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Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.

Abstract Schizophrenia (SCZ) is a chronic, severe, and complex psychiatric disorder that affects all aspects of personal functioning. While SCZ has a very strong biological component, there are still no objective diagnostic tests. Lately, special attention has been given to epigenetic biomarkers in SCZ. In this study, we introduce a three-step, automated machine learning (AutoML)-based, data-driven, biomarker discovery pipeline approach, using genome-wide DNA methylation datasets and laboratory validation, to deliver a highly performing, blood-based epigenetic biosignature of diagnostic clinical value in SCZ. Publicly available blood methylomes from SCZ patients and healthy individuals were analyzed via AutoML, to identify SCZ-specific biomarkers. The methylation of the identified genes was then analyzed by targeted qMSP assays in blood gDNA of 30 first-episode drug-naïve SCZ patients and 30 healthy controls (CTRL). Finally, AutoML was used to produce an optimized disease-specific biosignature based on patient methylation data combined with demographics. AutoML identified a SCZ-specific set of novel gene methylation biomarkers including IGF2BP1, CENPI, and PSME4. Functional analysis investigated correlations with SCZ pathology. Methylation levels of IGF2BP1 and PSME4, but not CENPI were found to differ, IGF2BP1 being higher and PSME4 lower in the SCZ group as compared to the CTRL group. Additional AutoML classification analysis of our experimental patient data led to a five-feature biosignature including all three genes, as well as age and sex, that discriminated SCZ patients from healthy individuals [AUC 0.755 (0.636, 0.862) and average precision 0.758 (0.690, 0.825)]. In conclusion, this three-step pipeline enabled the discovery of three novel genes and an epigenetic biosignature bearing potential value as promising SCZ blood-based diagnostics.

BackgroundThe Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score".MethodsThe COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed.ResultsFrom >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex.ConclusionsCOH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health.

The autonomic nervous system (ANS) is responsible for the precise regulation of tissue functions and organs and, thus, is crucial for optimal stress reactivity, adaptive responses and health in basic and challenged states (survival). The fine-tuning of central ANS activity relies on the internal central autonomic regulation system of the central autonomic network (CAN), while the peripheral activity relies mainly on the two main and interdependent peripheral ANS tracts, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). In disease, autonomic imbalance is associated with decreased dynamic adaptability and increased morbidity and mortality. Acute or prolonged autonomic dysregulation, as observed in stress-related disorders, affects CAN core centers, thereby altering downstream peripheral ANS function. One of the best established and most widely used non-invasive methods for the quantitative assessment of ANS activity is the computerized analysis of heart rate variability (HRV). HRV, which is determined by different methods from those used to determine the fluctuation of instantaneous heart rate (HR), has been used in many studies as a powerful index of autonomic (re)activity and an indicator of cardiac risk and ageing. Psychiatric patients regularly show altered autonomic function with increased HR, reduced HRV and blunted diurnal/circadian changes compared to the healthy state. The aim of this article is to provide basic knowledge on ANS function and (re)activity assessment and, thus, to support a much broader use of HRV as a valid, transdiagnostic and fully translational dynamic biomarker of stress system sensitivity and vulnerability to stress-related disorders in neuroscience research and clinical psychiatric practice. In particular, we review the functional levels of central and peripheral ANS control, the main neurobiophysiologic theoretical models (e.g., polyvagal theory, neurovisceral integration model), the precise autonomic influence on cardiac function and the definition and main aspects of HRV and its different measures (i.e., time, frequency and nonlinear domains). We also provide recommendations for the proper use of electrocardiogram recordings for HRV assessment in clinical and research settings and highlight pathophysiological, clinical and research implications for a better functional understanding of the neural and molecular mechanisms underlying healthy and malfunctioning brain–heart interactions in individual stress reactivity and psychiatric disorders.

