Mineralocorticoid receptor activation and depression severity in early antidepressant treatment: longitudinal insights from the EMC study cohort

Introduction

The Dysregulation of the hypothalamic pituitary adrenal (HPA) axis is a consistent finding in major depressive disorder (MDD) [1]. The renin angiotensin aldosterone system (RAAS) is also discussed, as relevant to the pathophysiology of major depressive disorder and treatment response particularly in certain subgroups [2]. The mineralocorticoid receptor (MR), which binds glucocorticoids (cortisol) and mineralocorticoids (aldosterone), modulates HPA activity and thereby influences stress responses suggesting a plausible link to the occurrence of depressive symptoms and MDD severity. As a measure of MR activation, previous publications used the ratio of aldosterone to cortisol as a functional marker [3]. The aim of this presented analysis is to investigate longitudinal associations between MR activation and progression of depression severity during the early treatment phase of major depressive disorder.

Methods

In this secondary analysis of the Early Medication Change (EMC) cohort, morning cortisol and aldosterone levels were measured at baseline (BL) and after four weeks of antidepressant treatment in a sample of N = 474 patients (x̄ = 40.6 years; 57,6 % female). Depression was assessed weekly by trained clinical staff using the Hamilton Depression Scale (HAMD 17). Statistical analysis was performed using a linear mixed effects model comprising of HAMD Scores (dependent variable) and the MR activation (independent variable) as well as relevant covariates (age, sex, body mass index, smoking status). Statistical Analysis was performed in R Studio (Version 4.5.1) using the lme 4 package.

Results

The mixed effects model revealed a significant main effect of time (β = -10.81, p < .001), but no significant interaction between time and the aldosterone to cortisol ratio (MR activation) (p = 0.3). None of the Covariates displayed statistical significance. Thus, no longitudinal associations between MR activation and the development of MDD severity were identified during the early phase of treatment. Furthermore, the model did not show any significant cross sectional associations between MDD severity and MR activation.

Conclusions

The results serve as evidence against a direct association between MR activation and disease progression during the early treatment phase of major depressive disorder. This finding may indicate that there is indeed no meaningful effect of MR activation on early disease trajectories concerning the Early Medication Change Cohort. Alternatively, the aldosterone / cortisol ratio used in this study may not represent a sufficiently sensitive or specific proxy for central MR activation, given the complex regulation of the receptor beyond peripheral hormone levels. However, subgroup specific effects remain conceivable, as alterations in MR related pathways may only be present in a subset of patients. A further, subgroup specific analysis of the longitudinal association is still pending at the moment and will be presented at the conference.

References

1. Holsboer, F. (2001). Stress, hypercortisolism and corticosteroid receptors in depression: implicatons for therapy. Journal Of Affective Disorders, 62(1–2), 77–91. https://doi.org/10.1016/s0165-0327(00)00352-9
2. Häfner, S., Baumert, J., Emeny, R., Lacruz, M., Bidlingmaier, M., Reincke, M., Kuenzel, H., Holle, R., Rupprecht, R. & Ladwig, K. (2011). To live alone and to be depressed, an alarming combination for the renin–angiotensin–aldosterone-system (RAAS). Psychoneuroendocrinology, 37(2), 230–237. https://doi.org/10.1016/j.psyneuen.2011.06.007
3. Ustohal, L., Hlavacova, N., Mayerova, M., Ceskova, E. & Jezova, D. (2018). Aldosterone and aldosterone/cortisol ratio is higher in serum of long-term compared to first episode schizophrenia patients: A pilot study. Journal of Psychiatric Research, 104, 36-49. https://doi.org/10.1016/j.psychires.2018.06.021