time ofintensified hardship and disruption due to the SARS-CoV-2 (COVID-19) pandemic, communities, practitioners, and state and local governments have had to rapidly implement and adapt strategies that support mental health and wellbeing during a global pandemic. Prior to the COVID-19 pandemic, suicide was the 10th leading cause of death in the United States, and at least half of the top 10 leading causes of death have been associated with adverse childhood experiences (ACEs). A number of established risk factors for suicide and ACEs may have been exacerbated by the pandemic, including loneliness and the lack of connectedness., Method: This article briefly considers the effects of COVID-19 on social connection and outlines the importance of adapting and developing programming and resources that address suicide and ACEs prevention during a time of infrastructure disruption. Practical Applications: The COVID-19 pandemic has affected the ways that many individuals are able to safely interact and socially connect due to public health prevention strategies implemented to slow the spread of COVID-19. Local, city, and state government, community organizations, and public health and medical practitioners should consider the adaptation and development of existing and new programming, resources, and activities that support and strengthen social connection. In addition to implementing programs, policies may help address systemic and structural barriers to social connection, such as access to parks and open space, public transportation, or digital connectivity., (Published by Elsevier Ltd.)

Background: Psychological trauma can damage the brain, especially in areas where glucocorticoid receptors are expressed, via perturbed secretion of cortisol. Childhood trauma is associated with blunted basal cortisol secretion, brain alterations, and autobiographical memory deficits referred to as overgeneral autobiographical memory (OGM). However, it remains unknown whether childhood trauma affects OGM through altered cortisol and brain alterations., Methods: Using resting-state fMRI in 100 healthy humans, we examined whether childhood trauma affects OGM through its related basal cortisol and brain functional connectivity (FC). Trauma and OGM were assessed using the Childhood Trauma Questionnaire (CTQ) and Autobiographical Memory Test (AMT), respectively. Basal cortisol levels were measured by 10 points-in-time across two days. Multiple mediation analysis was employed., Results: CTQ was associated with greater semantic-associate memory of OGM, a retrieval tendency toward semantic content with no specific contextual details of an experienced event, as well as blunted basal cortisol levels. While CTQ was correlated with decreased FC between the hippocampus and medial prefrontal cortex (PFC), it showed a more predominant correlation with increased FC between the lateral and anteromedial PFC and extrastriate cortex. Importantly, the increased prefrontal-extrastriate FC completely mediated the relationship between CTQ and semantic-associate memory, affected by hyposecretion of cortisol., Conclusion: Childhood trauma may lead to the lack of visuoperceptual contextual details in autobiographical memory by altering basal cortisol secretion and connectivity of the prefrontal-hippocampal-extrastriate regions. The intensified prefrontal-extrastriate connectivity may contribute to OGM formation by strengthening the semantic content in memory retrieval. Understanding the mechanisms underlying the trauma-cortisol-brain-memory link will provide important clinical implications for trauma-related mental disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Early Life Stress (ELS) is thought to influence Hypothalamic-Pituitary-Adrenal-Axis (HPAA) functioning, contributing to an increased risk for psychopathology through dysregulation of biological stress responses. Research exploring relationships between ELS and HPAA functioning has largely focused on its key hormonal output, cortisol. However, findings have been inconsistent, potentially due to cortisol's distinctive diurnal patterns and dynamic nature complicating its accurate measurement. Thus, this study explored the link between ELS and a more stable, structural component of the HPAA, specifically, anterior pituitary gland volume (PGV) in a community sample of children (N = 129, 68 female). PGV was traced from Magnetic Resonance Imaging brain scans across two time-points at ages 8 (baseline) and 10 years (follow-up). ELS exposure was assessed at baseline through parent-report questionnaires and maternal affective behavior observed in mother-child interaction tasks. ELS variables were reduced to a 5-factor structure using exploratory factor analysis - Uninvolved Parenting, Negative Affective Parenting, Neglect, Trauma, and Dysfunctional Discipline. Direct and sex-moderated associations between ELS and PGV were explored using regression and linear mixed models analyses. PGV-mediated associations between ELS and internalizing symptoms were also investigated. Childhood Neglect was significantly associated with greater baseline anterior PGV, that was stable over the follow-up period. This effect was found in