Higher overcommitment to work is associated with higher plasma cortisol but not ACTH responses in the combined dexamethasone/CRH test in apparently healthy men and women.

BACKGROUND: Overcommitment (OC) is a pattern of excessive striving that has been associated with alterations in the hypothalamus-pituitary-adrenal (HPA) system. To investigate whether overcommitment is associated with alterations in HPA system function we measured cortisol and adrenocorticotropin (ACTH) release in response to the combined dexamethasone/CRH test. METHODS: We recruited 92 men and 108 women of a wide range of OC scores including the minimum (6) and maximum (24) of possible OC scores (mean+/-SEM: 13.25+/-.27). We repeatedly measured plasma cortisol and ACTH levels in the combined dexamethasone/CRH test after injection of 100mul CRH preceded by administration of 1.5mg dexamethasone the night before. Moreover, we assessed depressive symptoms (Beck Depression Inventory, BDI) and work stress (effort-reward-imbalance, ERI). RESULTS: Independent of age and gender, higher OC was associated with higher repeated cortisol (interaction time-by-OC: p=.014, f=.15) but not ACTH (p=.22) secretion in the combined dexamethasone/CRH test. Similarly, higher cortisol (beta=.16, p=.029, R(2)=.02) but not ACTH (p=.47) increase following CRH injection was predicted by higher OC. Depressive symptoms (BDI score) and work stress scores (effort-reward-ratio) did not relate to neuroendocrine responses to the dexamethasone/CRH test. Controlling for depressive symptoms and work stress scores in addition to age and gender did not change results. OC was not associated with ACTH or cortisol pre-test levels. DISCUSSION: Whereas OC was not associated with alterations in negative feedback sensitivity after dexamethasone administration, our findings indicate that with increasing OC scores, a higher reactivity of the adrenal cortex together with a normal reactivity of the pituitary is observed following subsequent stimulation by CRH injection.

Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.

BACKGROUND: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. METHODS: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. RESULTS: Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. CONCLUSION: Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.