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Glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) function, associate to psychoneuroendocrine and psychometric assessment as outcome predictor in depressive patients

Grant number: 07/05084-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2007
Effective date (End): July 31, 2009
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Frederico Guilherme Graeff
Grantee:Mario Francisco Pereira Juruena
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:07/03685-3 - Typical and atypical neurotransmitters in neuropsychiatric disorders, AP.TEM

Abstract

The main problem in psychiatry diagnostic is that the classification today are solely based on subjective descriptions of symptoms. Phenomenology includes the description of multiple clinical subtypes; but, there is no biological feature that distinguishes one subtype from another. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in major depression is one of the most consistent findings in psychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol in the plasma, urine, saliva and cerebrospinal fluid; an exaggerated cortisol response to adrenocorticotropic hormone (ACTH); and an enlargement of both the pituitary and adrenal glands. The hypercortisolemia is linked to depression and it depends on the type and severity of the illness, genotype, history of early life and recent stress. The dexamethasone suppression test (DST) showed that patients with various affective disorders had elevated cortisol levels, thus escaping the suppressive effect of dexamethasone (DEX). Unfortunately, DEX has pharmacodynamic and pharmacokinetic features that are very distinct from cortisol. Recently, a suppressive test using another synthetic glucocorticoid, prednisolone has been developed; such test has a higher affinity for the mineralocorticoid receptor (MR) and can probe both receptors. The first results with the prednisolone test in depressed patients seem to confirm the notion that MR-mediated negative feedback in depression is intact in depressed patients. Studies have described patients receiving the DEX/CRF test after the admission and before the discharge. These studies found that those patients who had an increase in the cortisol levels test between admission and discharge tended to relapse during the follow-up period, while those who showed a decrease in cortisol levels tended to remain clinically stable in the follow-up period. Therefore, these studies suggest that evaluation of the HPA axis during the antidepressant treatment may be helpful in identifying those who are at higher risk of relapse. The initial hypotheses to be test are as follows: 1) patients will show characteristic neurobiological changes to the HPA axis feedback compared to controls; specifically, in glucocorticoid receptor (GR) function and MR function there will be hypercortisolemia and relative non-suppression of cortisol in patients; 2) antidepressant will normalize GR function and/or MR function and normalize HPA axis in patients with depression; 3) different subtypes of depression are associate with specific HPA axis alterations and related to GR function and MR function; 4) patients with a greater HPA axis impairment will be more resistant to treatment; therefore, greater degrees of non-suppression to prednisolone will predict a poorer response to treatment and relapse.The study will use a placebo-controlled design and compare the effects of prednisolone, DEX and spironolactone on 35 patients and 35 controls. In a 4-day protocol: awakening salivary cortisol on day 1 will be assess after subjects have taken one capsule at 10:00 pm the night before containing placebo. On day 2 after subjects have taken one capsule at 10:00 pm the night before with prednisolone. Day 3 will be undertaken after taken Spironolactone at 10:00 pm the night before. Finally, on day 4, after taken dexamethasone at 10:00 pm the night before. Awakening salivary cortisol and plasma levels of ACTH, dehydroepiandrosterone (DHEA), vasopressin (AVP) and aldosterone at 9 am will be collect. Will utilize the detailed assessment procedures to diagnostic axis I disorders, axis II, treatment resistance, clinical severity, suicide assessment, cognitive function, functional capacity and adaptation, sleep and stress. These assessments will be repete in patients after clinical response (more than 50% according Hamilton scale) or between 12 to 16 weeks in non-responders and in the follow up of 06-12 months.