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Major depressive disorder (MDD) is associated with impairments in spatial learning and memory and with altered functioning of central mineralocorticoid receptors (MR) and glutamatergic N-methyl-D-aspartate receptors (NMDA-R). Both receptors are highly expressed in the hippocampus and prefrontal cortex - brain areas that are critical for spatial learning and memory. Here, we examined the effects of separate and combined MR and NMDA-R stimulation on spatial learning and memory in individuals with MDD and healthy controls.We used a randomized, double-blind, placebo-controlled between-group study design to examine the effects of separate and combined stimulation of the MR (with 0.4 mg fludrocortisone) and NMDA-R (with 250 mg D-cycloserine) in 116 unmedicated individuals with MDD (mean age: 34.7 ± 13.3 years; 78.4% women) and 116 age-, sex-, and education-matched healthy controls. Participants were randomly assigned to one of four conditions: 1) placebo; 2) MR stimulation; 3) NMDA-R stimulation; and 4) combined MR/NMDA-R stimulation. Three hours after drug administration, spatial learning and memory were assessed using a virtual Morris Water Maze task.Individuals with MDD and healthy controls did not differ in spatial learning and memory performance. Neither separate nor combined MR or NMDA-R stimulation altered measures of spatial performance.In this study of relatively young, predominantly female, and unmedicated individuals, we found no effect of MDD and no effect of separate or combined MR and NMDA-R stimulation on spatial learning and memory.

Stress plays a fundamental role in the development and maintenance of major depressive disorder (MDD). Importantly, maladaptive changes in the physiological stress regulation systems have been demonstrated. In the locus coeruleus-noradrenergic (LC-NA) system, up-regulated central alpha2-adrenergic receptors in patients with MDD affect cognitive functions. Although cognitive deficits are core symptoms of MDD, the relationship between the LC-NA system and cognitive processes has rarely been investigated in depressed patients. The aim of our study was to investigate whether noradrenergic stimulation affects cognitive flexibility in MDD. In addition, we aimed to further disentangle the effects of MDD and adverse childhood experiences (ACE), such as physical or sexual abuse on cognitive function. In a double-blind placebo-controlled study, MDD patients with ACE, MDD patients without ACE, healthy participants with ACE and healthy control participants without MDD or ACE were tested with a task switching task (total N = 125). Participants were tested twice after treatment with either 10 mg yohimbine or a placebo. Switch costs (differences between switch and repetition trials) in reaction times and accuracy served as the independent variables. We found higher switch costs in MDD patients as compared with controls, while ACE did not affect task performance. Yohimbine administration had no effect on task switching. The results of this study contribute to a better understanding of the role of the LC-NA system as a neurobiological mechanism of cognitive processes in patients with MDD.