Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

Randomized controlled trial of bikram yoga and aerobic exercise for depression in women: Efficacy and stress-based mechanisms.

BACKGROUND: The current study presents a randomized controlled 8-week trial of Bikram yoga, aerobic exercise, and waitlist for depression. Bikram yoga was chosen specifically for its standardized nature. Further, we examined changes in three stress-related constructs-perceived stress, rumination, and mindfulness-as mediators of antidepressant effects. METHOD: Fifty-three women (age 18-65; 74% White) with a unipolar depressive disorder were randomly assigned to one of the three conditions. Response was defined as >50% reduction on the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as no longer meeting criteria for depression and a HAM-D ≤ 7. Self-reported perceived stress, rumination, and mindfulness were assessed weekly. RESULTS: In the intention-to-treat sample (n = 53), response rates were significantly higher in the Bikram yoga (61.1%; χ2 = 10.48, p = .001) and aerobic exercise (60.0%; χ2 = 10.44, p = .001) conditions relative to waitlist (6.7%). In the completer sample (n = 42), 73.3% (χ2 = 11.41, p = .001) of women in yoga and 80.0% (χ2 = 13.72, p < .001) in exercise achieved response compared to 8.3% in waitlist. Reductions in rumination significantly mediated HAM-D change for both active treatments, and mindful acceptance was a partial mediator in the exercise condition. LIMITATIONS: The sample was small in size, consisted of women only, and was ethnically homogenous. Inter-rater reliability was not assessed, aerobic exercise was not standardized, and mediators were assessed by self-report. CONCLUSIONS: Bikram yoga showed descriptively similar efficacy to aerobic exercise and both may work, in part, by helping individuals interrupt negative thinking.

The impact of acute mental stress on brachial artery flow-mediated dilation in women diagnosed with depression.

Endothelial function, assessed by flow-mediated dilation (FMD), may be transiently attenuated in healthy adults following acute mental stress. However, the impact of acute mental stress on endothelial function in the context of clinical depression is unknown. This study examined the impact of acute mental stress on FMD in women with a diagnosis of a depressive disorder. Forty-three otherwise healthy women (33 ±â€¯14 years) participated. Brachial artery diameter and blood velocity were assessed with ultrasound. FMD was assessed immediately prior to and 15 min following the Trier Social Stress Test (TSST). The FMD protocol included 5 min of forearm cuff occlusion (pressure = 250 mm Hg), followed by release. Shear stress was estimated by calculating shear rate (SR = brachial artery blood velocity/diameter). Stress reactivity was assessed via changes in mean arterial pressure (MAP), heart rate (HR) and salivary cortisol. Results are mean ±â€¯SD. A significant stress response was elicited by the TSST [MAP, HR and salivary cortisol increased (p < 0.05)]. Neither the SR stimulus nor FMD response differed pre-versus post-stress (p = 0.124 and p = 0.641, respectively). There was a modest negative correlation between cortisol reactivity and change in FMD from pre- to post-stress (R = -0.392, p = 0.011). To conclude, acute mental stress did not consistently impair endothelial function in women diagnosed with a depressive disorder; however, higher cortisol reactivity may increase the likelihood of post-stress endothelial dysfunction. Further research is required to better understand the factors influencing the relationship between acute mental stress, cortisol and endothelial function in women with depression.