The European psychiatric association (EPA) - early career psychiatrists committee survey on trainees' and early-career psychiatrists' attitudes towards therapeutic drug monitoring (TDM) use and utility during antipsychotic treatment.

OBJECTIVES: This survey assessed psychiatry residents'/early-career psychiatrists' attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics. METHODS: 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. RESULTS: 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). DISCUSSION: TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability.

A novel blood-based epigenetic biosignature in first-episode schizophrenia patients through automated machine learning.

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.

[Comparative study of stress and psychological well-being in parents of children with and without special education needs during the COVID-19 pandemic].

The COVID-19 pandemic, which rapidly spread worldwide in early 2020, has affected the daily lives of parents and their children in various ways. This study assessed the overall mental health status and stress experienced by parents during the COVID-19 pandemic and the differences between parents of children with special educational needs and parents of typically developing children. Additionally, we explored potential demographic factors that may influence these experiences. In this cross-sectional study, data were collected through questionnaires completed by a sample of 205 parents (103 of children with typical development attending regular mainstream schools and 102 of children with special educational needs attending special education schools) from February to April 2021. Participants completed the Perceived Stress Scale (PSS-10), the short form of the Profile of Mood States (POMS-S), and a demographic questionnaire. Our findings confirmed that parents of children attending special education schools reported higher levels of anxiety, reduced coping abilities, and poorer overall emotional well-being during the pandemic compared to parents of children attending regular schools. The type of educational setting that children attended was identified through multivariate analyses as the only factor consistently influencing all psychometric outcomes. Factors influencing anxiety levels included gender, older age, and family status, while family status and unemployment negatively impacted coping abilities. Taken together, the pandemic appears to have had a greater impact on the mental health of parents of children with special education needs compared to parents of children attending regular schools, highlighting the need for increased psychosocial support within this population group.

Childhood Trauma Questionnaire (CTQ): Greek translation and psychometric validation in general and clinical population.

Exposure to childhood trauma experiences shows a high prevalence worldwide, with approximately two-thirds of the general population reporting traumatic experiences during childhood. The valid psychometric assessment of childhood trauma experience represents, however, a significant challenge in clinical research and practice. The Childhood Trauma Questionnaire - Short Form (CTQ-SF) embodies the most valid and internationally widely used tool for the retrospective assessment of traumatic experiences during childhood to date. The purpose of this study was the Greek translation of the questionnaire and its validation in both a general and clinical population. Participants completed electronically the Greek translation of the CTQ-SF, the Early Trauma Questionnaire (ETI-SR-SF), the Trauma Symptom Checklist (TSC-40), the Positive and Negative Affect Scale (PANAS- SF), the Well-Being Index (WHO-5) and the Patient Health Questionnaire (PHQ-4) to examine psychometric properties of the questionnaire (e.g., internal consistency, concurrent, convergent and divergent validity), but also to investigate the relationship between childhood trauma exposure and psychological well-being and symptoms of anxiety and depression. The total study sample (TS) consisted of 722 adults (606 women), of which 155 declared the existence of a psychiatric diagnosis (PD) and 567 constituted the general population (GP) sample. The most common trauma types reported were emotional abuse (29.1%), emotional neglect (23.7%), and physical abuse (24.6%). The CTQ-SF questionnaire showed high levels of internal consistency based on the Cronbach α coefficient (TS = 0.92, PD = 0.92, GP = 0.92), high concurrent and convergent validity and satisfactory convergent validity. In addition, self-reported childhood trauma was highly positively correlated to negative affect and anxiety and depression symptoms, as well as negatively to psychological well-being. Our results confirm that the Greek Version of Childhood Trauma Questionnaire (CTQ-SF) is a reliable and valid tool that can be used for the retrospective assessment of traumatic childhood experiences both in the general and in the clinical adult Greek population.

Inflammation in Posttraumatic Stress Disorder: Dysregulation or Recalibration?

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.

[The human circadian system: physiology, pathophysiology and interactions with sleep and stress reactivity].

