Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive syniptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MOD recurrence (P = 0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T + and TCE +); 461 days for T - and TCE + patients; 773 days for T + and TCE - patients and 866 days for T - and TCE - patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P = 0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MOD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MOD recurrence after exposure to childhood trauma

Childhood trauma and dysregulation of multiple biological stress systems in adulthood:Results from the Netherlands Study of Depression and Anxiety (NESDA)

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

Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

RATIONALE: Repeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission. OBJECTIVE: The present study investigated molecular and functional alterations in GABA(A) receptor (GABA(A)R) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF. METHODS: CRF(1) receptor, GABA(A)R, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABA(A)R α subunits and mGluRs in the amygdala and hypothalamus. RESULTS: CRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF(1) receptor antagonists CP154,526 and DMP695, the GABA(A)R α(3)-selective agonist TP003 (0–3 mg/kg) and the mGluR(2/3) agonist LY379268 (0–10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABA(A)R agonist diazepam (0–4 mg/kg) and the α(1)-subunit-selective GABA(A)R agonist zolpidem (0–10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA(A)R α(5)-subunit preferential compound SH-053-2′F-R-CH(3) and mGluR(5) antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABA(A)R α(2) subunit and mGluR(3) mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α(1) and α(5) GABA(A)R subunits. CONCLUSIONS: We found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABA(A) and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission

Stress-related psychopathology after cardiac surgery and intensive care treatment

Objective: Cardiac surgery patients are at risk for psychopathology. Symptoms of post-traumatic stress disorder (PTSD) and depression occur in 10–20% of these patients and affect their quality of life. The aim of this study was to assess factors associated with psychopathology after cardiac surgery. Methods: We followed participants of the multi-center randomized clinical trial Dexamethasone for Cardiac Surgery (DECS), on a single, intravenous dose of dexamethasone (1 mg/kg) or placebo during cardiac surgery, using validated questionnaires to assess PTSD and depressive symptoms after 1.5 to 4 years, as well as childhood trauma, trait anxiety, pre-existing psychopathology, and substance use. Saliva was used for genotyping of the hypothalamic-pituitary-adrenal-axis (HPA axis) glucocorticoid receptor gene. Linear backward regression analysis was performed with these factors, including pre-specified interaction terms of dexamethasone with sex and genotype. Results: Complete data was available for 90% of cases (n = 1111). The model including trait anxiety and the [dexamethasone x female sex] interaction explained 57% of variance in PTSD symptoms (Model fit F (2;4.817)=643.043, p<.001; R2=0 0.57). Similar explained variance was seen for depressive symptoms, where age, trait anxiety and the [dexamethasone x female sex] interaction provided the optimal model (Model fit F (3;4.261)=435,960, p<.001; R2=0.58). Limitations: In this study psychopathology was assessed through validated questionnaires. Variability in data collection detail was present. Conclusion: This study suggests that the occurrence of psychopathology after cardiac surgery is influenced by higher trait anxiety. Female cardiac surgery patients may benefit from intra-operative dexamethasone administration

The methodological quality of 176,620 randomized controlled trials published between 1966 and 2018 reveals a positive trend but also an urgent need for improvement

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed

A more unstable resting-state functional network in cognitively declining multiple sclerosis

Cognitive impairment is common in people with multiple sclerosis and strongly affects their daily functioning. Reports have linked disturbed cognitive functioning in multiple sclerosis to changes in the organization of the functional network. In a healthy brain, communication between brain regions and which network a region belongs to is continuously and dynamically adapted to enable adequate cognitive function. However, this dynamic network adaptation has not been investigated in multiple sclerosis, and longitudinal network data remain particularly rare. Therefore, the aim of this study was to longitudinally identify patterns of dynamic network reconfigurations that are related to the worsening of cognitive decline in multiple sclerosis. Resting-state functional MRI and cognitive scores (expanded Brief Repeatable Battery of Neuropsychological tests) were acquired in 230 patients with multiple sclerosis and 59 matched healthy controls, at baseline (mean disease duration: 15 years) and at 5-year follow-up. A sliding-window approach was used for functional MRI analyses, where brain regions were dynamically assigned to one of seven literature-based subnetworks. Dynamic reconfigurations of subnetworks were characterized using measures of promiscuity (number of subnetworks switched to), flexibility (number of switches), cohesion (mutual switches) and disjointedness (independent switches). Cross-sectional differences between cognitive groups and longitudinal changes were assessed, as well as relations with structural damage and performance on specific cognitive domains. At baseline, 23% of patients were cognitively impaired (≥2/7 domains Z < -2) and 18% were mildly impaired (≥2/7 domains Z < -1.5). Longitudinally, 28% of patients declined over time (0.25 yearly change on ≥2/7 domains based on reliable change index). Cognitively impaired patients displayed more dynamic network reconfigurations across the whole brain compared with cognitively preserved patients and controls, i.e. showing higher promiscuity (P = 0.047), flexibility (P = 0.008) and cohesion (P = 0.008). Over time, cognitively declining patients showed a further increase in cohesion (P = 0.004), which was not seen in stable patients (P = 0.544). More cohesion was related to more severe structural damage (average r = 0.166, P = 0.015) and worse verbal memory (r = -0.156, P = 0.022), information processing speed (r = -0.202, P = 0.003) and working memory (r = -0.163, P = 0.017). Cognitively impaired multiple sclerosis patients exhibited a more unstable network reconfiguration compared to preserved patients, i.e. brain regions switched between subnetworks more often, which was related to structural damage. This shift to more unstable network reconfigurations was also demonstrated longitudinally in patients that showed cognitive decline only. These results indicate the potential relevance of a progressive destabilization of network topology for understanding cognitive decline in multiple sclerosis

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders

Background: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure. Methods: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]). Results: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders. Conclusions: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population