the whole sample, and in males, specifically. No mediation effects were found. Results suggest that neglect may play a unique role in HPAA neurodevelopment; however, it is important that future research extends into adolescence to more clearly characterize these neurodevelopmental associations and any subsequent psychopathological outcomes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Adverse childhood experiences (ACEs) have been associated with poorer health across the life course. Previous studies have used cumulative risk scores (ACE scores) or individual ACEs but these two approaches have important shortcomings. ACE scores assume that each adversity is equally important for the outcome of interest and the single adversity approach assumes that ACEs do not co-occur. Latent class analysis (LCA) is an alternative approach to operationalising ACEs data, identifying groups of people co-reporting similar ACEs. Here we apply these three approaches for ACEs operationalisation with inflammation in childhood with the aim of identifying particular ACEs or ACE combinations that are particularly associated with higher inflammation in early life., Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we compare ACE scores, single adversities and LCA-derived ACE clusters in their relationships with Interleukin-6 at age 9 (n = 4935) and C-Reactive Protein (CRP) at age 9 (n = 4887). ACEs included were parental separation/divorce, parental alcohol problems, parental mental health problems, parental offending, inter-parental violence, parental drug misuse, and physical, emotional and sexual abuse., Results: Two thirds of the sample reported at least one ACE. Mother's mental health problems was the most frequently reported ACE (32.3 %). LCA identified four ACE classes - 'Low ACEs' (81.1 %), 'Maternal mental health problems' (10.3 %), 'Maternal mental health problems and physical abuse' (6.3 %) and 'Parental conflict, mental health problems and emotional abuse' (2.4 %). Parental separation/divorce was associated with higher IL-6. Parental alcohol problems, paternal mental health problems, parental convictions and emotional abuse were associated with lower levels of IL-6. Associations for paternal mental health problems and emotional abuse were only observed for boys. ACE score and LCA-derived ACE classes were not associated with differences in IL-6. Girls in the 'Maternal mental health problems' cluster had lower CRP levels., Conclusions: Specific adversities and adversity combinations are important for differences in childhood inflammation. Some associations were only observed for girls or boys., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive., Methods: In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood., Results: Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems' activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, β = .088, p =  .007; AUCi, β = .084, p =  .010), cumulative HPA-axis markers (β = .115, p =  .001), C-reactive protein (β = .055, p = .032), interleukin-6 (β = .053, p =  .038), cumulative inflammation (β = .060, p =  .020), and cumulative markers across all systems (β = .125, p =  .0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases., Conclusion: While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Early-life environments have been associated with various social behaviors, including trust, in late adolescence and adulthood. Given that the oxytocin receptor gene polymorphism (OXTR rs53576) moderates the impact of childhood experience on social behaviors, in the present study, we examined the main effect of childhood adversity through a self-report measure and its interactions with OXTR rs53576 on general trust among 203 Japanese and 200 European Canadian undergraduate students. After controlling for the effect of culture, the results indicated that childhood adversity had a negative association with general trust, and that OXTR rs53576 moderated the impact of childhood adversity on general trust. Specifically, the negative association between childhood adversity and general trust is only significant among homozygote A-allele carriers. These findings demonstrated that OXTR rs53576 moderated the relations between childhood experiences and social functioning in early adulthood., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathophysiology of post-traumatic stress disorder (PTSD). However, there has been little study of HPA stress reactivity in association with PTSD symptoms (PTSS) in children; and there is limited research on PTSD in low and middle-income countries, where trauma exposure is more common and co-occurring stressors more likely., Method: We assessed the relationship between PTSS and cortisol stress reactivity in children aged 13 years (N = 291) from an impoverished South African community. HPA axis stress reactivity was indexed by salivary cortisol during the Trier Social Stress Test (TSST)., Results: In regression analyses both trauma exposure and PTSS showed small inverse associations with total cortisol output (area under the curve with respect to ground) during the TSST, but PTSS effects did not withstand correction for covariates. In addition, hierarchical