A common mineralocorticoid receptor polymorphism (I180V) interacts with life events in relation to perfectionism in eating disorders: a pilot study.

The stress response is regulated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). When the balance between GR and MR signalling is disturbed, one's capacity to cope with a stressful event is diminished. In this pilot study, we tested the hypothesis that an interaction between common variants in the MR (rs5522) or GR gene (rs41423247) and stressful life events influences perfectionism levels in a group of patients with an eating disorder (ED; n = 113). Patients carrying the minor G allele of rs5522 had a higher perfectionism score if more stressful life events were experienced [ß = 0.95, t(109) = 3.75, p < 0.01]. This effect was not found for patients carrying the AA genotype. These results suggest that rs5522 G allele carriers might be vulnerable to stressful life events. When patients with an ED are carriers and experience multiple life events, this might fuel their insecurity, which in turn may engender higher levels of perfectionism. Further studies are necessary to replicate and expand our findings.

C-reactive protein polymorphisms are associated with the cortisol awakening response in basal conditions in human subjects.

Cortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present study, associations were explored between CRP haplotypes with plasma CRP concentrations and basal salivary cortisol level. We included 266 physically healthy Caucasian subjects (103 females and 163 males) aged between 18 and 65 years of whom 94 had a psychiatric disorder in a genetic association study. Six tag single-nucleotide polymorphisms capturing the common genetic variation of the CRP gene were genotyped (i.e. rs2808628, rs2808630, rs1205, rs1800947, rs1417938, and rs3091244) to yield common CRP haplotypes. Plasma CRP concentrations, the salivary cortisol awakening response (CAR) (0, 30, 45, and 60?min after awakening), and the diurnal cortisol decline (11:00, 15:00, 19:00, and 23:00 h) were assessed for 2 days. rs2808628, rs1205, rs1417938, and rs3091244 showed expected associations not only with CRP concentrations, but also with salivary cortisol levels during the CAR. Five well-characterized CRP haplotypes were arranged in ascending order according to increasing CRP levels. There was an inverse linear association between CRP haplotypes and cortisol levels during the CAR, but no association with the diurnal cortisol decline. Hence, genetic variants in the CRP gene that are associated with lifetime plasma CRP levels were also associated with salivary cortisol levels after awakening, in basal, non-inflammatory conditions.

Basal cortisol levels in relation to dimensions and DSM-IV categories of depression and anxiety.

The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety disorders. Continuous phenotypic dimensions may correlate better with underlying neuroendocrine dysregulations. We compared the categorical DSM-IV diagnoses with a dimensional approach in the same group of outpatients with depressive (n=36), anxiety (n=18), and comorbid depressive and anxiety (n=19) disorders, who were free of psychotropic medication, and in 36 healthy controls. The Mood and Anxiety Symptom Questionnaire (MASQ) was used to measure the three dimensions of the tripartite model, i.e., anhedonic depression, anxious arousal, and general distress. The salivary cortisol awakening response (CAR) (0, 30, 45, and 60 min after awakening), and diurnal cortisol decline (11:00 h, 15:00 h, 19:00 h, and 23:00 h) were analyzed for linear and nonlinear associations. The CAR showed statistically significant nonlinear relationships with two MASQ dimensions, i.e., anhedonic depression and general distress, but no differences between DSM-IV categories. The diurnal cortisol decline was linearly related to the MASQ dimensions anhedonic depression and general distress and significantly higher AUC(diurnal) levels and a steeper slope were found in depressive patients compared to controls using DSM-IV categories. The present study shows that linear and nonlinear associations with salivary cortisol are detected when using phenotypic dimensions and may be complementary to phenotypic DSM-IV categories when doing neuroendocrine research.

Salivary cortisol levels in persons with and without different anxiety disorders.

