Early and chronic stress was reported to alter the hypothalamic-pituitary-adrenal axis functioning which regulates the secretion of cortisol. Nevertheless, few studies mainly focused on specific study populations (e.g. adolescents, pregnant women, and psychiatric patients), and researched interactive associations of pituitary volumes and single stress markers. The present study used pituitary volumes of two adult general-population cohorts of the Study of Health in Pomerania (SHIP-START-2: N = 1026, 54% Men, 30-90 years; SHIP-TREND-0: N = 1868, 53% Men, 21-82 years). In linear regression models, main effects of the pituitary volumes as well as interaction effects with childhood abuse and neglect (Childhood Trauma Questionnaire) were estimated using depressive symptoms (Beck Depression Inventory-II), and serum cortisol concentrations as outcome variables. The results of both cohorts were integrated via meta-analyses. No main effect between pituitary volumes and depressive symptoms was observed (START-2: β = -0.004 [-0.082; 0.075], p = .929; TREND-0: β = 0.020 [-0.033; 0.073], p = .466; Meta-analysis: β = 0.012 [-0.031; 0.056], p = .580). However, larger pituitary volumes were associated with more depressive symptoms in participants with more severe childhood neglect (START-2: β = 0.051 [-0.024; 0.126], p = .183; TREND-0: β = 0.083 [0.006; 0.159], p = .034; Meta-analysis: β = 0.066 [0.013; 0.120], p = .015). Further, larger pituitary volumes were associated with lower serum cortisol concentrations in participants with more severe depressive symptoms (START-2: β = -0.087 [-0.145; -0.030], p = .003; TREND-0: β = -0.053 [-0.091; -0.015], p = .006; Meta-analysis: β = -0.063 [-0.095; -0.032], p = 8.39e-05). Summarizing, larger pituitary volumes were associated with more severe psychopathological symptoms, particularly in participants reporting early life stress. This was supported by stronger associations between pituitary volumes and cortisol concentrations in participants with more severe depressive symptoms. Future studies are needed to transfer these results into developmental stages of high hormonal changes and patient samples.

Chronic stress and depression are potential risk factors for mild cognitive impairment and dementia, including Alzheimer disease. The aim was to investigate whether any such risk is additive.
Cohort study including 1 362 548 people (665 997 women, 696 551 men) with records in the Region Stockholm administrative healthcare database (VAL). Exposure was a recorded ICD-10 diagnosis of chronic stress, depression, or both, recorded in 2012 or 2013. Outcome was a diagnosis of Alzheimer disease, other dementia, or mild cognitive impairment recorded from 2014 through 2022. Odds ratios with 99% confidence intervals (CI) adjusted for age, sex, neighborhood socioeconomic status, diabetes, and cardiovascular disorders were calculated.
During the exposure period, 4 346 patients were diagnosed with chronic stress, 40 101 with depression, and 1 898 with both. The average age at baseline was around 40 years in all groups. In the fully adjusted model, the odds ratio of Alzheimer disease was 2.45 (99% CI 1.22-4.91) in patients with chronic stress, 2.32 (99% CI 1.85-2.90) in patients with depression, and 4.00 (99% CI 1.67-9.58) in patients with chronic stress and depression. The odds ratio of mild cognitive impairment was 1.87 (99% CI 1.20-2.91) in patients with chronic stress, 2.85 (99% CI 2.53-3.22) in patients with depression, and 3.87 (99% CI 2.39-6.27) in patients with both. When other dementia was analyzed, the odds ratio was significant only in patients with depression, 2.39 (99% CI 1.92-2.96).
Documented chronic stress increased the risk of mild cognitive impairment and Alzheimer disease. The same was seen with depression. The novel finding is the potential additive effect of chronic stress to depression, on risk of MCI and AD.

In randomized controlled trials (RCTs) within medical research, applied interventions are compared to treatment-as-usual (TAU) as the control condition. The aim of the current study was to examine how the concept of TAU is described when used as control condition in RCTs evaluating treatments for depression, anxiety syndromes, and stress-related mental disorders in primary care.
A systematic review of RCTs utilizing TAU as control group in the RCT in accordance with PRISMA standards was conducted. We used one multidisciplinary database (Scopus), one database focused on nursing (Cinahl), and one medical database (PubMed). The searches were conducted in November 2021 and May 2022.
The included 32 studies comprised of 7803 participants. The content of TAU was classified as follows: 1) Basic descriptions of TAU lacking a detailed account as well as reference to local or national guidelines, 2) Moderate description of TAU including reference to national or local guidelines or a detailed description 3) Advanced description of TAU including references to national guidelines and a detailed description containing five key concepts: early assessment, accessibility, psychological treatment, medication, somatic examination. 18 studies had basic, 11 moderate, and 3 advanced descriptions of TAU.
The limitations were that only studies published in English were included.
The current study provides an assessment tool with three classification levels for TAU. The description of TAU is still insufficient in RCT studies conducted in primary care, which may affect the interpretation of results. In future research a detailed description of TAU is recommended.