linear modelling (HLM) found that PTSS were associated with alterations in the shape of the profile of cortisol reactivity that were moderated by sex. In girls, PTSS were associated with reduced linear slope but larger quadratic slopes, whereas the opposite pattern was found in boys. Thus, elevated PTSS were associated with overall blunted profiles of cortisol stress reactivity in girls, but a larger quadratic slope in boys reflects a steeper cortisol increase and decline in boys. There was no relationship between trauma exposure (with or without PTSS) and cortisol reactivity profiles in HLM analyses., Conclusion: In children from a high adversity, low and middle income country context, sex specific associations were found between PTSS and cortisol responses to psychosocial stress. Further research should probe HPA axis functioning more comprehensively in such populations to understand the biological associations of PTSS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Bipolar disorder (BD) is highly associated with childhood maltreatment (CM), the exposure to such early adversity being suggested to disrupt the expression of several biological pathways. This study aims at exploring associations between the mRNA levels of 9 HPA axis genes in lymphoblastoid cell lines from patients with BD according to their self-reported exposure to CM., Methods: The sample consisted of 33 Caucasian patients with a diagnosis of BD type 1, assessed for the exposure to CM with the Childhood Trauma Questionnaire (CTQ). Quantitative RT-PCR was performed on 9 transcripts of the HPA axis genes: DGKH, FKBP5, NR3C1, SGK1, SGK2, SGK3, SKA2, STAT5A and UCN. RT-qPCR data were analyzed using the method of disjoint gene networks with SARP.compo package for R., Results: We found no associations between CTQ total score and the amount of HPA axis transcripts neither in univariate analyses, nor with network analyses. Emotional abuse (EA) was associated with a significant decreased expression of two transcripts, DGKH (p = 0.009) and NR3C1 (p = 0.04). This was confirmed by the disjoint network analysis, which showed that NR3C1 and DGKH were expressed differently from the rest of the HPA axis network in presence of emotional abuse., Discussion: This study described the expression levels of a comprehensive set of HPA axis genes according to childhood maltreatment in a sample of patients with BD type 1 and suggested that emotional abuse decreased the expression of NR3C1 and DGKH. Our results require further replication in independent larger samples., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Maternal early life maltreatment (ELM) and history of depression can bear a risk for adverse development in the child. One neurobiological pathway for the transmission of both maternal ELM and remitted depression (MDD) might be altered maternal cortisol levels. In the present study, we examine (1) main and interacting effects of maternal ELM and remitted MDD on hair cortisol concentration (HCC) in mothers, whether (2) maternal HCC explains the association between maternal ELM or remitted MDD and maternal child abuse potential, and (3) whether maternal child abuse potential as well as maternal HCC are associated with maternal report of child well-being., Methods: The current study involved 127 mother-child dyads. Maternal history of ELM and psychopathology were assessed via the Mini International Neuropsychiatric Interview (M.I.N.I.) and Childhood Experience and Care (CECA) interview. The Child Abuse Potential Inventory (CAPI) was used to assess maternal child abuse and neglect potential. We applied the Kidscreen-27 parent report to study child well-being. To assess HCC, hair strands were taken from the mothers. To test the research questions, a two-factorial analysis of covariance, mediation analysis using ordinary least squares regressions with bootstrapping, and Pearson correlations were calculated., Results: Mothers with ELM had significantly increased HCC. There was no effect of remitted MDD on HCC, nor an interaction effect of both factors. HCC was a significant mediator of the association between maternal ELM and maternal child abuse potential. Maternal child abuse potential as well as HCC were significantly associated with reduced child well-being., Discussion: Our data suggest that adverse experiences in childhood are associated with altered HPA-axis functioning reflected in increased levels of HCC. HPA-axis activity is not altered in mothers with remitted MDD. From a clinical point of view, one might speculate that the partially mediating effect of maternal HCC could indicate a starting point in the prevention of the intergenerational cycle of abuse., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Exposure to maltreatment in childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) was associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of CSA-related effects by measuring TL in both CSA-exposed and non-exposed mothers and their children., Methods: Participants were a subset of females and their children in a prospective-longitudinal cohort study of sexually abused females and a demographically comparable control group from the same