The dramatic fluctuations in the energy demands of living organisms by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for a biological temporal organization necessary for maintenance of homeostasis and adaptation to environmental changes across phylogeny. The intrinsic circadian system (CS) represents a highly conserved and complex internal biological "clock", adjusted to the 24-hour rotation of the earth about itself. This system creates and maintains cellular and organismal rhythmicity and enables a nyctohemeral coordination of multi-level physiologic processes, ranging from gene expression to behaviour. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker of the circadian system of the organism, while a ubiquitous peripheral oscillating network of cellular molecular clocks participates in a complex circadian hierarchy. A critical loss of this harmoniously timed circadian order at different organizational levels is defined as "chronodisruption", a condition that may alter the fundamental properties of basic homeostatic systems at molecular, cellular and organismal levels, and lead to a breakdown of biobehavioral adaptive mechanisms, resulting in maladaptive stress regulation and increased sensitivity and vulnerability to stress. Chronodisruption has been linked to neuroendocrine, immune, cardiometabolic and autonomic dysregulation, with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as with altered circadian gene expression. This condition may, thus, play a central role in the development of mental and somatic disease. Nevertheless, circadian and sleep disturbances are often clinically considered as "secondary" manifestations in most disorders, neglecting the potentially important pathophysiological role of CS. Understanding the pathophysiologic mechanisms of circadian dysregulation and their role in stress-related, systemic disease could provide new insights into disease mechanisms and could help advance chronobiological treatment possibilities and preventive strategies in populations at risk.

Heart Rate Variability as a Translational Dynamic Biomarker of Altered Autonomic Function in Health and Psychiatric Disease.

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.

Morning salivary dehydroepiandrosterone (DHEA) qualifies as the only neuroendocrine biomarker separating depressed patients with and without prior history of depression: An HPA axis challenge study.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depression (MDD) have been consistently reported in psychiatry and extend to several neurosteroids. However, recurrence and chronicity may heavily influence HPA axis dynamics in MDD along its course and also explain conflicting results in literature. Thus, the mechanistic understanding of HPA axis (re)activity changes over time could be of major importance for unravelling the dynamic pathophysiology of MDD. METHODS: This study simultaneously assessed several baseline and dynamic HPA-axis-related endocrine biomarkers in both saliva (dehydroepiandrosterone, DHEA; sulfated DHEA, DHEA-s; cortisol, CORT) and plasma (CORT; adrenocorticotropic hormone, ACTH; copeptin, CoP) over three consecutive days using overnight HPA axis stimulation (metyrapone) and suppression (dexamethasone) challenges in order to investigate differences between antidepressant-free MDD patients (n = 14) with and without history of prior depressive episodes (i.e., first vs. recurrent episode). RESULTS: Our results suggest group differences only with respect to saliva DHEA levels, with recurrent-episode MDD patients showing overall lower saliva DHEA levels across the three days, and statistically significant differences mainly at day 1 (baseline) across all three timepoints (awakening, +30 min, +60 min), even after adjustment for confounders. CONCLUSIONS: Our study supports that salivary DHEA levels could represent a significant biomarker of MDD progression and individual stress resilience. DHEA deserves additional attention in the research of pathophysiology, staging and individualized treatment of MDD. Prospective longitudinal studies are needed to evaluate HPA axis reactivity along MDD course and progression to better understand temporal effects on stress-system-related alterations, related phenotypes and appropriate treatment.

Immune Cell Ratios Are Higher in Bipolar Affective than Unipolar Depressive Disorder and Modulated by Mood Episode: A Retrospective, Cross-Sectional Study.

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.

[Neurobiology of early life traumatic stress and trauma: Prolonged neuroendocrine dysregulation as a neurodevelopmental risk factor].

Early life stressors display a high universal prevalence and constitute a major public health problem with two thirds of youth being exposed to potentially traumatic experiences by the age of 17. Traumatic stress exposure during critical periods of development may have essential and long-lasting effects on the physical and mental health of individuals and represents a developmental risk factor mediating risk for disease. Early-life stress (ELS) and childhood trauma (CT) can both have an impact on sensitive neuronal brain networks involved in stress reactions, and could exert a programming effect on glucocorticoid signaling leading to chronic hyper- or hypo-activation of the stress system. 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/CT. 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 most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS/CT even decades later. Future studies should prospectively investigate potential confounders, their temporal sequence and combined effects at the biological level, while considering the potentially delayed time-frame for the expression of their effects. Finally, screening strategies for ELS/CT and trauma need to be improved. Information about ELS/CT history and the number of adverse experiences could help to better identify the individual risk for disease development, predict individual treatment response and design prevention strategies to reduce the negative effects of ELS/CT.

