Genetic, molecular and clinical determinants for the involvement of aldosterone and its receptors in major depression.

Major depression (MDE) has metabolic and neuroendocrine correlates, which point to a biological overlap between MDE and cardiovascular diseases. Whereas the hypothalamic-pituitary-adrenocortical axis has long been recognized for its involvement in depression, the focus was mostly on cortisol/corticosterone, whereas aldosterone appears to be the 'forgotten' stress hormone. Part of the reason for this is that the receptors for aldosterone, the mineralocorticoid receptors (MR), were thought to be occupied by glucocorticoids in most parts of the brain. However, recently it turned out that aldosterone acts selectively in relevant mood-regulating brain areas, without competing with cortisol/corticosterone. These areas include the nucleus of the solitary tract (NTS), the amygdala and the paraventricular nucleus of the hypothalamus. These regions are intimately involved in the close relationship between emotional and vegetative symptoms. Genetic analysis supports the role of aldosterone and of MR-related pathways in the pathophysiology of depression. Functional markers for these pathways in animal models as well as in humans are available and allow an indirect assessment of NTS function. They include heart rate variability, baroreceptor reflex sensitivity, blood pressure, salt taste sensitivity and slow-wave sleep. MR activation in the periphery is related to electrolyte regulation. MR overactivity is a risk factor for diabetes mellitus and a trigger of inflammatory processes. These markers can be used not only to assist the development of new treatment compounds, but also for a personalized approach to treat patients with depression and related disorders by individual dose titration with an active medication, which targets this system.

Brain ventricle and choroid plexus morphology as predictor of treatment response in major depression: Findings from the EMBARC study.

Recent observations suggest a role of the volume of the cerebral ventricle volume, corpus callosum (CC) segment volume, in particular that of the central-anterior part, and choroid plexus (CP) volume for treatment resistance of major depressive disorder (MDD). An increased CP volume has been associated with increased inflammatory activity and changes in the structure of the ventricles and corpus callosum. We attempt to replicate and confirm that these imaging markers are associated with clinical outcome in subjects from the EMBARC study, as implied by a recent pilot study. The EMBARC study is a placebo controlled randomized study comparing sertraline vs. placebo in patients with MDD to identify biological markers of therapy resistance. Association of baseline volumes of the lateral ventricles (LVV), choroid plexus volume (CPV) and volume of segments of the CC with treatment response after 4 weeks treatment was evaluated. 171 subjects (61 male, 110 female) completed the 4 week assessments; gender and age were taken into account for this analyses. As previously reported, no treatment effect of sertraline vs. placebo was observed, therefore the study characterized prognostic markers of response in the pooled population. Change in depression severity was identified by the ratio of the Hamilton-Depression rating scale 17 (HAMD-17) at week 4 divided by the HAMD-17 at baseline (HAMD-17 ratio). Volumes of the lateral ventricles and choroid plexi were positively correlated with the HAMD-17 ratio, indication worse outcome with larger ventricles and choroid plexus volumes, whereas the volume of the central-anterior corpus callosum was negatively correlated with the HAMD-17 ratio. Responders (n = 54) had significantly smaller volumes of the lateral ventricles and CP compared to non-responders (n = 117), whereas the volume of mid-anterior CC was significantly larger compared to non-responders (n = 117), confirming our previous findings. In an exploratory way associations between enlarged LVV and CPV and signs of lipid dysregulation were observed. In conclusion, we confirmed that volumes of lateral ventricles, choroid plexi and the mid-anterior corpus callosum are associated with clinical improvement of depression and may be indicators of metabolic/inflammatory activity.

Treatment with Glycyrrhiza glabra Extract Induces Anxiolytic Effects Associated with Reduced Salt Preference and Changes in Barrier Protein Gene Expression.

