Major depressive disorder
MDD is one of the most prevalent mental disorders (Otte et al. , 2016). A major depressive episode has depressed mood and/or loss of interest or pleasure as its core symptoms. Cognitive deficits, such as memory complaints and lack of concentration are also frequent in MDD (Bora et al. , 2013; Rock et al. , 2014) and some studies suggest an association between elevated cortisol and cognitive impairments (Gomez et al. , 2006; Hinkelmann et al. , 2009). Endocrine features often include increased basal cortisol release, reduced feedback sensitivity and changes in GR function (Holsboer and Ising, 2009; Otte et al. , 2016). In addition to high cortisol levels in MDD patients, enhanced aldosterone secretion was reported (Nowacki, Wingenfeld, Kaczmarczyk, Chae, Salchow, et al. , 2020), as was decreased MR expression in the hippocampus and prefrontal cortex (Melanie D Klok et al. , 2011; Medina et al. , 2013; Qiet al. , 2013).
Haplotypes of single nucleotide polymorphisms (SNPs) of the MR gene (NR3C2) have been associated with depression (M D Klok et al. , 2011) and cognitive function (Keller et al. , 2017). An association between MR polymorphisms and emotional memory has been reported in remitted MDD patients (Vrijsen et al. , 2015). Interestingly, this association was more prevalent with a history of childhood trauma, which fits nicely to an earlier study in adolescents (Bogdan, Williamson and Hariri, 2012). In general, the gain of function haplotype (CA), by MR-2G/C and MRI180V, has a protective effect in all these aspects.
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Interestingly, cognitive empathy scores were higher in patients with MDD compared with controls in the placebo condition but not after single administration of spironolactone (Wingenfeld et al. , 2016). Thus, MR blockade appeared to ‘normalise’ cognitive empathy in MDD patients. Together, these findings fit to the model presented in figure 3, hypothesizing that enhanced MR signalling due to increased cortisol secretion might be responsible for some aspects of impaired cognition in MDD patients. Future studies should therefore investigate whether treatment with MR antagonists might exert beneficial effects on cognitive symptoms in MDD.
Given that several studies have demonstrated acute beneficial effects on cognition in healthy humans, it is plausible that MR stimulation with fludrocortisone could improve cognitive performance in MDD. A dedicated study found promising initial results: relatively young medication-free patients with MDD as well as healthy control individuals showed improved verbal memory and executive function after one-time administration of fludrocortisone compared with placebo (Otte, Wingenfeld, Kuehl, Richter,et al. , 2015). However, a recent study tested if such effects could be extended to depression-related emotionally salient stimuli, but there was no effect of fludrocortisone on selective attention to emotional stimuli or on facial emotion recognition in MDD and healthy controls (Nowacki et al. , 2021).
In sum, the available few studies suggest that (acute) MR effects in MDD differ depending on the cognitive domain that is examined. Further age and sex seem to be important moderators in this respect (Hinkelmannet al. , 2015; Otte, Wingenfeld, Kuehl, Kaczmarczyk, et al. , 2015). Finally, the MDD population is heterogenous with melancholic, psychotic, or anxious subtypes. Some evidence suggests MR alterations are most pronounced in patients with psychotic symptoms or treatment resistance (Juruena et al. , 2013; Lembke et al. , 2013).