Washington, D.C. area. TL was measured using qPCR in both leukocyte and buccal samples from females (N = 108, mean age 36.3 years) and buccal samples from their children (N = 124, mean age 10.5 years). Multilevel models were used to test associations between CSA-exposure and TL measured in leukocytes and buccal tissue in females and to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children., Results: CSA-exposure was not associated with TL in adult females. Maternal TL and biological sex were significant predictors of child TL such that longer maternal TL predicted longer TL in children, and female children had longer TL than male children. However, maternal-CSA exposure did not predict TL in children., Discussion: CSA-exposure was not associated with TL in this cohort of middle-aged females, nor was there evidence for an intergenerational effect of maternal-CSA exposure on child TL. This finding is in line with some previous results on CSA and adult TL. Previous significant results associating child maltreatment with shorter TL may be capturing a population of individuals exposed to either multiple types of maltreatment compared to controls with no childhood adversity, or maltreatment in childhood with concurrent TL measurements., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Much work has documented hypothalamic pituitary adrenal (HPA) axis abnormalities in major depressive disorder (MDD), but inconsistencies leave this system's role in the illness unclear. Comparisons across studies are complicated by variation in co-morbidity (Posttraumatic Stress Disorder-PTSD, anxiety disorders), exposure to trauma, and timing of trauma (child vs. adult). Here, we examined the impact of these factors on HPA axis profiles in depression., Methods: We recruited 5 groups of participants: MDD (n = 14), comorbid MDD + PTSD following adulthood trauma (MDD + PTSD-Adult; n = 12), comorbid MDD + PTSD following childhood trauma (MDD + PTSD-Child; n = 18), comorbid MDD + social anxiety disorder (MDD + SAD; n = 12), and non-depressed control participants who were sex and age matched to patients (combined total n = 36). HPA axis function was assessed using three challenges: stress reactivity via the Trier Social Stress Test (TSST), feedback sensitivity via a dexamethasone suppression test (DST), and central drive via a metyrapone challenge (MET). We compared hormonal responses between patient groups and their respective non-depressed controls., Results: MDD + PTSD-Child showed low cortisol levels at baseline, and reduced adrenocorticotropic hormone (ACTH) levels at baseline and throughout the TSST. MDD-only, MDD + PTSD-Adult, and MDD + SAD did not differ from non-depressed controls in HPA axis responses to the TSST. Controlling for childhood trauma severity, the reduced baseline levels in MDD + PTSD-Child were no longer significant and significantly reduced baseline cortisol levels emerged for MDD + PTSD-Adult. No diagnostic group effects were detected with DST and MET. Childhood maltreatment subtypes were associated with unique HPA axis responses to TSST and MET., Conclusion: Comorbidity and trauma exposure, as well as their timing and type, contribute to inconsistencies in the depression literature and must be included in efforts to clarify the role of the HPA axis in MDD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Adverse childhood experiences (ACE) are associated with greater neuroendocrine responses to social stress in substance users. The neuropeptide oxytocin might attenuate this relationship. Given sex differences in ACE exposure and neuroendocrine stress reactivity, it is unknown whether this association is similar for males and females. Therefore, this secondary analysis evaluated the interactive effect of sex, ACE, and acute oxytocin administration on neuroendocrine stress responses in adult cigarette smokers (N = 144). Participants completed the Adverse Childhood Experiences Questionnaire at screening and were randomized to receive intranasal oxytocin or placebo before undergoing the Trier Social Stress Task (TSST). Cortisol levels were assessed at pre- and post-medication administration and at 20 and 40 min following the TSST. Generalized linear mixed models were developed to predict post-TSST cortisol levels. Predictors included treatment assignment (placebo vs. oxytocin), sex (male vs. female), ACE (0-10 total score), pre-medication cortisol levels, and minutes since medication administration. The hypothesized three-way interaction between sex, oxytocin, and ACE scores was significant. Linear associations between ACE scores and cortisol reactivity indicated higher ACE scores were associated with attenuated cortisol response in females, regardless of treatment condition. For males, higher ACE scores were associated with heightened cortisol response, an effect that was attenuated by oxytocin. Results indicate that the association between ACE and neuroendocrine reactivity to social stress, as well as the attenuating effect of oxytocin, is differentially impacted by sex. Males with greater childhood adversity may be more likely to benefit from oxytocin's anxiolytic properties., (Copyright © 2020. Published by Elsevier Ltd.)