We have previously identified that low responsiveness to antidepressive therapy is associated with higher aldosterone/cortisol ratio, lower systolic blood pressure, and higher salt preference. Glycyrrhiza glabra (GG) contains glycyrrhizin, an inhibitor of 11ß-hydroxysteroid-dehydrogenase type-2 and antagonist of toll-like receptor 4. The primary hypothesis of this study is that food enrichment with GG extract results in decreased anxiety behavior and reduced salt preference under stress and non-stress conditions. The secondary hypothesis is that the mentioned changes are associated with altered gene expression of barrier proteins in the prefrontal cortex. Male Sprague-Dawley rats were exposed to chronic mild stress for five weeks. Both stressed and unstressed rats were fed a diet with or without an extract of GG roots for the last two weeks. GG induced anxiolytic effects in animals independent of stress exposure, as measured in elevated plus maze test. Salt preference and intake were significantly reduced by GG under control, but not stress conditions. The gene expression of the barrier protein claudin-11 in the prefrontal cortex was increased in control rats exposed to GG, whereas stress-induced rise was prevented. Exposure to GG-enriched diet resulted in reduced ZO-1 expression irrespective of stress conditions. In conclusion, the observed effects of GG are in line with a reduction in the activity of central mineralocorticoid receptors. The treatment with GG extract or its active components may, therefore, be a useful adjunct therapy for patients with subtypes of depression and anxiety disorders with heightened renin-angiotensin-aldosterone system and/or inflammatory activity.

Sleep disturbances in primary aldosteronism are associated to depressive symptoms - Could specific mineralocorticoidreceptors be a common pathway?

Symptoms of depression and anxiety are frequent in patients with primary aldosteronism (PA) and are supposed to be independent risk factors for cardiovascular diseases (CVD). As patients with PA have an increased cardiovascular risk compared to patients with essential hypertension, sleep disturbances, which often accompany depressive and anxiety symptoms, may be an additional contributor to the cardiometabolic consequences of PA. To clarify this possible link we investigated 132 patients with PA at baseline and after one year after initiation of treatment either by adrenalectomy (ADX) or mineralocorticoid-receptor-antagonist (MRA). Sleep disturbances and daytime sleepiness were assessed with Pittsburg sleep Inventory (PSQI) and Epworth sleepiness scale (ESS). Patients with PA showed pathological scores for sleep disturbances at baseline according to PSQI, with females being more affected (8.1 vs. 5.7 p < 0.001), which was significantly improved after initiation of specific treatment (p = 0.002). For ESS we found scores within the normal range, but higher than the general population, which significantly improved at follow-up (p < 0.001). The intensity of sleep disturbances was highly correlated with scores of anxiety and depression at baseline and follow-up. However, clinical and biochemical markers of PA (e.g. aldosterone, blood pressure) and metabolic markers did not show a consistent association with sleep changes. The degree of improvement in PSQI was significantly associated with the improvement of brief patients health questionnaire (PHQD) (p = 0.0151). Sleep disturbances seem not to be an independent risk factor for cardiovascular and metabolic problems in PA. They are strongly associated to depressive symptoms and maybe mediated by the same mineralocorticoid receptor circuits.

A viewpoint on aldosterone and BMI related brain morphology in relation to treatment outcome in patients with major depression.

An abundance of knowledge has been collected describing the involvement of neuroendocrine parameters in major depression. The hypothalamic-pituitary-adrenocortical (HPA) axis regulating cortisol release has been extensively studied; however, attempts to target the HPA axis pharmacologically to treat major depression have failed. This review focuses on the importance of the adrenocortical stress hormone aldosterone, which is released by adrenocorticotropic hormone and angiotensin, and the mineralocorticoid receptor (MR) in depression. Depressed patients, in particular those with atypical depression, have signs of central hyperactivation of the aldosterone sensitive MR, potentially as a consequence of a reactive aldosterone release induced by low blood pressure and as a result of low sensitivity of peripheral MR. This is reflected in reduced heart rate variability, increased salt appetite and sleep changes in this group of patients. In addition, enlarged brain ventricles, compressed corpus callosum and changes of the choroid plexus are associated with increased aldosterone (in relation to cortisol). Furthermore, subjects with these features often show obesity. These characteristics are related to a worse antidepressant treatment outcome. Alterations in choroid plexus function as a consequence of increased aldosterone levels, autonomic dysregulation, metabolic changes and/or inflammation may be involved. The characterization of this regulatory system is in its early days but may identify new targets for therapeutic interventions.