Immune dysregulation is implicated in the pathophysiology of both bipolar and major depressive disorder, while immune cell ratios (IRCs) have recently been proposed as clinically applicable immune biomarkers. We investigated IRCs differences in affective disorders and their association with current mood episodes and clinical features. This retrospective cohort study analyzed neutrophil–lymphocyte (NLR), monocyte–lymphocyte (MLR), and platelet–lymphocyte (PLR) ratios upon admission in 135 affective disorder in-patients with mania (MA, n = 36), bipolar depression (BiD, n = 38), and unipolar depression (MDD, n = 61). Demographic, clinical, and immune data were extracted from medical records. Monocyte count was significantly higher in BiD compared to MDD (p < 0.001). Multivariable regression models suggested higher NLR in MA compared to MDD (p = 0.039), higher MLR in both MA and BiD compared to MDD (p < 0.001 and p = 0.004 respectively), while we found neither group differences in PLR nor an effect of type and duration of hospitalization, current psychotic, or suicidal features and psychiatric history on IRCs. Here, we show that IRCs are elevated in bipolar disorder versus MDD and affected by mood episode, while MLR could be especially valuable in the differential diagnosis between bipolar and unipolar depression. IRCs represent inexpensive, routinely accessible and clinically applicable biomarkers with diagnostic validity in affective disorders that could be easily implemented as illness activity indicators, to better follow the course of illness and eventually predict relapse or treatment response and, thus, guide therapeutic targeting.

This survey assessed psychiatry residents'/early-career psychiatrists' attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics. A previously developed questionnaire on attitudes on TDM utility during antipsychotic treatment was cross-sectionally disseminated by national coordinators between 01/01/2022–31/12/2023. The frequency of using TDM for antipsychotics other than clozapine was the main outcome in a linear regression analysis, including sex, clinical setting, caseload, and factors generated by an exploratory factor analysis. Comparisons between residents and early-career psychiatrists, respondents working in in- and outpatient settings, and low-/middle- and high–income countries were performed. Altogether, 1,237 respondents completed the survey, with 37.9% having never used TDM for antipsychotics. Seven factors explained 41% of response variance; six of them were associated with frequency of TDM use (p < 0.05). Items with highest loadings for factors included clinical benefits of TDM (factors A and E: 0.7), negative expectations for beliefs of patients towards TDM (factor B: 0.6–0.7), weak TDM scientific evidence (factor C: 0.8), and TDM availability (factor D: −0.8). Respondents from low-/middle-income countries were less likely to frequently/almost always use TDM compared to high-income countries (9.4% vs. 21.5%, p < 0.001). TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability. [ABSTRACT FROM AUTHOR]

The mission of the human stress system is the maintenance of homeostasis in the presence of real or perceived, acute or chronic stressors. The hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS) are the stress system-related neuroendocrine pathways. There is abundant evidence that children and adolescents with autism spectrum disorder (ASD) may exhibit atypical function within the HPA axis and the ANS both at the resting state and during the presence of social and/or non-social stressors. The aim of this review is to provide an up-to-date summary of the findings regarding stress system alterations in children and adolescents with ASD. We focus on the variations of stress hormones circadian rhythms, specifically cortisol and alpha-amylase (i.e., a surrogate index of epinephrine/norepinephrine secretion), and on the alterations of stress system responsivity to different stressors. Also, we present imaging and immunological findings that have been associated with stress system dysregulation in children and adolescents with ASD. Finally, we review the pivotal role of HPA axis-ANS coordination, the developmental trajectory of the stress system in ASD, and the possible role of early life stress in the dysregulation of the stress system demonstrated in children and adolescents with ASD. This synthesis will hopefully provide researchers with a foundation for an integrated approach to future research into stress system variations in children and adolescents with ASD.

Purpose of reviewThe human circadian system creates and maintains cellular and systemic rhythmicity essential to homeostasis. Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune and autonomic system, similar to chronic stress and, thus, may play a central role in the development of stress-related disorders. This article focuses on the role of circadian misalignment in the pathophysiology of posttraumatic stress disorder (PTSD).Recent findingsSleep disruption is a core feature of PTSD supporting the important supraordinate pathophysiological role of circadian system in PTSD. Furthermore, direct and indirect human and animal PTSD research suggests circadian system linked neuroendocrine, immune, metabolic and autonomic dysregulation with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as endocannabinoid and neuropeptide Y system alterations and altered circadian gene expression, linking circadian misalignment to PTSD pathophysiology.SummaryPTSD development is associated with chronodisruption findings. Evaluation and treatment of sleep and circadian disruption should be the first steps in PTSD management. State-of-the-art methods of circadian rhythm assessment should be applied to bridge the gap between clinical significance and limited understanding of the relationship between traumatic stress, sleep and circadian system.