OBJECTIVE: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to hypothalamic-pituitary-adrenal (HPA) axis activity, although results are scarce and inconsistent. No earlier studies have examined consistency of HPA axis findings across several anxiety subtypes and whether associations are state or trait dependent. METHODS: Data are derived from 1427 participants of the Netherlands Study of Depression and Anxiety. Three groups were compared: 342 control participants without psychiatric disorders; 311 persons with a remitted (no current) anxiety disorder (social phobia, generalized anxiety disorder, panic disorder); and 774 persons with a current anxiety disorder, as diagnosed using the Composite International Diagnostic Interview psychiatric interview. Cortisol levels were measured in seven saliva samples, determining the 1-hour cortisol awakening response, evening cortisol, and cortisol response after 0.5 mg of dexamethasone ingestion. RESULTS: Current anxiety disorder was associated with higher awakening cortisol levels (p = .002). These findings were mainly present for patients with panic disorder with agoraphobia and anxious patients with comorbid depressive disorder. Remitted anxiety only showed a trend toward higher morning cortisol (p = .08). No associations were observed for anxiety status and evening cortisol level or cortisol suppression after dexamethasone. CONCLUSIONS: This study showed a modest but significantly higher 1-hour cortisol awakening response among anxiety patients, which was driven by those with panic disorder with agoraphobia and those with comorbid depression.

Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder.

OBJECTIVES: In affective disorders, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is a frequently observed phenomenon. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR gene (NR3C1) may be at the base of the altered reaction of the HPA axis to stress and subsequently related to the development and course of affective disorders. The aim of our study is to evaluate associations between GR gene polymorphisms and bipolar disorder (BD). METHODS: In this study, 245 patients with BD were interviewed to confirm diagnosis and BD subtype. Data on medication use and sociodemographic details were also collected. The control group consisted of 532 healthy blood donors, from which data on sex and age were collected. To perform genotyping, blood was collected from all patients and healthy controls. RESULTS: A trend was found for a protective effect of the exon 9beta polymorphism (p = 0.14) and the TthIIII polymorphism (p < 0.05) on the manifestation of the disease. These effects were significantly influenced by male gender for both polymorphisms. Patients with BD and the A/G variant in exon 9beta had significantly fewer manic and hypomanic episodes than noncarriers (p < 0.05). No further associations were found with the other investigated GR gene polymorphisms and BD. These findings were not corrected for multiple comparisons. CONCLUSIONS: We conclude that the exon 9beta polymorphism and the TthIIII polymorphism of the GR gene may be associated with a protective effect on the clinical manifestation and course in patients with BD. Furthermore, no associations were found between the other studied GR gene polymorphisms and this disease.

Single nucleotide polymorphisms related to HPA axis reactivity.

A very important question in the neuroendocrinology of stress-related disorders is why some individuals thrive and others break down under similar adverse conditions. The hypothalamic-pituitary-adrenal (HPA) axis is the central component of the stress system, displaying extensive variability in reactivity among human subjects. Common gene variants have been associated with several changes in HPA axis reactivity. These gene variants are identified in the GABA(A) receptor, the mu-opioid receptor, the serotonin transporter, catechol O-methyltransferase (COMT), monoamine oxidase (MAOA), the alpha(2)-adrenergic receptor, brain-derived neurotrophic factor and the anginotensin-converting enzyme. Most extensively studied are genetic variants of the two central corticosteroid receptors, the high-affinity mineralocorticoid receptor (MR) and the lower-affinity glucocorticoid receptor (GR). In the GR, the TthIIII, NR3C1-1, ER22/23EK, N363S, BclI and the A3669G, and in the MR, the -2 G/C and the I180V all modify HPA axis responsiveness at several levels. As a result of these genetic variants, HPA axis reactivity will be changed exposing not only the brain but the whole body to suboptimal cortisol levels during challenges. We propose that these genetic variants which modulate HPA axis reactivity are part of the genetic makeup that determines individual stress responsivity and coping style, affecting vulnerability to disease.

Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience.

Why some individuals thrive and others break down under similar adverse conditions, is a central question in the neuroendocrinology of stress related psychopathology. The brain mineralocorticoid (MR) and glucocorticoid receptors (GR) operate in balance to coordinate behavioural, autonomic and neuroendocrine response patterns involved in homeostasis and health. Genetic variants of both the MR and GR have been functionally characterized. The four GR-gene single nucleotide polymorphisms (SNPs) (ER22/23EK (allele frequency: 3%), N363S (4%), BclI (37%), A3669G (15%)) and the two MR-gene SNPs (-2 G/C (50%), MR-I180V (11%)) showed in vitro changes in transactivational capacity, or affect stability of the mRNA (GR exon 9beta A3669G). All of these MR-and GR-SNPs change the regulation of the hypothalamus-pituitary-adrenal (HPA) axis at different levels including basal level (-2 G/C), dexamethasone induced negative feedback (ER22/23EK, N363S, BclI, 9beta A3669G) or following a psychosocial stress test (Trier Social Stress Test (TSST); all of the MR-and GR-SNPs). Importantly, the MR-I180V increased autonomic output and enhanced cortisol secretion during the TSST. Recently, several of these MR-and GR-variants have been found associated with psychopathology (depression, bipolar disorder). These data provide evidence that dysregulation of MR and GR are causative in the pathogenesis of depression and that these MR-and GR-gene variants are part of the genetic make up that determines individual stress-responsivity and coping style, affecting vulnerability to disease.

Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health.

The stress-response, including autonomic and hypothalamic-pituitary-adrenal (HPA) axis reactivity, is essential for maintaining homeostasis during a challenge. Brain mineralocorticoid receptors and glucocorticoid receptors operate in balance to coordinate the stress-response. Genetic variants in both the human mineralocorticoid and glucocorticoid receptor-genes have been functionally characterized. In vitro effects of these genetic variants on transactivation and mRNA stability have been described. In vivo, two mineralocorticoid receptor-gene SNPs (-2 G/C (allele frequency: 50%), MR I180V (11%)) and four glucocorticoid receptor-gene SNPs (ER22/23EK (3%), N363S (4%), BclI (37%), A3669G (15%)) are associated with changes in hypothalamic-pituitary-adrenal (HPA) axis reactivity. Importantly, the two mineralocorticoid receptor-gene variants (but none of the glucocorticoid receptor-gene variants) also associate with changes in autonomic output as measured as increased heart beat following a psychosocial stress (TSST). Moreover, several of these mineralocorticorticoid receptor- and glucocorticoid receptor variants have been found associated with stress-related disorders, including depression. These data indicate that dysregulation of mineralocorticoid- and glucocorticoid receptor are causative in the pathogenesis of depression. Moreover, these mineralocorticoid- and glucocorticoid receptor-gene variants constitute part of the genetic make up that determines individual stress-responsiveness inducing vulnerability to disease. Furthermore, mineralocorticoid- and glucocorticoid receptors are drug targets, thereby aiming at the underlying mechanisms of stress-related disorders.

A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness.

CONTEXT: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. OBJECTIVE: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. DESIGN: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. RESULTS: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger's test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. CONCLUSION: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.

Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity.

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.

Anxious-retarded depression: relation with plasma vasopressin and cortisol.

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is related to melancholic or endogenous depression; however, the strength of this relationship depends on the definition of the specific depression subcategory. A two-dimensionally defined subcategory, anxious-retarded depression, is related to melancholic depression. Since arginine vasopressin (AVP) activates the HPA axis, and both major depression and the melancholic subcategory are associated with elevated plasma AVP levels, we investigated whether the plasma AVP level is also elevated in anxious-retarded depression, melancholic depression and anxious-retarded melancholic depression, and whether plasma AVP and cortisol levels are correlated in these subcategories. A total of 66 patients with major depression not using oral contraception were investigated. Patients with anxious-retarded depression had a highly significant AVP-cortisol correlation, while no such correlation was found in patients with nonanxious-retarded depression. Log-transformed mean plasma AVP values were higher in patients with anxious-retarded depression than in patients with nonanxious-retarded depression. Patients with anxious-retarded melancholic depression also had a significantly elevated level of plasma AVP and a highly significant correlation between plasma AVP and cortisol levels. The correlation was low in patients with melancholic depression. Anxious-retarded depression may be a useful refinement of the melancholic subcategory with regard to dysregulation of the HPA axis and plasma AVP release.

Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production.

We assessed corticosteroid sensitivity in multiple sclerosis (MS) patients compared to control subjects, using an in vitro assay of dexamethasone (Dex) inhibition of lipopolysaccharide (LPS) stimulated-blood interleukin-6 production. Significantly higher concentrations of dexamethasone were needed to obtain 50%-inhibition (ID(50)) of in vitro LPS stimulated interleukin (IL)-6 production (28.4 x 10(-7) M) in relapsing-remitting MS (RRMS) patients compared to chronic progressive MS (CPMS) patients (6.2 x 10(-7) M) or compared to controls (3.0 x 10(-7) M). We also found a trend towards worsening of clinical status over time with increasing corticosteroid resistance. These data suggest that corticosteroid sensitivity may be a factor in the pathogenesis and could be used for prognosis of MS.

