Despite the very strong preclinical and clinical data of a dysregulation of the HPA axis in stress-related mental disorders, such as major depression, no drug has been approved that targets specific components of the HPA axis. Thus, the HPA axis plays an important role in the target development of psychiatric disorders. With access to advanced technologies, first-rate laboratories, and professional scientists, Creative Biolabs provides a full range of services to support our customers in psychotropic drug development.
Introduction to HPA-Axis
Physical and psychological disruptions to daily function elicit the body's adaptive responses. A stressor can be any real or perceived disturbance that threatens homeostasis and the physiological and endocrine responses to these stressors are aimed at restoring homeostasis, and thus, are critical for survival. One major component of the neuroendocrine response is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This cascade of events is initiated in the paraventricular nucleus of the hypothalamus (PVN) which leads to the release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). These two hormones synergistically stimulate the release of adrenocorticotropic hormones (ACTH) from the anterior pituitary corticotropes and subsequent synthesis and secretion of glucocorticoids from the adrenal cortex. Systemic concentrations of glucocorticoids rise transiently and then eventually return to baseline levels due to negative feedback processes occurring in the brain and pituitary.
HPA-Axis and Diseases
The correct definition of depression subtypes remains a cornerstone of biological research in affective disorders. The presence of different HPA axis functions between melancholic and atypical depression, and a trend towards a more robust association with biological, or vegetative symptoms, or reverse vegetative symptoms, respectively. Patients with Melancholic depression are associated with increased cortisol levels, both baseline and post different challenges. Moreover, the research data also suggest a reduction of inhibitory feedback in patients with melancholic depression, demonstrated by increased cortisol concentrations and the number of non-suppressive patients following the HPA axis challenge, mainly dexamethasone.
Studies of HPA-Axis Antagonists
Numerous factors regulate HPA axis responsiveness: at the hypothalamic level corticotrophin-releasing hormone (CRH) and receptors such as the CRH1- and CRH2-receptor, modulators such as agonistic vasopressin and antagonistic atriopeptins are involved in the central regulation of HPA activity. At the molecular level, glucocorticoid receptor (GR) polymorphisms may be associated either with hypofunction or hyperfunction which could contribute to these findings. Other factors are the influences of steroids like estrogen and progesterone.
Pivotal studies have been conducted in the past, applying the dexamethasone-induced suppression of HPA activity, the CRH stimulation test of HPA activity, and the combined dexamethasone-CRH test to predict treatment response. In an investigation by Schüle et al, the attenuation of HPA axis activity after 1 week of antidepressant pharmacotherapy was significantly associated with subsequent improvement of depressive symptoms. Also, other single tests revealed a predictive potency of the dexamethasone-CRH test. These findings are in line with studies reported by Ising et al, who found normalized HPA activity in a subsequent dexamethasone-CRH test 2 or 3 weeks after the first test at beginning of treatment with an association of psychopathological improvement after 5 weeks.
Based on numerous findings of an HPA axis hyperactivity in patients with psychotic depression, researchers focused on the GR antagonist (and also progesterone antagonist) mifepristone. Subsequent evidence has shown that mifepristone ameliorates cognitive deficits in major depression and bipolar disorder. Thus, for depressed patients with psychotic features, a GR antagonist such as mifepristone may be an individualized treatment option.
Services at Creative Biolabs
As an industry-leading CRO company, Creative Biolabs has established a comprehensive drug development system. With a fit-for-purpose experiment platform, Ph.D. level experts, and hundreds of successful precedents, we are capable of providing our clients with high-quality target development services. Our scientists will help in every link including but not limited to target discovery, in vivo/in vitro test, and animal model development during drug development.
Advantages:
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Worry-free one-stop services.
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Professional expert team.
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Efficient, experienced, and cost-effective.
HPA-axis has been closely watched in the target development of psychiatric disorders. Based on an advanced technology platform and extensive experience accumulated, Creative Biolabs provides comprehensive target development services to global customers. Our scientists will customize the optimal scheme for you to meet any detailed requirements. If you have any questions, please feel free to contact us for more information.
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