Brain Ventricle and Choroid Plexus Morphology as Predictor of Treatment Response: Findings from the EMBARC Study.

Recent observations suggest a role of the choroid plexus (CP) and cerebral ventricle volume (CV), to identify treatment resistance of major depressive disorder (MDD). We tested the hypothesis that these markers are associated with clinical improvement in subjects from the EMBARC study, as implied by a recent pilot study. The EMBARC study characterized biological markers in a randomized placebo-controlled trial of sertraline vs. placebo in patients with MDD. Association of baseline volumes of CV, CP and of the corpus callosum (CC) with treatment response after 4 weeks treatment were evaluated. 171 subjects (61 male, 110 female) completed the 4 week assessments; gender, site and age were taken into account for this analyses. As previously reported, no treatment effect of sertraline was observed, but prognostic markers for clinical improvement were identified. Responders (n = 54) had significantly smaller volumes of the CP and lateral ventricles, whereas the volume of mid-anterior and mid-posterior CC was significantly larger compared to non-responders (n = 117). A positive correlation between CV volume and CP volume was observed, whereas a negative correlation between CV volume and both central-anterior and central-posterior parts of the CC emerged. In an exploratory way correlations between enlarged VV and CP volume on the one hand and signs of metabolic syndrome, in particular triglyceride plasma concentrations, were observed. A primary abnormality of CP function in MDD may be associated with increased ventricles, compression of white matter volume, which may affect treatment response speed or outcome. Metabolic markers may mediate this relationship.

Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder.

The potential role of aldosterone in the pathophysiology of depression is unclear. The aim of this study was to test the hypothesis that prolonged elevation of circulating aldosterone induces depression-like behaviour accompanied by disease-relevant changes in gene expression in the hippocampus. Subchronic (2-wk) treatment with aldosterone (2 µg/100 g body weight per day) or vehicle via subcutaneous osmotic minipumps was used to induce hyperaldosteronism in male rats. All rats (n = 20/treatment group) underwent a modified sucrose preference test. Half of the animals from each treatment group were exposed to the forced swim test (FST), which served both as a tool to assess depression-like behaviour and as a stress stimulus. Affymetrix microarray analysis was used to screen the entire rat genome for gene expression changes in the hippocampus. Aldosterone treatment induced an anhedonic state manifested by decreased sucrose preference. In the FST, depressogenic action of aldosterone was manifested by decreased latency to immobility and increased time spent immobile. Aldosterone treatment resulted in transcriptional changes of genes in the hippocampus involved in inflammation, glutamatergic activity, and synaptic and neuritic remodelling. Furthermore, aldosterone-regulated genes substantially overlapped with genes affected by stress in the FST. This study demonstrates the existence of a causal relationship between the hyperaldosteronism and depressive behaviour. In addition, aldosterone treatment induced changes in gene expression that may be relevant to the aetiology of major depressive disorder. Subchronic treatment with aldosterone represents a new animal model of depression, which may contribute to the development of novel targets for the treatment of depression.

The neurobiology of childhood trauma-aldosterone and blood pressure changes in a community sample.

OBJECTIVE: Childhood trauma is an important risk factor for the onset and course of psychiatric disorders and particularly major depression. Recently, the renin-angiotensin-aldosterone system, one of the core stress hormone systems, has been demonstrated to be modified by childhood trauma. METHODS: Childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ) in a community-dwelling sample (N = 2038). Plasma concentrations of renin and aldosterone were measured in subjects with childhood trauma (CT; N = 385) vs. subjects without this experience (NoCT; N = 1653). Multivariable linear regression models were calculated to assess the associations between CTQ, systolic and diastolic blood pressure, renin and aldosterone concentrations, and the ratio of aldosterone and systolic blood pressure (A/SBP). RESULTS: CT subjects demonstrated higher plasma aldosterone (A) concentrations, a lower systolic and diastolic blood pressure, and a higher A/SBP. In addition, both aldosterone concentrations, as well as A/SBP, correlated with the severity of childhood trauma. These findings could not be attributed to differences in concomitant medication. CONCLUSIONS: In conclusion, childhood trauma was associated with neurobiological markers, which may impact the risk for psychiatric disorders, primarily major depression. The altered A/SBP ratio points to a desensitisation of peripheral mineralocorticoid receptor function, which may be a target for therapeutic interventions.

Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from the early medication change trial in major depressive disorder.

OBJECTIVES: Previous studies indicated a relationship between aldosterone, the mineralocorticoid receptor (MR), and antidepressant treatment outcome. Physiological indicators of MR function (blood pressure and electrolytes) are easily accessible and may therefore serve as useful predictors. Thus, our aim was to investigate the predictive value of peripheral MR-related markers for antidepressant treatment outcomes. METHODS: 826 MDD patients who had participated in the randomised-controlled Early Medication Change (EMC) trial were analysed. Depression severity and MR-related markers were assessed weekly. In 562 patients, genetic variation of five MR-related genes was determined. RESULTS: Patients with blood pressure <120mmHg showed higher depression severity (p = 0.005) than patients with blood pressure ≥120mmHg. Patients with a melancholic subtype had significantly lower blood pressures (p = 0.004). Na+/K+ ratio was positively and K+-concentration was negatively correlated to depression severity and to relative changes in HAMD from baseline to day 14, and 56 respectively (p < 0.001). For none of the MR-related genes, genetic variation was associated with treatment outcomes. CONCLUSIONS: We confirmed early observations of an altered peripheral MR sensitivity, reflected by lower blood pressure, low K+ or high Na+/K+ ratio in patients with more severe depression. These routinely collected biomarkers may potentially be useful for risk stratification in an early stage of treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00974155; https://www.clinicaltrials.gov/ct2/results?term=NCT00974155.

Differential central regulatory mineralocorticoidreceptor systems for anxiety and depression - Could KCNJ5 be an interesting target for further investigations in major depression?

The mineralocorticoid receptor (MR) is suggested to play a role in the pathophysiology of depression and anxiety. Main support comes from studies in patients with primary aldosteronism (PA) which suggested different central pathways for depression and anxiety mediated via the MR and gender differences. We investigated 118 patients with PA over 3 years using self-rating questionnaires for anxiety (GAD-7) and depression (PHQD) at baseline and once a year under specific treatment with adrenalectomy (ADX; n = 48) or a MR antagonist (MRA; n = 70). Genotyping for KCNJ5 mutation was performed in resected tumors. At baseline, patients treated by ADX or MRA had comparable scores for anxiety and depression. Females showed a better metabolic profile but higher scores of depression and anxiety, compared to males. Initiation of specific treatment for PA resulted in a better response in depressive symptoms after ADX and of anxiety under MRA treatment. However, GAD-7 and PHQD remained high in women over the three-year follow-up. KCNJ5 mutation, linked to co-secretion of hybrid steroids as 18-oxocortisol and 18-hydroxycortisol, was detected in 10 female and 2 male patients. They tended to have higher GAD and PHQD scores at baseline compared to patients without KNCJ5 mutation, but showed a significant better reduction in symptoms of anxiety during the 3-year follow up compared to patients without this mutation (all p < 0.05). These data support a differentiated regulation of depression and anxiety by the MR. Moreover, genetic mutations such as KCNJ5 could affect the pathophysiology of these disorders by impacting in adrenal steroidogenesis.

Food Enrichment with Glycyrrhiza glabra Extract Suppresses ACE2 mRNA and Protein Expression in Rats-Possible Implications for COVID-19.

