HPA axis genetic variation, cortisol and psychosis in major depression.
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ABSTRACT:
SUBMITTER: Schatzberg AF
PROVIDER: S-EPMC4339288 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
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Project description:The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.
| S-EPMC5313380 | biostudies-literature
Project description:More than 700,000 people worldwide die by suicide every year, and the number of suicide attempts is estimated as 20 times higher, most of them being associated with psychiatric disorders, especially major depression. Knowledge about effective methods for preventing suicide attempts in individuals at high risk for suicide is still scarce. Dysregulation of the neuroendocrine stress response system, i.e., the hypothalamic-pituitary-adrenocortical (HPA) axis, is one of the most consistent neurobiological findings in both major depression and suicidality. While the HPA axis is mostly overactive in depression, individuals with a history of suicide attempts exhibit an attenuated hormonal response to stress. It is unknown, however, whether the HPA axis is constantly attenuated in repeated suicide attempters or whether it regains normal responsivity after recovery from depression. Using the combined dexamethasone suppression/corticotropin-releasing hormone (dex/CRH) test, we assessed HPA axis regulation in acute depression (N = 237) and after recovery with respect to previous suicide attempts. Patients without previous suicide attempts show normalization of the stress hormone response to the second dex/CRH (basal ACTH response and cortisol response) after recovery from acute depression, while patients with multiple previous SA show an increased ACTH response. The change in HPA axis responsivity in patients with only one previous SA lies between the response patterns of the other groups with no change in HPA axis reactivity. Our findings suggest that patients with a history of suicide attempts belong to a subgroup of individuals that exhibit a distinct pattern of stress hormone response during acute depression and after recovery. Future studies may extend our approach by investigating additional psychological stress tasks to gain a broader understanding of the stress pathology of recurrent suicide attempters.
| S-EPMC9412752 | biostudies-literature
Project description:Mammalian skin incorporates a local equivalent of the hypothalamic-pituitary-adrenal (HPA) axis that is critical in coordinating homeostatic responses against external noxious stimuli. Ultraviolet radiation B (UVB) is a skin-specific stressor that can activate this cutaneous HPA axis. Since C57BL/6 (B6) and DBA/2J (D2) strains of mice have different predispositions to sensorineural pathway activation, we quantified expression of HPA axis components at the gene and protein levels in skin incubated ex vivo after UVB or sham irradiation. Urocortin mRNA was up-regulated after all doses of UVB with a maximum level at 50 mJ/cm(2) after 12h for D2 and at 200 mJ/cm(2) after 24h for B6. Proopiomelanocortin mRNA was enhanced after 6h with the peak after 12h and at 200 mJ/cm(2) for both genotypes of mice. ACTH levels in tissue and media increased after 24h in B6 but not in D2. UVB stimulated ?-endorphin expression was higher in D2 than in B6. Melanocortin receptor 2 mRNA was stimulated by UVB in a dose-dependent manner, with a peak at 200 mJ/cm(2) after 12h for both strains. The expression of Cyp11a1 mRNA - a key mitochondrial P450 enzyme in steroidogenesis, was stimulated at all doses of UVB irradiation, with the most pronounced effect after 12-24h. UVB radiation caused, independently of genotype, a dose-dependent increase in corticosterone production in the skin, mainly after 24h of histoculture. Thus, basal and UVB stimulated expression of the cutaneous HPA axis differs as a function of genotype: D2 responds to UVB earlier and with higher amplitude than B6, while B6 shows prolonged (up to 48 h) stress response to a noxious stimulus such as UVB.
| S-EPMC3807248 | biostudies-literature
Project description:BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning. METHODOLOGY/PRINCIPAL FINDINGS: In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition. CONCLUSIONS/SIGNIFICANCE: As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.