Owing to the COVID-19 pandemic and the associated post-COVID syndrome, the concept \"fatigue\" has gained significant importance. However, both the definition and the causes of fatigue differ depending on the disease pattern in question. Moreover, individuals who describe their symptoms in everyday clinical settings seem almost universally to use the terms tiredness, fatigue and exhaustion synonymously. In 2007, Olson described these three terms as being distinct states in her view, but that they can be placed in relation to each other on a continuum. Taking up this consideration, an overview of current research is provided. For this purpose, the published literature of the last 2 years was searched for the terms \"tiredness\", \"fatigue\" and \"exhaustion\". Some common diagnostic instruments can be found. However, the great variety of instruments used to capture the three terms is striking. Despite these different diagnostic and definition possibilities, different therapeutic measures can be derived for each of the three symptoms. It is crucial, especially with regard to further therapy, to separate the three terms tiredness, fatigue and exhaustion from each other and to consider each of them separately on the common continuum. This is the only way to establish both an accurate diagnosis and the successful individual therapy that goes along with it.

Despite extensive research on COVID-19\'s impact on healthcare workers, few studies have targeted mental health workers (MHWs) and none have investigated previous traumatic events. We investigated psychological distress in MHWs after the first lockdown in Italy to understand which COVID-19, sociodemographic, and professional variables represented greater effects, and the role of previous trauma. The survey included sociodemographic and professional questions, COVID-19 variables, and the questionnaires Life Events Checklist for DSM-5 (LEC-5), Impact of Event Scale-Revised (IES-R), and Depression Anxiety Stress Scales 21 (DASS-21). On the 271 MHWs who completed the survey (73.1% female; mean age 45.37), we obtained significant effects for contagion fear, experience of patients\' death, increased workload, and worse team relationship during the first wave. Nurses were more affected and showed more post-traumatic stress symptoms, assessed by IES-R, and more depressive, anxiety, and stress symptoms, assessed by DASS-21. The strongest risk factors for distress were greater age, professional role, increased workload, worse team relationship, and separation from family members. Previous experience of severe human suffering and unwanted sexual experiences negatively impacted IES-R and DASS-21 scores. Being a psychiatrist or psychologist/psychotherapist and good team relationships were protective factors. Recent but also previous severe stressful events might represent relevant risk factors for distress, reducing resilience skills. Identifying vulnerable factors and professional categories may help in the development of dedicated measures to prevent emotional burden and support psychological health. Highlights: Psychological distress in mental health workers in the COVID-19 pandemic is more frequent in nurses, who experience more depression, anxiety, and post-traumatic stress symptoms. Previous and recent stressful events are risk factors for distress and should guide intervention strategies.

Major depressive disorders (MDDs) and anxiety and stress-related disorders (ASRDs) have overlapping symptoms and high rates of comorbidity. However, the underlying mechanisms remain largely unknown. Here, we aimed to examine whether MDD and ASRD share genetic risk factors utilizing recent large-scale genome-wide association studies (GWASs). To examine the genetic overlap between MDD and ASRD, we applied genetic correlation analysis to analyze GWAS summary statistics for MDD (16,823 cases and 25,632 controls) and ASRD (12,665 cases and 19,225 controls). We found positive and significant genetic correlations between MDD and ASRD (GNOVA: rho = 0.59, se = 0.01, P = 5.32 × 10-45). Our latent causal variable (LCV) analysis indicated the genetic correlation result from pleiotropic effects (gcp = -0.56, se = 0.31, Pgcp = 0.1). Based on pleiotropic enrichment, we performed a cross-trait meta-analysis of MDD and ASRD GWAS and fine-mapped the identified loci. In total, we identified 5 pleiotropic loci simultaneously associated with MDD and ASRD at P < 5 × 10-8. At the gene level, we further demonstrated that MDD- and ASRD-inferred gene expression overlapped across 48 tissues and highlighted the NUP210L gene as a potential mediator of the genetic correlation. Our study highlights a shared underlying genetic risk for MDD and ASRD, which may help to improve the understanding of high comorbidity and overlapping genetic mechanisms between the two traits.

Fatigue is widespread in the population, particularly among working people. Exhaustion disorder (ED), a clinical manifestation of burnout, is common, but, after treatment, about one-third still experience fatigue and other physical symptoms. We propose that in some instances, fatigue as a persistent physical symptom (PPS) might be a more appropriate formulation of ED patients\' fatigue problems, and we suggest that ED patients who meet fatigue PPS criteria will differ from other ED patients in terms of psychological distress, non-fatigue PPSs and functional impairment. Questionnaires were sent to 10,956 members of a trade union of which 2479 (22.6%) responded. Of 1090 participants who met criteria for ED, 106 (9.7%) met criteria for fatigue as a PPS. Participants who met fatigue PPS criteria scored on average higher on measures of depression, anxiety and functional impairment and were more likely to have clinically significant scores. Moreover, they had 27 times higher odds of meeting other PPS subtypes and reported more non-fatigue PPS subtypes, suggesting a more complex health problem. Specific evidence-based interventions are available for both ED and PPSs, and therefore, it is crucial to accurately formulate the fatigue problem reported by patients to provide appropriate treatment.