Angiotensin converting enzyme 2 (ACE2) is a key entry point of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus known to induce Coronavirus disease 2019 (COVID-19). We have recently outlined a concept to reduce ACE2 expression by the administration of glycyrrhizin, a component of Glycyrrhiza glabra extract, via its inhibitory activity on 11beta hydroxysteroid dehydrogenase type 2 (11betaHSD2) and resulting activation of mineralocorticoid receptor (MR). We hypothesized that in organs such as the ileum, which co-express 11betaHSD2, MR and ACE2, the expression of ACE2 would be suppressed. We studied organ tissues from an experiment originally designed to address the effects of Glycyrrhiza glabra extract on stress response. Male Sprague Dawley rats were left undisturbed or exposed to chronic mild stress for five weeks. For the last two weeks, animals continued with a placebo diet or received a diet containing extract of Glycyrrhiza glabra root at a dose of 150 mg/kg of body weight/day. Quantitative PCR measurements showed a significant decrease in gene expression of ACE2 in the small intestine of rats fed with diet containing Glycyrrhiza glabra extract. This effect was independent of the stress condition and failed to be observed in non-target tissues, namely the heart and the brain cortex. In the small intestine we also confirmed the reduction of ACE2 at the protein level. Present findings provide evidence to support the hypothesis that Glycyrrhiza glabra extract may reduce an entry point of SARS-CoV-2. Whether this phenomenon, when confirmed in additional studies, is linked to the susceptibility of cells to the virus requires further studies.

Ventricular volume, white matter alterations and outcome of major depression and their relationship to endocrine parameters - A pilot study.

OBJECTIVES: Brain morphology and its relation to endocrine parameters were examined, in order to determine the link of these parameters to treatment outcome to psychopharmacological treatment in depressed patients. METHODS: We examined the potentially predictive value of Magnetic Resonance Imaging (MRI) parameters related to mineralocorticoid receptor (MR) function on the treatment outcome of depression. 16 inpatients with a major depressive episode (MDE) were studied at baseline and 14 of them approximately six weeks later. Physiological biomarkers and 3-T-structural MRI based volume measures, using FreeSurfer 6.0 software, were determined. RESULTS: Non-responders (<50% reduction of HAMD-21; n = 6) had a significantly smaller volume of the right anterior cingulate cortex, a significantly larger ventricle to brain ratio (VBR) and third ventricle volume, and smaller volumes of the central and central-anterior corpus callosum (CC) in comparison to responders (n = 7; all p ≤ 0.05). Correlational analysis (Spearman) demonstrated that larger ventricle volume was correlated to a worse treatment outcome, higher body mass index (BMI) and smaller CC segment volume, whereas the total CC volume was negatively correlated to the saliva aldosterone/cortisol concentration ratio (AC-ratio). CONCLUSION: Large ventricular volume may be a predictive marker for worse treatment response to standard antidepressant treatment, potentially via compression of white matter structures. A mediating role of the previously identified markers BMI and the AC-ratio, is suggested.

Early onset of depression and treatment outcome in patients with major depressive disorder.

Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.

Differential effects of reduced mineralocorticoid receptor activation by unilateral adrenalectomy vs mineralocorticoid antagonist treatment in patients with primary aldosteronism - Implications for depression and anxiety.

The mineralocorticoid receptor (MR) and its ligand aldosterone have been found to play a major role in the pathophysiology of depression. Both could be targets of therapeutic interventions. We analyzed laboratory data and questionnaires evaluating anxiety (using GAD-7 questionnaire) and depression (using PHQD questionnaire) of up to 210 patients with primary aldosteronism (PA) (82 females, 54.7 ± 12.0yrs; 128 males, 48.7 ± 12.8yrs) before and one year after initiation of specific treatment of PA by either adrenalectomy (ADX) or treatment with mineralocorticoid receptor antagonists (MRA). After ADX normalization of aldosterone excess was observed. This was associated with a significant reduction of depressive symptoms, but no significant change in GAD-7 score. MRA treatment was accompanied with persistent high aldosterone levels, but led to a significant improvement of anxiety, but no significant changes in PHQD scores. These data suggest different mechanistic pathways for depression and anxiety mediated via the MR. For treatment of depression a reduction of aldosterone levels might be relevant at CNS locations specific for aldosterone, whereas MRA targets MR more broadly, including areas, where cortisol is the main ligand. MRA may be useful in treatment of anxiety related behavior.