Many women with no history of cognitive difficulties experience executive dysfunction during menopause. Significant adversity during childhood negatively impacts executive function into adulthood and may be an indicator of women at risk of a mid-life cognitive decline. Previous studies have indicated that alterations in functional network connectivity underlie these negative effects of childhood adversity. There is growing evidence that functional brain networks are not static during executive tasks; instead, such networks reconfigure over time. Optimal dynamics are necessary for efficient executive function; while too little reconfiguration is insufficient for peak performance, too much reconfiguration (supra-optimal reconfiguration) is also maladaptive and associated with poorer performance. Here we examined the impact of adverse childhood experiences (ACEs) on network flexibility, a measure of dynamic reconfiguration, during a letter n-back task within three networks that support executive function: frontoparietal, salience, and default mode networks. Several animal and human subject studies have suggested that childhood adversity exerts lasting effects on executive function via serotonergic mechanisms. Tryptophan depletion (TD) was used to examine whether serotonin function drives ACE effects on network flexibility. We hypothesized that ACE would be associated with higher flexibility (supra-optimal flexibility) and that TD would further increase this measure. Forty women underwent functional imaging at two time points in this double-blind, placebo controlled, crossover study. Participants also completed the Penn Conditional Exclusion Test, a task assessing abstraction and mental flexibility. The effects of ACE and TD were evaluated using generalized estimating equations. ACE was associated with higher flexibility across networks (frontoparietal β = 0.00748, D = 2.79, p = 0.005; salience β = 0.00679, D = 3.02, p = 0.003; and default mode β = 0.00910, D = 3.53, p = 0.0004). While there was no interaction between ACE and TD, active TD increased network flexibility in both ACE groups in comparison to sham depletion (frontoparietal β = 0.00489, D = 2.15, p = 0.03; salience β = 0.00393, D = 1.91, p = 0.06; default mode β = 0.00334, D = 1.73, p = 0.08). These results suggest that childhood adversity has lasting impacts on dynamic reconfiguration of functional brain networks supporting executive function and that decreasing serotonin levels may exacerbate these effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Studies on gene x environment interaction (GxE) have provided vital information for uncovering the origins of complex diseases. When considering the etiology of bipolar disorder (BD), the role of such interactions is unknown. Here, we tested whether trauma during childhood could modify the effect of two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) in terms of susceptibility to BD. The study enrolled 878 Caucasian young adults in a cross-sectional population-based survey. BD diagnosis was performed using a clinical interview MINI 5.0, and trauma was assessed with the childhood trauma questionnaire (CTQ). Binary logistic regression models were employed to test the main effects of polymorphisms, haplotypes, and GxE interactions using sex as a confounder. We did not observe an association between the polymorphisms and diagnosis of BD. However, we noted that childhood trauma modified the effect of the rs4765913 polymorphism (p = .018) and the AA haplotype (rs1006737 - rs4765913) (p = .018) on BD susceptibility. A allele carriers of the rs4765913 polymorphism or the AA haplotype exposed to childhood trauma are more likely to develop BD compared to the individuals without a genetic risk. Thus, this study showed that the risk of developing BD in individuals exposed to childhood trauma was influenced by the individual's genetic background, varying according to the CACNA1C genotypes., Competing Interests: Declaration of Competing Interest All authors disclose no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Early life trauma is strongly associated with an increased vulnerability to abuse illicit drugs and the impairment of neural development. This includes alterations to the development