Non-selective α2-adrenoreceptor (AR) stimulation delivers favourable sedative, analgesic, muscle relaxant and anxiolytic actions in companion animals, but is associated with cardiovascular and respiratory side effects. Anxiety conditions underscore monoamine disturbances amenable to α2-AR modulation. We investigated sub-chronic (14 day s.c.) treatment with the selective α2C-AR antagonist, ORM-10921 (0.03, 0.1, 0.3 mg/kg/d) on hippocampal noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their turnover levels in stress sensitive Flinders Sensitive Line (FSL) rats versus Flinders Resistant Line (FRL) controls, using high performance liquid chromatography. The effects of ORM-10921 were compared to the non-selective α2-AR antagonist, idazoxan (IDAZ; 3 mg/kg/d), and to imipramine (IMI; 15 mg/kg/d), a reference antidepressant in this model. FSL rats displayed significantly reduced 5-HT (p = 0.03) and DA (p = 0.02) levels vs. FRL controls, while NA levels showed a similar trend. ORM-10921 significantly increased NA (all doses p ≤ 0.02), 5-HT (0.1 and 0.3 mg/kg p ≤ 0.03) and DA levels (all doses p ≤ 0.03), which correlated with decreased monoamine turnover. In contrast, IDAZ significantly elevated NA (p < 0.005) and DA (p < 0.004) but not 5-HT levels. IMI also significantly increased 5-HT (p < 0.009), with a tendency to increase NA (p = 0.09) but not DA. ORM-10921 exerts similar albeit broader effects on hippocampal monoamines than IDAZ, explaining earlier established efficacy associated with α2C-AR antagonism in animal models of depression and cognitive dysfunction. These and the current studies encourage application of ORM-10921 in depression in humans, as well as raise the intriguing possibility that selective α2C-AR antagonists may be beneficial in anxiety and stress-related disorders in companion animals. Both warrant further study.

Chronic stress is a major cause of mental health problems and primary medical issues. Milk has been studied for its stress-reducing effects. Tryptophan, which is abundant in milk, is a precursor of the neuroactive compounds serotonin and melatonin. This study investigated the preventive effects of milk casein on brain dysfunction and anxiety-like behavior induced by chronic stress. Mice were exposed to unpredictable chronic mild stress (UCMS) and milk casein was administered for 10 weeks. Milk casein significantly reduced stress-induced changes in serum corticosterone and serotonin levels. The negative effects of UCMS on the expression of proteins associated with neuroendocrine function, neurodegeneration, neuronal inflammation, and barrier function of the blood-brain barrier were statistically normalized by casein treatment. Pretreatment with casein significantly prevented anxiety-like behavior induced by UCMS. These results suggest that milk casein has the potential to prevent stress-induced brain dysfunction and anxiety-like behavior.

BACKGROUND: Suffering linked to previous interpersonal trauma is common among patients in mental health care. Diagnostic labels may vary, but the clinical picture is often characterized by long-lasting and complex psychological and somatic symptoms, subjective distress and reduced quality of health and life. A substantial proportion of patients do not recover after individual treatment in ordinary specialized mental healthcare settings, despite the proven usefulness of individual trauma-specific treatments. The therapeutic factors that arise in group settings, such as normalization, shame reduction and corrective relational experiences, may be particularly useful for trauma survivors. However, evidence in support of group treatment for trauma survivors is scarce. This study aims to test whether combining a novel group intervention to individual treatment is superior to conventional individual out-patient treatment in an ordinary community mental health hospital.
METHODS: In a single-site, non-blinded, randomized controlled trial (RCT), the effect of a combined group-based stabilization and skill-training (SST) intervention added to individual treatment will be compared to conventional treatment (treatment as usual, TAU) alone. Participants (N = 160) with ongoing and long-lasting reactions related to known adverse life events from the past will be recruited among patients at general outpatient clinics in a community mental health centre at St. Olav\'s University Hospital, Trondheim, Norway. Following baseline assessment and randomization, participants will complete follow-up measures at 4, 8, 13 and 19 months post-baseline. The primary outcome is personal recovery (The questionnaire about the process of recovery , QPR). Secondary outcomes include (1) self-reported symptoms of posttraumatic stress, general mental and somatic health symptoms, well-being, functional impairment and client satisfaction, (2) immunological and endocrine response measured in blood samples and (3) national registry data on occupational status, use of mental health services and pharmacological treatment. Additionally, mechanisms of change via posttraumatic cognitions will be examined.
CONCLUSIONS: The addition of a group-based intervention to individual treatment for trauma survivors might prove to be an efficient way to meet the need of long-lasting high-intensity treatment in a large group of patients in mental health care, thereby reducing their suffering and increasing their psychosocial functioning.
BACKGROUND: ClinicalTrials.gov: NCT03887559. Registered on 25 March 2019.