Early Life Stress in Depressive Patients: HPA Axis Response to GR and MR Agonist

Abstract

Background: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients.Methods: We included 30 subjects, 20 patients with current major depression (HAM-D21 ≥ 17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist).Results: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p = 0.028) show differences between placebo vs. MR agonist (R = 0.51; p < 0.05) but not after GR agonist; in depressive patients, without ELS the data show differences between placebo vs. MR agonist (R = 0.69; p < 0.05); but now as well placebo vs. GR agonist (R = 0.53; p < 0.05).Conclusion: Our findings indicate that MR activity is impaired in depressed patients compared with controls. Furthermore, in spite of the previous limitations described, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction.

Target-based biomarker selection – Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression

“…Because prednisolone does not cross the blood brain barrier in relevant amounts when administered in low doses (Karssen et al, 2002) the effect of prednisolone appears to act primarily at the pituitary. A further moderator of MR-function appears to be a history of early live stress, which leads to a reduced awakening cortisol and increased sensitivity for the suppression with prednisolone in comparison to patients without early live stress (Baes et al, 2014). It has been suggested that the history of trauma and these biological characteristics may be related to clinical symptoms of atypical depression (Baes et al, 2014;Juruena et al, 2013;).…”

“…A further moderator of MR-function appears to be a history of early live stress, which leads to a reduced awakening cortisol and increased sensitivity for the suppression with prednisolone in comparison to patients without early live stress (Baes et al, 2014). It has been suggested that the history of trauma and these biological characteristics may be related to clinical symptoms of atypical depression (Baes et al, 2014;Juruena et al, 2013;). An interesting aspect is that the sensitivity of the MR appears to be a trait rather than a state marker, as acutely depressed and recovered patients are not different (Juruena et al, 2010), which is also reflected in a reduced hippocampal MR expression in depressed patients post mortem independent of depressive state at time of death (Klok et al, 2011).…”

“…Conversely, major depressive disorder has also been associated with an increased incidence of type 2 diabetes mellitus and cardiovascular disorders Lakka et al, 2002;Mezuk et al, 2008). Other moderators of treatment response as well as of neuroendocrine characteristics are related to early life trauma (Baes et al, 2014;Juruena, 2014;Juruena et al, 2015).…”

Trauma and stressor-related disorders

“…4 Evidências adicionais sugerem que tais pacientes apresentam alterações no eixo hipotálamo-pituitária-adrenal (HPA) indicando assim que a resposta ao estresse está cronicamente ativada. 49,50 No que se refere ao prognóstico deste quadro psicopatológico, pesquisas científicas apontam que quanto mais precoce for realizada as intervenções terapêuticas maiores serão as chances do paciente apresentar um bom prognóstico. 46 A Tabela 1 descreve os critérios diagnósticos para o TEPT.…”

“…58,59,60 Diferentes estudos ainda examinam a relação entre o estresse, funcionamento do eixo HPA e depressão no adulto, 61 enfatizando a importância do eixo HPA como um potencial biomarcador para prever a ocorrência e recaída de quadros psicopatológicos no adulto. 49,62 Entretanto deve se considerar que nem todas as pessoas expostas ao EP irão desenvolver psicopatologias, sendo fundamental a compreensão das diferenças individuais na vulnerabilidade e a resiliência aos efeitos patogênicos do estresse. Assim, fatores preexistentes conhecidos para modular a capacidade do organismo de compensar, em resposta ao desafio emocional, poderia interferir em uma adaptação bem sucedida e transmitir a vulnerabilidade no desenvolvimento de tais psicopatologias.…”