Symptomatic Protective Action of Glycyrrhizin (Licorice) in COVID-19 Infection?

The role of the ACE2 enzyme in the COVID-19 infection is 2-fold, with opposing implications for the disease development. 1. The membrane bound angiotensin converting enzyme 2 (ACE2) serves as the entry point of COVID-19 2. Conversely, it supports an anti-inflammatory pathway. This led to the controversy of the impact of medications, which influence its expression. ACE2 is part of the wider renin-angiotensin-aldosterone system (RAAS) and is upregulated via compounds, which inhibits the classical ACE, thereby plasma aldosterone and aldosterone receptor (MR) activation. MR activation may therefore protect organs from binding the COVID-19 by reducing ACE2 expression. Glycyrrhizin (GL) is a frequent component in traditional Chinese medicines, which have been used to control COVID-19 infections. Its systemically active metabolite glycyrrhetinic acid (GA) inhibits 11beta hydroxysteroid dehydrogenase(11betaHSD2) and activates MR in organs, which express this enzyme, including the lungs. Does this affect the protective effect of ACE2? Importantly, GL has anti-inflammatory properties by itself via toll like receptor 4 (TLR4) antagonism and therefore compensates for the reduced protection of the downregulated ACE2. Finally, a direct effect of GL or GA to reduce virus transmission exists, which may involve reduced expression of type 2 transmembrane serine protease (TMPRSS2), which is required for virus uptake. Glycyrrhizin may reduce the severity of an infection with COVID-19 at the two stages of the COVID-19 induced disease process, 1. To block the number of entry points and 2. provide an ACE2 independent anti-inflammatory mechanism.

Adjunct Therapy With Glycyrrhiza Glabra Rapidly Improves Outcome in Depression-A Pilot Study to Support 11-Beta-Hydroxysteroid Dehydrogenase Type 2 Inhibition as a New Target.

Mineralocorticoid-receptor (MR) dysfunction as expressed by low systolic blood pressure and a high salivary aldosterone/cortisol ratio predicts less favorable antidepressant treatment outcome. Inhibition of peripheral 11-beta-hydroxysteroid-dehydrogenase type 2 (11betaHSD2) reverses these markers. We therefore tested the hypothesis that the 11betaHSD2 inhibitor glycyrrhizin affects treatment outcome via this mechanism. We administered Glycyrrhiza glabra (GG) extract containing 7-8 % of glycyrrhizin at a dose of 2 × 700 mg daily adjunct to standard antidepressants in hospitalized patients with major depression. These subjects were compared in an open-label fashion with patients, who did not receive GG (treatment as usual, TAU). Assessments were done at baseline and approximately 2 weeks after. Twelve subjects were treated with GG and compared to 55 subjects with TAU. At week 2, the Hamilton Depression Rating Scale (HAMD-21) change from baseline as well as the CGI-S change showed a significant time × treatment interaction (p < 0.03), indicating a possible therapeutic benefit of GG. Clinical benefit seems to be more pronounced in subjects with lower systolic blood pressure and significantly correlated with reduced sleep duration in the GG group. Our preliminary data show that treatment with the 11betaHSD2 inhibitor glycyrrhizin may possess a beneficial effect on antidepressant response, which may be specific to a defined depression subtype.

The potential pathophysiological role of aldosterone and the mineralocorticoid receptor in anxiety and depression - Lessons from primary aldosteronism.