Very low levels of the glucocorticoid receptor beta isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry.

The hippocampus is an important target for glucocorticoid hormones. Glucocorticoid receptor (GR) mediated feedback in this area is important for control of behavioural adaptation. An alternative splice variant, the GRbeta (GRbeta) isoform, does not bind ligand and has been proposed to inhibit classic GRalpha-mediated transactivation of target genes. Hence, an increased ratio of GRbeta to GRalpha may induce relative corticosteroid-resistance, as e.g. presumed to occur in major depression. To investigate whether GRbeta is involved in the human hippocampus, we studied GRalpha and GRbeta expression levels in postmortem hippocampal tissue of control subjects by quantitative PCR (Taqman RT-PCR) and immunocytochemistry. Taqman RT-PCR demonstrated a very low relative abundance of GRbeta in the human hippocampus (GRalpha:GRbeta ratio approximately 14,500:1). Immunohistochemical analysis confirmed the occurrence of isolated profiles indeed displaying nuclear staining in the main hippocampal subregions. Subsequent double immunofluorescent analysis revealed that >98% of these GRbeta positive cells were double positive for leucocyte common antigen, that identifies exclusively blood-derived cells of haematopoietic origin, including microglia. We conclude that GRbeta is present in very low amounts in the control human hippocampus, and that of these low numbers of cells, notably, almost all are derived from blood which is inevitably present in postmortem tissue. A functionally relevant role for the GRbeta in control of the human hippocampus is therefore not very likely. Whether this is altered in disease conditions awaits further research.

Salivary cortisol levels and the 2-year course of depressive and anxiety disorders.

INTRODUCTION: Depression and anxiety disorders have been associated with hyperactivity of the hypothalamic-pituitary adrenal (HPA) axis. However, lower cortisol levels have also been observed in depressed patients. Whether cortisol level predicts the course of these disorders has not been examined in detail. We examined whether salivary cortisol indicators predict the 2-year course of depression and anxiety disorders. METHODS: Longitudinal data are obtained from 837 participants of the Netherlands Study of Depression and Anxiety, with a DSM-IV based depressive and/or anxiety disorder at baseline. At baseline, seven saliva samples were obtained, including the 1-h cortisol awakening response, evening cortisol level and a 0.5mg dexamethasone suppression test. At follow-up, DSM-IV based diagnostic interviews and Life Chart Interview integrating diagnostic and symptom trajectories over 2 years were administered to determine an unfavorable course. RESULTS: 41.5% of the respondents had a 2-year unfavorable course trajectory without remission longer than 3 months. Adjusted analyses showed that a lower awakening response was associated with an unfavorable course (RR=0.83, p=0.03). No associations were found between evening cortisol or cortisol suppression after dexamethasone ingestion and an unfavorable course trajectory. CONCLUSIONS: Among patients with depressive or anxiety disorders, a lower cortisol awakening response - which may be indicative of underlying exhaustion of the HPA axis - predicted an unfavorable course trajectory.

Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior.

We tested if common mineralocorticoid receptor (MR) gene variants contribute to the variability in neuroendocrine control and behavioral reactivity as observed in humans. For that purpose we screened for genetic variability and tested functionality of the identified human MR gene variants in vitro. Four haplotypes were tested for transactivational capacity in vitro and showed profound significant differences when stimulated with cortisol. The MR gene variants were associated with basal levels of cortisol, cortisol levels after dexamethasone administration and with stress-induced hypothalamic-pituitary-adrenal axis and autonomic reactivity. In an elderly cohort, one of the functional MR gene variants, MR-I180V, associated with higher feelings of depression. Moreover, we found an association with neuroticism in a second cohort consisting of depressed patients. In conclusion, we report here new findings on common functional human MR gene variants which reveal a hitherto unknown role of these variants in neuroticism conferring vulnerability to stress-related mental disorders, such as depression and posttraumatic stress syndrome.

Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response.