Validation of the Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) questionnaire for adults.

BACKGROUND: The 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". METHODS: The 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. RESULTS: From >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. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health.

Prognostic Significance of Blood-Based Baseline Biomarkers in Treatment-Resistant Depression: A Literature Review of Available Studies on Treatment Response.

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.

A large-scale meta-analytic atlas of mental health problems prevalence during the COVID-19 early pandemic.

The COVID-19 pandemic and related restrictions can impact mental health. To quantify the mental health burden of COVID-19 pandemic, we conducted a systematic review and meta-analysis, searching World Health Organization COVID-19/PsycInfo/PubMed databases (09/29/2020), including observational studies reporting on mental health outcomes in any population affected by COVID-19. Primary outcomes were the prevalence of anxiety, depression, stress, sleep problems, posttraumatic symptoms. Sensitivity analyses were conducted on severe mental health problems, in high-quality studies, and in representative samples. Subgroup analyses were conducted stratified by age, sex, country income level, and COVID-19 infection status. One-hundred-seventy-three studies from February to July 2020 were included (n = 502,261, median sample = 948, age = 34.4 years, females = 63%). Ninety-one percent were cross-sectional studies, and 18.5%/57.2% were of high/moderate quality. The highest prevalence emerged for posttraumatic symptoms in COVID-19 infected people (94%), followed by behavioral problems in those with prior mental disorders (77%), fear in healthcare workers (71%), anxiety in caregivers/family members of people with COVID-19 (42%), general health/social contact/passive coping style in the general population (38%), depression in those with prior somatic disorders (37%), and fear in other-than-healthcare workers (29%). Females and people with COVID-19 infection had higher rates of almost all outcomes; college students/young adults of anxiety, depression, sleep problems, suicidal ideation; adults of fear and posttraumatic symptoms. Anxiety, depression, and posttraumatic symptoms were more prevalent in low-/middle-income countries, sleep problems in high-income countries. The COVID-19 pandemic adversely impacts mental health in a unique manner across population subgroups. Our results inform tailored preventive strategies and interventions to mitigate current, future, and transgenerational adverse mental health of the COVID-19 pandemic.

Immune signature of multiple sclerosis-associated depression.

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.

Physical and mental health impact of COVID-19 on children, adolescents, and their families: The Collaborative Outcomes study on Health and Functioning during Infection Times - Children and Adolescents (COH-FIT-C&A).

BACKGROUND: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial. METHODS: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life. RESULTS: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries. LIMITATIONS: Cross-sectional and anonymous design. CONCLUSIONS: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth.

The neuroendocrinology of stress: the stress-related continuum of chronic disease development.

Stress is defined as a state of threatened homeodynamic balance by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli, defined as stressors. To preserve this optimal homeodynamic state within a physiologic range, organisms have developed a highly sophisticated system, the stress system, which serves self-regulation and adaptability of the organism by energy redirection according to the current needs. Repeated, ephemeral, and motivating stress states lead to adaptive responses and response habituations, being fairly beneficial; in contrast, inadequate, aversive, excessive, or prolonged stress may surpass the regulatory capacity and adjustive resources of the organism and produce maladaptive responses and a chronically altered homeodynamic state associated with compromised mental and physical health and life expectancy. Neuroendocrine responses to stress depend on developmental timing, duration, time of day and nature of stressors leading to a vulnerable phenotype with disrupted stress reactivity (i.e., hyper- or hypoactivation of the stress system), impaired glucocorticoid signaling, and accumulated cacostatic load with cumulatively elevated long-term risk of mental and physical morbidity. This article offers a brief overview on the organization and physiology of the human stress system and its (re)activity, refreshes the plethora of somatic effects of acute and chronic stress and discusses a conceptual model of acute and chronic stress pathophysiology as a continuum in chronic disease development.