of the oxytocin system, which plays a pivotal role in the regulation of social behaviours and emotion. Dysregulation of this important system also contributes to increased susceptibility to develop drug addiction. In this review, we provide an overview of the animal models of early life stress that are widely used, and discuss the impact that early life stress has on drug-taking behaviour in adolescence and adulthood in both sexes. We link this to the changes that early life stress has on the endogenous oxytocin system, and how exogenously administered oxytocin may help to re-establish functioning of the system, and in turn, reduce drug-taking behaviour., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Exposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous physical and mental health problems. In recent years, measures of DNA methylation-based epigenetic age--known as "epigenetic clocks"--have been used to estimate accelerated epigenetic aging. Although a small number of studies have found an effect of adversity exposure on epigenetic age in children, none have investigated if there are "sensitive periods" when adversity is most impactful., Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 973), we tested the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7.5 using the Horvath and Hannum epigenetic clocks. With a Least Angle Regression variable selection procedure, we evaluated potential sensitive period effects., Results: We found that exposure to abuse, financial hardship, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of Hannum-based epigenetic age from chronological age, even after considering the role of adversity accumulation and recency. Secondary sex-stratified analyses identified particularly strong sensitive period effects. These effects were undetected in analyses comparing children "exposed" versus "unexposed" to adversity. We did not identify any associations between adversity and epigenetic age using the Horvath epigenetic clock., Conclusions: Our results suggest that adversity may alter methylation processes in ways that either directly or indirectly perturb normal cellular aging and that these effects may be heightened during specific life stages., Competing Interests: Declarations of Competing Interest None., (Copyright © 2019. Published by Elsevier Ltd.)

Major depressive disorder (MDD) has been associated with changes in the biological stress systems, including the locus coeruleus-noradrenergic system. Accumulated evidence suggests an upregulation of central alpha2-receptors, leading to decreased noradrenergic activity on a central level in MDD patients. Adverse childhood experiences (ACE) such as physical or sexual abuse might contribute to those changes. Furthermore, noradrenaline can affect cognitive processes, e.g. learning and memory. Cognitive dysfunctions constitute an important symptom of MDD. We aimed to investigate the relationship of alpha2-receptor dysregulation with learning processes in MDD by conducting a differential fear conditioning paradigm after double-blind administration of the alpha2-receptor antagonist yohimbine versus placebo. To investigate the role of ACE systematically, we included four groups of healthy participants and MDD patients with and without ACE (MDD-/ACE-: N = 44, MDD-/ACE+: N = 26, MDD+/ACE-: N = 24, MDD+/ACE+: N = 24; without antidepressant medication). We found increased noradrenergic activity after yohimbine administration across groups as measured by alpha-amylase and blood pressure. Overall, fear responses were higher after yohimbine as indicated by skin conductance responses and fear-potentiated startle responses. While we found no significant MDD effect, ACE had significant impact on the ability to discriminate between both conditioned stimuli (CS+ predicting an aversive stimulus, CS- predicting none), depending on drug condition. After yohimbine, CS discrimination decreased in individuals without ACE, but not in individuals with ACE. Differences in the response to yohimbine might be explained by aberrant alpha2-receptor regulation in individuals with ACE. Impaired discrimination of threat and safety signals might contribute to enhanced vulnerability following ACE., (Copyright © 2019. Published by Elsevier Inc.)