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in secretion of corticosteroids which facilitate behavioural adaptation. These effects exerted by corticosteroids are mediated by two brain corticosteroid receptor types, the mineralocorticoid receptor (MR), with a high affinity already occupied under basal conditions and the glucocorticoid receptor (GR), with a low affinity only activated during stress. Here, we studied MR gene haplotypes constituted by the two single nucleotide polymorphisms MR-2G/C (rs2070951) and MRI180V (rs5522). The haplotypes showed differences in cortisol-induced gene transcription and protein expression while the structural variant MRI180V did not affect ligand binding. Moreover, in a well characterized cohort of 166 school teachers these haplotypes have been associated with perceived chronic stress (Trier Inventory for the Assessment of Chronic Stress, TICS) and, in a subgroup of 47 subjects, with ACTH, cortisol and heart rate responses to acute psychosocial stress (Trier Social Stress Test, TSST). MR haplotypes were significantly associated with the TICS scales "excessive demands at work" and "social overload". Subjects homozygous for haplotype MR-2C/MRI180, which in vitro showed highest expression and transactivational activity, displayed the highest salivary cortisol (p<0.001), plasma cortisol (p=0.010), plasma ACTH (p=0.003) and heart rate (p=0.018) responses. It is concluded that the investigated MR haplotypes modulate cortisol-induced gene transcription in vitro. Moreover, these haplotypes may contribute to individual differences in perceived chronic stress as well as neuroendocrine and cardiovascular stress responses.

Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs.

BACKGROUND: Cortisol controls the activity of the hypothalamic-pituitary-adrenal (HPA) axis during stress and during the circadian cycle through central mineralocorticoid (MR) and glucocorticoid receptors (GR). Changes in MR and GR functioning, therefore, may affect HPA axis activity. In this study we examined the effect of common functional MR gene variants on the cortisol awakening response (CAR), which is often disturbed in stress-related disorders like depression. METHODS: Common functional MR single nucleotide polymorphisms (SNPs; MR -2G/C and I180V) and haplotypes were tested for association with variability in the CAR in a large cohort (Netherlands Study of Depression and Anxiety, NESDA) of patients diagnosed with a lifetime major depressive disorder (MDD). Saliva cortisol measurements and genotypes could be obtained from a total of 1026 individuals, including 324 males and 702 females. RESULTS: The MR -2C/C genotype was associated with an attenuated CAR increase in women (p=.03) but not in men (p=.18; p=.01 for SNP-by-sex interaction). The MR I180V SNP had no significant effect on the CAR. Additional analysis revealed that effect of the -2G/C SNP on the CAR was due to an interaction with frequent use of selective serotonin reuptake inhibitors (SSRIs). Only in subjects using SSRIs (men and women) highest total morning cortisol levels were observed in -2G/G carriers, while the CAR was completely flattened in women with the -2C/C genotype (p<.05). The results were independent of multiple potential confounders and had an effect size of r=.14-.27. CONCLUSIONS: This study shows that the MR -2G/C SNP modulated the CAR only in the MDD patients using SSRIs, with a clear allele-dose effect in women. This suggests that effect of SSRIs on cortisol regulation depends in part on the MR genotype with possible implications for future treatment selection.

Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder.

Appropriate signaling in the brain by the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is critical in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, emotional arousal and cognitive performance. To date, few data exist on MR (and GR) expression in the brain of patients suffering from major depressive disorder (MDD). With the help of quantitative PCR we assessed MR and GR mRNA expression, including the splice variants MRα and MRß, in tissue samples from the hippocampus, amygdala, inferior frontal gyrus, cingulate gyrus and nucleus accumbens. Expression levels were compared between tissue samples from six MDD patients and six non-depressed subjects. Relative to total GR, total MR mRNA expression was higher in hippocampus and lower in the amygdala, inferior frontal gyrus and nucleus accumbens. Both MRα and MRß could be detected in all brain regions that were analyzed, although MRß expression was low. Significantly lower expression levels (30-50%) were detected for MR or GR in hippocampal, inferior frontal gyrus and cingulate gyrus tissue from MDD patients (p < .05), while no differences were found in the amygdala or nucleus accumbens. The data show that both MRα and MRß mRNA are expressed throughout the human limbic brain with highest expressions in the hippocampus. A decreased expression of corticosteroid receptors in specific brain regions of MDD patients could underlie HPA hyperactivity, mood and cognitive disturbances often observed in patients suffering from stress-related psychopathologies.