The role of mineralocorticoid receptors (MR) and N-methyl-D-aspartate receptors (NMDA-R) in steroid hormone secretion and social cognition in major depressive disorder

In reaction to stress, activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to the secretion of the steroid hormone cortisol which binds upon mineralocorticoid (MR) and glucocorticoid receptors (GR). Patients with major depressive disorder (MDD) suffer from altered MR and GR functioning and there is evidence that this might contribute to alterations in steroid hormone systems (cortisol, aldosterone, DHEA-S) and to cognitive deficits that have been found in MDD. Interestingly, MR stimulation decreases cortisol secretion and enhances both memory and executive functioning in healthy individuals and patients with MDD. The current research project examined whether MR stimulation affects other steroid hormones and whether the beneficial effects of MR stimulation on cognition are extendable to processes of social cognition in MDD. Furthermore, MR stimulation leads to N-methyl-D-aspartate receptor (NMDA-R) mediated glutamatergic signal transmission and NMDA-R stimulation has cognitive-enhancing effects. Therefore, the current research project examined whether simultaneous NMDA-R stimulation might enhance the effects of MR stimulation in MDD. The central research question was: What is the effect of MR and NMDA-R stimulation on steroid hormone secretion and social cognition in healthy individuals and patients with MDD? One hundred and sixteen MDD patients and 116 healthy individuals matched in age, sex, and education years were randomly assigned to one treatment condition: no stimulation (placebo + placebo), MR stimulation (0.4 mg fludrocortisone + placebo), NMDA-R stimulation (placebo + 250 mg D-cycloserine, DCS) and MR/NMDA-R stimulation (both drugs). Salivary steroid hormone concentrations (cortisol, aldosterone, DHEA-S) were assessed hourly, and participants conducted social cognition tasks to measure cognitive empathy (ability to understand another person’s emotions), emotional empathy (ability to empathize with another person’s emotions), recognition of emotional facial expressions, and selective attention to emotional stimuli. The main observations are that: (1) separate MR stimulation decreases cortisol concentrations in healthy individuals and patients with MDD, (2) separate MR stimulation enhances cognitive empathy in both groups but has no effect on the other examined social cognitive processes, (3) simultaneous MR and NMDA-R stimulation has no effect on steroid hormone secretion and social cognition, and (4) separate NMDA-R stimulation decreases cognitive empathy in MDD patients and increases emotion recognition in both groups. In conclusion, the current research project confirms the important role of MR in the psycho-neuro-endocrinological stress response in healthy individuals and patients with MDD. The observations emphasize that the beneficial effects of MR stimulation on cognition might be partially extendable to social cognition in healthy individuals and patients with MDD. Evidently, these cognitive-enhancing effects are not improvable by simultaneous NMDA-R stimulation, yet NMDA-R appear to be involved in social cognitive processes. Thus, the current research project emphasizes an involvement of MR and NMDA-R in social cognition in healthy individuals and patients with MDD. Future research should examine whether MR and NMDA-R might serve as potential treatment targets to improve (social) cognition in MDD