ImportancePosttraumatic stress disorder (PTSD) has been associated in cross-sectional studies with peripheral inflammation. It is not known whether this observed association is the result of PTSD predisposing to inflammation (as sometimes postulated) or to inflammation predisposing to PTSD.ObjectiveTo determine whether plasma concentration of the inflammatory marker C-reactive protein (CRP) helps predict PTSD symptoms.Design, setting, and participantsThe Marine Resiliency Study, a prospective study of approximately 2600 war zone-deployed Marines, evaluated PTSD symptoms and various physiological and psychological parameters before deployment and at approximately 3 and 6 months following a 7-month deployment. Participants were recruited from 4 all-male infantry battalions imminently deploying to a war zone. Participation was requested of 2978 individuals; 2610 people (87.6%) consented and 2555 (85.8%) were included in the present analysis. Postdeployment data on combat-related trauma were included for 2208 participants (86.4% of the 2555 included) and on PTSD symptoms at 3 and 6 months after deployment for 1861 (72.8%) and 1617 (63.3%) participants, respectively.Main outcomes and measuresSeverity of PTSD symptoms 3 months after deployment assessed by the Clinician-Administered PTSD Scale (CAPS).ResultsWe determined the effects of baseline plasma CRP concentration on postdeployment CAPS using zero-inflated negative binomial regression (ZINBR), a procedure designed for distributions, such as CAPS in this study, that have an excess of zeroes in addition to being positively skewed. Adjusting for the baseline CAPS score, trauma exposure, and other relevant covariates, we found baseline plasma CRP concentration to be a highly significant overall predictor of postdeployment CAPS scores (P = .002): each 10-fold increment in CRP concentration was associated with an odds ratio of nonzero outcome (presence vs absence of any PTSD symptoms) of 1.51 (95% CI, 1.15-1.97; P = .003) and a fold increase in outcome with a nonzero value (extent of symptoms when present) of 1.06 (95% CI, 0.99-1.14; P = .09).ConclusionsAND RELEVANCE A marker of peripheral inflammation, plasma CRP may be prospectively associated with PTSD symptom emergence, suggesting that inflammation may predispose to PTSD.

Major depressive disorder is a leading cause of disability worldwide and a major contributor to the overall global burden of disease. While there are several options for antidepressant treatment, only about 40–60% of patients respond to initial monotherapy, while 30–40% of patients may even show resistance to treatment. This article offers a narrative review of those studies evaluating the predictive properties of various blood-based baseline biomarkers regarding treatment responses to the pharmacological, stimulation, or behavioral treatment of patients with treatment-resistant depression (TRD). Our results show that overall, there is only a very limited number of studies assessing baseline peripheral biomarkers regarding treatment response in TRD. Although there is some evidence for the predictive significance of particular biomarkers (e.g., IL-6, CRP, BDNF), the majority of the results are either single-study reports or studies with conflicting results. This may contribute to the wide variety of treatment protocols and different TRD definition criteria, the small number of patients included, and the existence of different biological phenotypes of the disorder used within the various studies. Taken together, there does not yet appear to be any specific baseline peripheral biomarker with sufficient discriminative predictive validity that can be used in the routine clinical practice of TRD. The discovery of new biomarkers and the better clinical characterization of known biomarkers could support the better classification and staging of TRD, the development of personalized treatment algorithms with higher rates of remission and fewer side effects, and the development of new precision drugs for specific subgroups of patients.

The human circadian system creates and maintains cellular and systemic rhythmicity essential for the temporal organization of physiological processes promoting homeostasis and environmental adaptation. Sleep disruption and loss of circadian rhythmicity fundamentally affects master homeostasic regulating systems at the crossroads of peripheral and central susceptibility pathways, similar to acute or chronic stress and, thus, may play a central role in the development of stress-related disorders. Direct and indirect human and animal PTSD research accordingly suggests circadian-system-linked sleep, neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Additionally, there is evidence that sleep and circadian disruption may represent a vital pre-existing risk factor in the prediction of PTSD development, while sleep-related symptoms are among the most prominent in trauma-associated disorders. These facts may represent a need for a shift towards a more chronobiological understanding of traumatic sequel and could support better prevention, evaluation and treatment of sleep and circadian disruption as first steps in PTSD management. In this special issue, we highlight and review recent advances from human sleep and chronobiological research that enhances our understanding of the development and maintenance of trauma-related disorders.

