Mineralocorticoid receptor polymorphism and function in patients with depression and early life stress

Abstract

Increasing evidence indicates that abandonment, neglect and abuse in childhood and adolescence are risk factors for psychiatric disorders. Studies in both animals and humans suggest that stress in the early stages of development may induce persistent changes in the ability of the hypothalamic-pituitary-adrenal (HPA) in response to stress in adult life leading to greater susceptibility to depression. The hyperactivity of the HP A axis, reduced negative feedback and hypercortisolism has been a constant finding in major depression. These abnormalities seem to be related to changes in the ability of circulating glucocorticoids to exert their negative feedback on secretion of hormones of the HP A axis by binding to mineralocorticoid receptors (MR) and glucocorticoid (GR) in HPA tissues. However, given the wide variety of stressors, as well as the different subtypes of depression, the findings of current studies have been inconsistent, therefore, become necessary for further studies that may elucidate the mechanisms underlying the link between maltreatment childhood and the development of depressive psychopathology in adult life. The central role of MR for the regulation of HP A genotype variant MR I180V SNP is associated with increased cortisol has a specific effect on depressive symptoms, regardless of cognitive function. Recently, it was discovered that the MR I180V polymorphism carriers had higher scores of depressive symptoms than non-carriers. The aim of this study is to assess the association between childhood maltreatment (physical abuse, sexual, neglect, or early stress) and specific alterations of the HPA axis and the function of GR and MR receptors in different subtypes of depression. To be recruited three groups: one group of patients with a history of childhood maltreatment and/or neglect and/or early life stress and current diagnosis of depressive episode, a group of patients without a history for child maltreatment and/or neglect and/or stress early diagnosis and current depressive episode and a group of healthy controls. Patients will be assessed by the Structured Clinical Interview for Disorders of Axis I DSM-IV (SCID¬I) for the diagnosis of depression, to assess the severity of the condition are used Hamilton Depression Rating Scale and Beck Depression Inventory II. Is also used the Beck Anxiety Inventory, the Beck Suicide Inventory and Beck Hopelessness Scale. The presence of a history of abuse, neglect and abuse in childhood will be confirmed through the application of the Childhood Trauma Questionnaire. The study will be placebo controlled, blinded by the controls and patients, with repeated measures used previously, where the effects of steroids as Fludrocortisone (0.5 mg), and Spironolactone (200mg) will be assess in salivary cortisol in patients and in healthy controls. This is a 5 days protocol, followed by the medications and placebo plus a 2-day interval between administration of a drug and another. The secretion of salivary cortisol will be evaluated to awaken in all subjects, after having taken the day before to 22h: a placebo capsule, Fludrocortisone and spironolactone. The salivary cortisol will be collected upon awakening, 30 and 60 minutes in the following days after the challenges. Our hypothesis is that the involvement of the HPA axis would be associated with clinically more severe depressive illness and a higher level of early life stress, which could lead to treatment-resistant depression (TRD). We therefore hypothesized that MR-I180V SNP modulates the prevalence of depressive symptoms in major depressive illness and may influence epigenetic events, such as early life stress. Thus, based on our hypothesis, patients must exhibit the following pattern of responses to the challenges: (1) an MR agonist (fludrocortisone), diminishing the role of MR, which exert an inhibitory effect on HPA axis activity, this effect would be less pronounced in individuals with higher levels of stress early in life and TRD, and (2) Moreover, Spironolactone, a MR antagonist would increase the role of MR and HPA axis activity, an effect that would be less pronounced in subjects with higher level of early life stress and TRD. Finally, an altered MR function in patients with the MR-I180V undermine the HPA axis leading to a clinically more severe depressive illness in patients with a higher level of early life stress, which could lead to TRD. Knowledge of these mechanisms will provide new targets in current treatments. (AU)