| S-EPMC3351438 | biostudies-other
Project description:BackgroundStress, elicited for example by aggressive interactions, has negative effects on various biological functions including immune defence, reproduction, growth, and, in livestock, on product quality. Stress response and aggressiveness are mutually interrelated and show large interindividual variation, partly attributable to genetic factors. In the pig little is known about the molecular-genetic background of the variation in stress responsiveness and aggressiveness. To identify candidate genes we analyzed association of DNA markers in each of ten genes (CRH g.233C>T, CRHR1 c.*866_867insA, CRHBP c.51G>A, POMC c.293_298del, MC2R c.306T>G, NR3C1 c.*2122A>G, AVP c.207A>G, AVPR1B c.1084A>G, UCN g.1329T>C, CRHR2 c.*13T>C) related to the hypothalamic-pituitary-adrenocortical (HPA) axis, one of the main stress-response systems, with various stress- and aggression-related parameters at slaughter. These parameters were: physiological measures of the stress response (plasma concentrations of cortisol, creatine kinase, glucose, and lactate), adrenal weight (which is a parameter reflecting activity of the central branch of the HPA axis over time) and aggressive behaviour (measured by means of lesion scoring) in the context of psychosocial stress of mixing individuals with different aggressive temperament.ResultsThe SNP NR3C1 c.*2122A>G showed association with cortisol concentration (p = 0.024), adrenal weight (p = 0.003) and aggressive behaviour (front lesion score, p = 0.012; total lesion score p = 0.045). The SNP AVPR1B c.1084A>G showed a highly significant association with aggressive behaviour (middle lesion score, p = 0.007; total lesion score p = 0.003). The SNP UCN g.1329T>C showed association with adrenal weight (p = 0.019) and aggressive behaviour (front lesion score, p = 0.029). The SNP CRH g.233C>T showed a significant association with glucose concentration (p = 0.002), and the polymorphisms POMC c.293_298del and MC2R c.306T>G with adrenal weight (p = 0.027 and p < 0.0001 respectively).ConclusionsThe multiple and consistent associations shown by SNP in NR3C1 and AVPR1B provide convincing evidence for genuine effects of their DNA sequence variation on stress responsiveness and aggressive behaviour. Identification of the causal functional molecular polymorphisms would not only provide markers useful for pig breeding but also insight into the molecular bases of the stress response and aggressive behaviour in general.
| S-EPMC2927472 | biostudies-literature
Project description:BackgroundThere is inconsistency in the literature regarding the nature of hypothalamic-pituitary-adrenal (HPA) axis functionality in post-traumatic stress disorder (PTSD).PurposeThe review aimed to investigate HPA axis functionality via the diurnal profile of cortisol as it relates to PTSD.MethodsThe authors conducted a systematic review of the literature from June 2017 - March 2019 in accordance with The PRISMA Statement in the following four databases: PubMed, MEDLINE, ScienceDirect and PsycINFO with Full Text. The search strategy was limited to articles in English language, published in peer-reviewed journals within the last decade and human studies. Search terms included "post-traumatic stress disorder" OR "PTSD", AND "hypothalamic pituitary adrenal axis" OR "HPA axis" AND "diurnal cortisol" OR "cortisol". PTSD sufferers of all trauma types, genders and socioeconomic statuses were included provided there was a "healthy" control group and an inclusion of reporting on inter-group measurements of diurnal cortisol profiles as a portrayal of HPA axis functionality.ResultsA total of 10 studies met the criteria for inclusion in this review. The association between HPA axis functionality and PTSD was evaluated by the measurement of salivary and/or plasma cortisol concentrations. Only two studies demonstrated an association between PTSD and diurnal cortisol when compared with respective control groups while three studies found no associations. The remaining five studies found partial, mostly negative associations between PTSD and diurnal cortisol.ConclusionDespite some indications of an association between PTSD and dysregulated HPA axis functionality as demonstrated by diurnal cortisol output, the current review has revealed mixed findings. As such, a complete understanding of HPA axis dysregulation as it relates to PTSD remains unestablished. Given the findings, further investigation into the relationship between PTSD trauma-exposed and non-PTSD trauma-exposed individuals and diurnal cortisol is warranted.
| S-EPMC6582238 | biostudies-literature
Project description:Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.
| S-EPMC7327513 | biostudies-literature
Project description:CONTEXT:Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). OBJECTIVE:To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis. DESIGN:Cross-sectional, case-control study. SETTING:Academic medical center. PARTICIPANTS:Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data. MAIN OUTCOME MEASURES:Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD. RESULTS:Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results. CONCLUSIONS:These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.
| S-EPMC3091621 | biostudies-literature
Project description:Major Depression (MDD) is a prevalent psychiatric disorder and exposure to stress is robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic stress induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of “chronic stress” using human induced pluripotent stem cell-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. MDD-specific DEGs related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.
2022-10-04 | GSE178071 | GEO
Project description:Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology.
| S-EPMC4662045 | biostudies-literature