Background: Humans have an evolutionary need for a well-preserved internal ‘clock’, adjusted to the 24-hour rotation period of our planet. This intrinsic circadian timing system enables the temporal organization of numerous physiologic processes, from gene expression to behaviour. The human circadian system is tightly and bidirectionally interconnected to the human stress system, as both systems regulate each other’s activity along the anticipated diurnal challenges. The understanding of the temporal relationship between stressors and stress responses is critical in the molecular pathophysiology of stress-and trauma-related diseases, such as posttraumatic stress disorder (PTSD). Objectives/Methods: In this narrative review, we present the functional components of the stress and circadian system and their multilevel interactions and discuss how traumatic stress can affect the harmonious interplay between the two systems. Results: Circadian dysregulation after trauma exposure (posttraumatic chronodisruption) may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of traumatic stress through a loss of the temporal order at different organizational levels. Posttraumatic chronodisruption may, thus, affect fundamental properties of neuroendocrine, immune and autonomic systems, leading to a breakdown of biobehavioral adaptive mechanisms with increased stress sensitivity and vulnerability. Given that many traumatic events occur in the late evening or night hours, we also describe how the time of day of trauma exposure can differentially affect the stress system and, finally, discuss potential chronotherapeutic interventions. Conclusion: Understanding the stress-related mechanisms susceptible to chronodisruption and their role in PTSD could deliver new insights into stress pathophysiology, provide better psychochronobiological treatment alternatives and enhance preventive strategies in stress-exposed populations.

Abstract Background Posttraumatic stress disorder (PTSD) is one of the most commonly observed stress-related conditions following combat exposure and its effective prevention is a high health-care priority. Reports of peritraumatic reactions have been shown to be highly associated with PTSD among combat exposed service members. However, existing instruments measuring peritraumatic symptoms were not specifically developed to assess combat-related peritraumatic stress and each demonstrates a different peritraumatic focus. We therefore developed the Peritraumatic Behavior Questionnaire (PBQ), a new military-specific rating scale focused upon the wide range of symptoms suggestive of combat-related peritraumatic distress in actively deployed Service Members. This study describes the development of the PBQ and reports on the psychometric properties of its self-rated version (PBQ-SR). Methods 688 Marine infantry service members were retrospectively assessed by the PBQ-SR within the scope of the Marine Resiliency Study after their deployment to war zone. Participants have been additionally assessed by a variety of questionnaires, as well as clinical interviews both pre and post-deployment. Results The PBQ-SR demonstrated satisfactory internal consistency, convergent and discriminant validity, as well as high correlation with trait dissociation prior to deployment. Component analysis suggested a latent bi-dimensional structure separating a peritraumatic emotional distress and physical awareness factor. The PBQ-SR total score showed high correlation to general anxiety, depression, poorer general health and posttraumatic symptoms after deployment and remained a significant predictor of PTSD severity, after controlling for those measures. The suggested screening cut-off score of 12 points demonstrated satisfactory predictive power. Conclusions This study confirms the ability of the PBQ-SR to unify the underlying peritraumatic symptom dimensions and reliably assess combat-related peritraumatic reaction as a general construct. The PBQ-SR demonstrated promise as a potential standard screening measure in military clinical practice, while It’s predictive power should be established in prospective studies.

BackgroundMajor depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40–60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice.ObjectiveThis study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD.MethodsWe measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment.ResultsOur findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future non-response screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response.ConclusionsThis pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a single-measurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies.

