Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications.

<b>Objective:</b> To examine the risk of depression and stress related disorders as a function of occupational exposure to violence and threats. <b>Design:</b> Population based nested case-control study. <b>Setting:</b> All gainfully employed Danes. <b>Cases and controls:</b> 14 166 hospital inpatients and outpatients, aged 18–65, treated for affective or stress related disorders during 1995–1998 selected from The Danish Psychiatric Central Research Register and 58 060 controls matched for age, sex, and time, drawn from Statistics Denmark’s Integrated Database for Labour Market Research. <b>Main outcome measure:</b> Clinical psychiatric diagnosis (WHO ICD-10) of affective (F30–39) or stress related (F40–48) disorders compared with controls by the occupation held the year before treatment. The occupation held the year before treatment was used as exposure proxy. <b>Results:</b> Potential exposure to occupational violence is associated with significantly increased relative risks of both disorders in either sex (women: depression RR 1.45 CI 1.27 to 1.65, stress RR 1.32 CI 1.19 to 1.46; men: depression RR 1.48 CI 1.18 to 1.86, stress RR 1.55 CI 1.29 to 1.84). Work related threats are associated with increase in the risk of depression in women (RR 1.48 CI 1.23 to 1.79) and the risk of stress related disorders in men (RR 1.59 CI 1.32 to 1.91). Risks rose with increasing prevalence of violence and threats. The results remain significant and only slightly attenuated after controlling for extent of professional contact with people other than colleagues. <b>Conclusions:</b> Employment in occupations involving exposure to work related threats and violence is a risk factor for depression and stress related disorders in both sexes. These findings have implications for health and safety at work policies.

Objective: To examine the risk of depression and stress related disorders as a function of occupational exposure to violence and threats. Design: Population based nested case-control study. Setting: All gainfully...

Background: Heart Rate Variability Biofeedback (HRVB) is a treatment in which patients learn self-regulation of a physiological dysregulated vagal nerve function. While the therapeutic approach of HRVB is promising for a variety of disorders, it has not yet been regularly offered in a mental health treatment setting. Aim: To provide a systematic review about the efficacy of HRV-Biofeedback in treatment of anxiety, depression, and stress related disorders. Method: Systematic review in PubMed and Web of Science in 2020 with terms HRV, biofeedback, Post-Traumatic Stress Disorder (PTSD), depression, panic disorder, and anxiety disorder. Selection, critical appraisal, and description of the Random Controlled Trials (RCT) studies. Combined with recent meta-analyses. Results: The search resulted in a total of 881 studies. After critical appraisal, nine RCTs have been selected as well as two other relevant studies. The RCTs with control groups treatment as usual, muscle relaxation training and a “placebo“-biofeedback instrument revealed significant clinical efficacy and better results compared with control conditions, mostly significant. In the depression studies average reduction at the Beck Depression Inventory (BDI) scale was 64% (HRVB plus Treatment as Usual (TAU) versus 25% (control group with TAU) and 30% reduction (HRVB) at the PSQ scale versus 7% (control group with TAU). In the PTSD studies average reduction at the BDI-scale was 53% (HRV plus TAU) versus 24% (control group with TAU) and 22% (HRVB) versus 10% (TAU) with the PTSD Checklist (PCL). In other systematic reviews significant effects have been shown for HRV-Biofeedback in treatment of asthma, coronary artery disease, sleeping disorders, postpartum depression and stress and anxiety. Conclusion: This systematic review shows significant improvement of the non-invasive HRVB training in stress related disorders like PTSD, depression, and panic disorder, in particular when combined with cognitive behavioral therapy or different TAU. Effects were visible after four weeks of training, but clinical practice in a longer daily self-treatment of eight weeks is more promising. More research to integrate HRVB in treatment of stress related disorders in psychiatry is warranted, as well as research focused on the neurophysiological mechanisms.

Chen A, ed. Stress Resilience: Molecular and Behavioral Aspects. London, England: Academic Press; 2020.

