Markers of mineralocorticoid receptor function: changes over time and relationship to response in patients with major depression

摘要

The renin-angiotensin-aldosterone system and its hormone receptors, i.e. the angiotensin and mineralocorticoid receptor (MR), have emerged as important targets for central nervous system disorders and in particular for major depression. We have recently characterized baseline MR function as a predictor for treatment outcome with standard antidepressants. The aims of this study are (i) to characterize how strongly an early biomarker change (after 2 weeks) is related to outcome and (ii) whether these biomarker changes are related to the final outcome, that is, could serve as surrogate markers for response. Twenty-four of 30 patients with unipolar major depression completed the observational trial. MR-related biomarkers were assessed at baseline, 2 weeks, and 6 weeks of standard antidepressant treatment. These biomarkers included slow wave sleep (SWS), salivary cortisol and aldosterone after awakening, heart rate variability measured as respiratory sinus arrhythmia (RSA), systolic blood pressure, salt taste intensity (STI), salt pleasantness (SP), and plasma electrolytes. The Hamilton depression rating scale with 21 items was primarily used to determine depression severity. In the overall sample, STI increased and SP decreased significantly with treatment without a clear relationship with treatment outcome. No other significant changes were observed. Reductions in cortisol and aldosterone after 2 weeks of treatment were significantly related to improvement after 6 weeks (P0.05). SWS increase after 2 and 6 weeks was by trend (P0.08) correlated to clinical improvement after 6 weeks. Systolic blood pressure differentiated responders and nonresponders at baseline (P0.05), but did not change significantly during treatment. We earlier identified a relationship between clinical outcome and baseline values of STI, SP, and RSA only in male patients; therefore, changes in this subgroup were analyzed separately: in male treatment responders, a trend toward an increase in SWS occurred after 2 (P0.07) and 6 (P0.07) weeks. Further, a trend toward RSA reduction (P0.07) was observed. Changes in STI and SP were similar to the total group, but did not reach levels of significance. Early changes in central MR-related biomarkers appear to influence the outcome of standard antidepressant treatment: reduced salivary cortisol, increased SWS, and reduced RSA are linked to a better treatment outcome. These features point to a mechanism involving increased central MR activation in responders to standard antidepressants, but not in nonresponders.