The dramatic fluctuations in energy demands by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for biological temporal organization across phylogeny. The intrinsic circadian timing system (CS) represents a highly conserved and sophisticated internal “clock,” adjusted to the 24-h rotation period of the earth, enabling a nyctohemeral coordination of numerous physiologic processes, from gene expression to behavior. The human CS is tightly and bidirectionally interconnected to the stress system (SS). Both systems are fundamental for survival and regulate each other’s activity in order to prepare the organism for the anticipated cyclic challenges. Thereby, the understanding of the temporal relationship between stressors and stress responses is critical for the comprehension of the molecular basis of physiology and pathogenesis of disease. A critical loss of the harmonious timed order at different organizational levels may affect the fundamental properties of neuroendocrine, immune, and autonomic systems, leading to a breakdown of biobehavioral adaptative mechanisms with increased stress sensitivity and vulnerability. In this review, following an overview of the functional components of the SS and CS, we present their multilevel interactions and discuss how traumatic stress can alter the interplay between the two systems. Circadian dysregulation after traumatic stress exposure may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of trauma through maladaptive stress regulation. Understanding the mechanisms susceptible to circadian dysregulation and their role in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and preventive strategies in stress-exposed populations.

Traumatic stress may chronically affect master homeostatic systems at the crossroads of peripheral and central susceptibility pathways and lead to the biological embedment of trauma-related allostatic trajectories through neurobiological alterations even decades later. Lately, there has been an exponential knowledge growth concerning the effect of traumatic stress on oxidative components and redox-state homeostasis. This extensive review encompasses a detailed description of the oxidative cascade components along with their physiological and pathophysiological functions and a systematic presentation of both preclinical and clinical, genetic and epigenetic human findings on trauma-related oxidative stress (OXS), followed by a substantial synthesis of the involved oxidative cascades into specific and functional, trauma-related pathways. The bulk of the evidence suggests an imbalance of pro-/anti-oxidative mechanisms under conditions of traumatic stress, respectively leading to a systemic oxidative dysregulation accompanied by toxic oxidation byproducts. Yet, there is substantial heterogeneity in findings probably relative to confounding, trauma-related parameters, as well as to the equivocal directionality of not only the involved oxidative mechanisms but other homeostatic ones. Accordingly, we also discuss the trauma-related OXS findings within the broader spectrum of systemic interactions with other major influencing systems, such as inflammation, the hypothalamic-pituitary-adrenal axis, and the circadian system. We intend to demonstrate the inherent complexity of all the systems involved, but also put forth associated caveats in the implementation and interpretation of OXS findings in trauma-related research and promote their comprehension within a broader context.

Early life stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the stress system and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system and inflammation, oxidative stress, cardiovascular system, gut microbiome, sleep and circadian system, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment.

Although acupuncture treatment is increasingly in demand among psychiatric patients, to date no studies have investigated the effectiveness of auricular acupuncture (AA) in treating anxiety disorders or major depressive disorder. Thus, this study aimed to compare the effectiveness of AA versus progressive muscle relaxation (PMR), a standardized and accepted relaxation method. We examined 162 patients with a primary diagnosis of anxiety disorder or major depressive disorder, and each patient chose between treatment with AA, executed according to the National Acupuncture Detoxification Association protocol, and treatment with PMR. Each group had treatments twice a week for 4 weeks. Before and after treatment, each participant rated four items on a visual analog scale: anxiety, tension, anger/aggression, and mood. Statistical analyses were performed with the original visual analog scale scores and the Change-Intensity Index, an appropriate indicator of the difference between two values of a variable. Our results show that treatment with AA significantly decreased tension, anxiety, and anger/aggression throughout the 4 weeks, but did not elevate mood. Between AA and PMR, no statistically significant differences were found at any time. Thus, we suggest that both AA and PMR may be useful, equally-effective additional interventions in the treatment of the above-mentioned disorders.

Traumatic stress exposure during critical periods of development may have essential and long-lasting effects on the physical and mental health of individuals. Two thirds of youth are exposed to potentially traumatic experiences by the age of 17, and approximately 5% of adolescents meet lifetime criteria for posttraumatic stress disorder (PTSD). The role of the stress system is the maintenance of homeostasis in the presence of real/perceived and acute/chronic stressors. Early-life stress (ELS) has an impact on neuronal brain networks involved in stress reactions, and could exert a programming effect on glucocorticoid signaling. Studies on pediatric PTSD reveal diverse neuroendocrine responses to adverse events and related long-term neuroendocrine and epigenetic alterations. Neuroendocrine, neuroimaging, and genetic studies in children with PTSD and ELS experiences are crucial in understanding risk and resilience factors, and also the natural history of PTSD.

While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case–control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/− cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vβ repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.