FKBP5 has been of special scientific interest in the behavioral sciences since it has been involved in the pathophysiology of several mental disorders. It is a gene with pleiotropic effects which encodes the protein FKBP5, a cochaperone that decreases glucocorticoid receptor (GR) affinity for glucocorticoids by competing with FKBP4, altering the GR chaperone complex, and impairing GR activation. As a key modulator of the stress response, FKBP5 plays a critical role in regulating cortisol levels in the organism. The FKBP5 gene is regulated through a combination of transcriptional, epigenetic, post-transcriptional, and environmental mechanisms, as well as genetic polymorphisms that influence its transcription and stress responsiveness. Notably, the rs1360780 T-allele in FKBP5 significantly affects FKBP5 regulation and has been linked to stress-related disorders by influencing transcription and stress responsiveness. In this narrative review, we aim to provide an overview of the role played by the single-nucleotide polymorphism rs1360780 in the FKBP5 locus in gene expression, its epigenetic regulation, and the impact of early stress in its functioning. We discuss some brain regions with differential expression of FKBP5 and some behavioral phenotypes linked to the locus. The T-allele of rs1360780 is considered a risk variant, as it leads to high FKBP5 induction, which delays negative feedback and increases GR resistance. This results in states of relative hypercortisolemia and brain morphofunctional alterations, particularly in regions sensitive to glucocorticoid activity during critical periods of neurodevelopment. Additionally, exposure to childhood maltreatment is associated with demethylation of the glucocorticoid response elements of FKBP5, further increasing its expression levels. Among the psychological dimensions analyzed in which FKBP5 is involved are neurocognition, aggression, suicidality, and social cognition. At the level of mental disorders, the gene may play a role in the pathogenesis of post-traumatic stress disorder, depression, and bipolar disorder. In psychotic disorders, its role is less clear. This knowledge enhances the understanding of disease mechanisms that operate through psychopathological dimensions, and highlights the need to design specific, person-centered psychopharmacological and environmental therapeutic interventions.

BackgroundNoninvasive brain stimulation techniques like transcranial direct current stimulation (tDCS) offer potential new approaches to treat stress-related mental health disorders. While the acceptability of tDCS as a treatment tool plays a crucial role in its development and implementation, little is known about tDCS acceptability for users in mental healthcare, especially in the context of stress-related disorders.MethodsUsing a mixed-methods approach, we investigated tDCS acceptability among 102 active duty and post-active military patients with stress-related symptoms (posttraumatic stress disorder, anxiety and impulsive aggression) who participated in a 5-session tDCS intervention. Quantitative dropout and adverse effects data was collected for all patients involved in the sham-controlled tDCS intervention. We additionally explored perspectives on the acceptability of tDCS treatment via a theory-based semi-structured interview. A subgroup of patients as well as their caregivers were interviewed to include the views of both patients and mental healthcare professionals.ResultsQuantitative outcomes showed minimal tDCS-related adverse effects (mild itching or burning sensations on the scalp) and high tDCS treatment adherence (dropout rate: 4% for active tDCS, 0% for sham). The qualitative outcomes showed predominantly positive attitudes towards tDCS interventions for stress-related disorders, but only as complementary to psychotherapy. Remarkably, despite the perception that sufficient explanation was provided, patients and caregivers stressed that tDCS treatment comprehension was limited and should improve. Also, the travel associated with frequent on-site tDCS sessions may produce a significant barrier to care for patients with stress-related disorders and active-duty military personnel.ConclusionsAcceptability numbers and perspectives from military patients and caregivers suggest that tDCS is an acceptable complementary tool in the treatment of stress-related disorders. Critically, however, if tDCS is to be used beyond scientific studies, adequately educating users on tDCS working mechanisms is vital to further improve its acceptability. Also, the perceived potential barrier to care due to frequent travel may favor home-based tDCS solutions.Trial registrationThe tDCS intervention was part of a sham-controlled trial registered on 05-18-2016 at the Netherlands Trial Register with ID NL5709.

The World Health Organization estimates that almost 300 million people suffer from depression worldwide. Depression is the most common mental health disorder and shows racial disparities in disease prevalence, age of onset, severity of symptoms, frequency of diagnosis, and treatment utilization across the United States. Since depression has both social and genetic risk factors, we propose a conceptual model wherein social stressors are primary risk factors for depression, but genetic variants increase or decrease individual susceptibility to the effects of the social stressors. Our research strategy incorporates both social and genetic data to investigate variation in symptoms of depression (CES-D scores). We collected data on financial strain (difficulty paying bills) and personal social networks (a model of an individual’s social environment), and we genotyped genetic variants in five genes involved in stress reactivity ( HTR1a, BDNF, GNB3, SLC6A4, and FKBP5 ) in 135 African Americans residing in Tallahassee, Florida. We found that high financial strain and a high percentage of people in one’s social network who are a source of stress or worry were significantly associated with higher CES-D scores and explained more variation in CES-D scores than did genetic factors. Only one genetic variant (rs1360780 in FKBP5 ) was significantly associated with CES-D scores and only when the social stressors were included in the model. Interestingly, the effect of FKPB5 appeared to be strongest in individuals with high financial strain such that participants with a T allele at rs1360780 in FKBP5 and high financial strain had the highest mean CES-D scores in our study population. These results suggest that material disadvantage and a stressful social environment increases the risk of depression, but that individual-level genetic variation may increase susceptibility to the adverse health consequences of social stressors.

Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.

Objective: Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). Method: The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Results: Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychitric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Conclusions: Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways. (Reprinted with permission from American Journal of Psychiatry 2003; 160:1554–1565)

Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680-92. ©2017 AACR.

Currently, treatment of stress-related gastrointestinal disorders, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), is mainly symptomatic since there is no drug on the market that solves effectively diverse disease symptoms and comorbid states. Recently GABA receptors have been identified within gastrointestinal system and it has been recognized that among various GABAergic drugs some of them influence gastrointestinal stress-related diseases. Among them benzodiazepines have been investigated due to their diverse effects: neuroimmunomodulatory, relief of visceral pain and anxiolytic action. The present review brings findings on the expression of GABA receptors in the gastrointestinal tract and the role of GABA within it. We also present knowledge on the role of neurotransmitter GABA and various GABAergic ligands on diverse physiologic gastrointestinal functions with special emphasize to stress-related disorders. The rationale for therapeutic use and further identification of a potential GABAergic treatment of stress-related disorders has been critically discussed.

As the incidence of obesity continues to grow, more children are exposed to less than optimal nutritional fetal environments. This has serious implications for the developing brain and the incidence stress-related disorders such as anxiety and depression, in addition to other neurodevelopmental disorders. Adult stress responding is programmed during developmental periods, resulting in individual variability in our responses to situations that threaten homeostasis. Under conditions of poor coping or excess exposure to stress, some individuals will be susceptible to developing stress-related mental health disorders. A poor prenatal metabolic/nutritional environment leads to altered programming of neural circuitry that supports adult stress responding, putting individuals at risk for stress-related disorders. More work is needed to manage obesity rates and to better understand the mechanisms underlying altered neural development as a result of parental diet.

Introduction Over the past few decades, the level of interest in the use of complex molecular pathways in the course of various diseases has increased significantly. Despite the rapid development of medicine, the potential and role of FKBP5 as a biomarker has not yet been fully characterized, although current studies are promising. Material and methods of research: The literature included in the PubMed databases is searched through the words such as FKBP5 gene, stress-related disorders, biomarkers. Aim of the study The aim of this paper is to provide a comprehensive review of the current state of knowledge regarding the characteristics, current use in diagnosis or treatment of various diseases and to determine the possible function of the biomarker for the FKBP5 gene. Description of the state of knowledge FKBP5 participates in the regulation of the HPA axis and thus in the stress response. This translates into the course of many diseases, but the exact mechanism of action has not been unequivocally confirmed in previous studies on all conditions involving FKBP5. Conclusions In general, FKBP5 has a huge diagnostic and therapeutic potential in many disease entities. FKBP5 may act as a biomarker. However, further studies are needed to clarify the current observations and to search for further implications in the pathogenesis or diagnostic and therapeutic procedures in the course of various diseases.

Genetic Factors in the Etiology of Palatally Displaced Canines

Knowledge on the impact of the psychosocial work environment on the occurrence of stress-related disorders (SRDs) can assist occupational physicians in the assessment of the work-relatedness of these disorders. To systematically review the contribution of work-related psychosocial risk factors to SRDs. A systematic review of the literature was carried out by searching Medline, PsycINFO and Embase for studies published up until October 2008. Studies eligible for inclusion were prospective cohort studies or patient-control studies of workers at risk for SRDs. Studies were included in the review when data on the association between exposure to psychosocial work factors and the occurrence of SRDs were presented. Where possible, meta-analysis was conducted to obtain summary odds ratios of the association. The strength of the evidence was assessed using four levels of evidence. From the 2426 studies identified, seven prospective studies were included in this review. Strong evidence was found that high job demands, low job control, low co-worker support, low supervisor support, low procedural justice, low relational justice and a high effort-reward imbalance predicted the incidence of SRDs. This systematic review points to the potential of preventing SRDs by improving the psychosocial work environment. However, more prospective studies are needed on the remaining factors, exposure assessment and the relative contributions of single factors, in order to enable consistent assessment of the work-relatedness of SRDs by occupational physicians.