High levels of aldosterone appear to be related to depressive and anxiety related behavior as demonstrated in therapy refractory depression and primary aldosteronism (PA). We analyzed data from a large register of patients with PA in order to clarify mediators and moderators of this influence. Up to 624 subjects were analyzed, however not all subjects had a complete dataset. Due to the known gender differences in subjects with PA we performed the analyses adjusted for gender. We compared subjects with (PHQ-9 ≥ 5) vs. no depressive symptomatology. 56% of men and 61% of women met this depression criterion. In women aldosterone concentration was significantly higher in depressed patients and renin levels were significantly increased with higher anxiety scores. This was not found in men. Depressive symptoms in men and women were significantly associated to BMI (men: dep vs non-dep: 29.6 vs. 28.4, p < 0.05; women: 26.9 vs. 24.5) and body weight (p < 0.05). Neither blood pressure nor electrolytes were different between depression groups. The relationship of these parameters to anxiety was less pronounced and partially unexpected: only in men higher anxiety (GAD ≥ 5) was related to lower systolic blood pressure. In conclusion, higher aldosterone appears to be associated with depressive symptoms in women, but less so in men with PA. BMI appears to be strongly and independently associated with depressive symptoms in patients with PA, independent of gender. Further studies are required to clarify the causal relationship.

The glutamatergic system and its relation to the clinical effect of therapeutic-sleep deprivation in depression - an MR spectroscopy study.

Rapid improvement of depressive symptoms occurs after the administration of the NMDA antagonist ketamine. Ketamine administration is accompanied by an increase in GLX (sum-peak of glutamate, glutamine (GLN) and GABA) and GLN in the brain, as measured by magnetic-resonance (MR) spectroscopy. In healthy subjects, we observed an increase in GLX and GLN levels after total sleep deprivation (TSD), which has a rapid antidepressant effects. We examined, if an increase in GLX or GLN is related to the therapeutic effect of TSD. We examined 13 patients with major depression by means of proton MR spectroscopy (field strength: 1.5T) before and after 24h of TSD. Two anatomical areas (dorsolateral prefrontal cortex (DLPC) and parieto-occipital cortex (POC)) were studied. In the DLPC TSD did not change GLX or its elements, whereas the total creatine and choline signal increased marginally. No change could be observed in the POC. For further exploration we took gender and the presence of vegetative characteristics of melancholic depression into account, i.e. the presence of early morning awakening, appetite and weight loss was taken into account, to define vegetative melancholia (VM). TSD led to an increase in GLX and GLN in the DLPC only of male patients. In patients with VM an increase in GLN occurred in this area. The low field strength limits the accuracy for GLX and GLN estimates. Despite the exploratory nature of the study, it nevertheless supports earlier data on the importance of glutamatergic neurotransmission and furthermore of gender and/or vegetative features in depression.

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

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 (P<0.05). SWS increase after 2 and 6 weeks was by trend (P<0.08) correlated to clinical improvement after 6 weeks. Systolic blood pressure differentiated responders and nonresponders at baseline (P<0.05), 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 (P<0.07) and 6 (P<0.07) weeks. Further, a trend toward RSA reduction (P<0.07) 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.

Mineralocorticoid receptor-related markers and outcome of major depression: focus on blood pressure and electrolytes.

A close association between vegetative regulation and affect is common knowledge. Recently, the role of aldosterone and the activity of its receptor [mineralocorticoid receptor (MR)] in the clinical outcome for treatment with standard antidepressants has been shown including low systolic blood pressure and a low concentration of plasma sodium (Na), both of which appear to be related to therapy resistance to standard antidepressants. We carried out a retrospective analysis of a double-blind placebo-controlled trial of St John's wort extract LI160 in 247 outpatients with major depression. The study did not show a difference between the treatment groups; therefore, a pooled dataset of the 6-week completer population of the trial was analyzed. The focus was on the moderating effect of blood pressure and electrolytes on clinical outcome (relative change in Montgomery-Asberg Depression Rating Scale). Low Na/K ratio and high K at screening predicted worse outcome after 6 weeks as measures with the Montgomery-Asberg Depression Rating Scale (P<0.01). Systolic blood pressure at the same time point did not influence the treatment outcome. In conclusion, signs of reduced peripheral MR sensitivity, as reflected by a lower plasma Na/K ratio and/or higher K concentration, predict worse outcome. This is in line with our recent data as well as neuroendocrine findings. The data indicate that widely collected biomarkers, which are related to MR activity, may be useful to identify patients, who are at risk of nonresponse to antidepressant treatment.