Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Autonomous Cortisol Secretion Influences Psychopathological Symptoms in Patients With Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is associated with impaired quality of life (QoL). Autonomous cortisol cosecretion (ACS) is a relevant phenotype of PA, which could contribute to depression and anxiety disorders. This has not been investigated so far. OBJECTIVE: To evaluate the prevalence of depression and anxiety in PA patients according to ACS. METHODS: We performed testing for hypercortisolism and evaluated anxiety, depression and QoL by self-rating questionnaires in newly diagnosed PA patients of the German Conn's Registry; 298 patients were reevaluated at follow-up. RESULTS: In the overall cohort, scores for anxiety (P < .001), depression (P < .001), and QoL (mental P = .021; physical P = .015) improved significantly at follow-up. This improvement was seen in both subgroups of patients with and without ACS, with the exception of the mental subscore in no-ACS patients. Analysis for sex differences showed that anxiety decreased significantly in females with ACS and no-ACS, whereas males with no-ACS failed to improve. Depression improved significantly in males and females with ACS (P = .004, P = 0.011 respectively), but not in those with no-ACS. Physical subscore of QoL improved significantly (P = .023) in females with ACS and mental subscore (P = .027) in males with ACS, whereas no differences were seen for the no-ACS groups. CONCLUSION: Improvement in depression and anxiety scores in response to treatment of PA is more pronounced in patients with ACS in contrast to no-ACS suggesting a role of ACS in the psychopathological symptoms of patients with PA. Furthermore, we observed significant differences in depression and anxiety scores between the sexes.

Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker?

BACKGROUND: Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in depression. In the present study, we examined whether change in HPA system function during the first weeks of hospitalization predicts response to antidepressant treatment in major depression and thus constitutes a potential biomarker. METHODS: We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression, once after study inclusion and a second time 2 to 3 weeks later while under continuous antidepressant treatment. RESULTS: We found increased ACTH and cortisol responses to the first DEX/CRH test compared with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of the 50 patients showed an attenuated cortisol response, while 14 patients did not display improvement or exhibited even aggravation of the altered HPA system function. Improved HPA system regulation in the second DEX/CRH test was associated with beneficial treatment response after 5 weeks and a higher remission rate at the end of hospitalization. CONCLUSIONS: The results suggest that change in HPA system regulation assessed with repeated DEX/CRH tests is a potential biomarker that may predict clinical outcome at follow-up. There is consensus that the drug development process could be improved, once reliable biomarkers become available that help to allow a judgement regarding the efficacy of a novel drug candidate. The combined DEX/CRH test seems to be a promising candidate for such a biomarker.

High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response.

There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF(1) antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague-Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF(1) receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 microg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.

Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder.

Information on the function of the hypothalamic-pituitary-adrenal (HPA) axis, the main mammalian system of stress response, in obsessive compulsive disorder (OCD) is inconsistent. In this study, nine inpatients with a DSM-IV diagnosis of OCD without comorbid major depression (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score >15; HAMD-21 total score 16) and nine healthy matched controls were included. Blood of patients (seven males; 31.8 +/- 9.3 years, Y-BOCS: 27.3 +/- 4.3, HAMD-21: 13.3 +/-1.9) and controls (seven males, 31.6 +/- 9.1 years) was drawn every 20 min between 23:00 and 7:00 h during sleep using a long catheter for later ACTH and cortisol analysis. Secretion patterns of cortisol and ACTH were similar in both groups, in OCD, however, at a higher level. Area under the curve plasma concentrations of both ACTH (p<0.05) and cortisol (p<0.005) were significantly greater in patients with OCD (ACTH: 674.3 +/- 57.4; cortisol: 2148.4 +/-271.7) than in controls (ACTH: 460.2 +/- 61.0; cortisol: 1191.2 +/- 124.1). In conclusion, our findings suggest that the activity of the HPA axis in patients with OCD is increased compared to healthy controls.

Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis.

BACKGROUND: In depressed patients, alterations in the hypothalamo-pituitary-adrenocortical (HPA) system are the most consistent neurobiological finding. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines. METHODS: We examined alterations in plasma levels of tumor necrosis factor-alpha (TNF-alpha), levels of its soluble receptors p55 (sTNF-R p55) and p75 (sTNF-R p75) as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 70 depressed inpatients without inflammation. RESULTS: On admission, TNF-alpha levels were inversely associated with the ACTH response to the combined dex/CRH test. Changes in TNF-alpha, sTNF-R p55, and sTNF-R p75 plasma levels from admission to discharge were positively correlated with the dex/CRH test outcome at discharge. Subgroup analysis revealed that this association was restricted to those patients achieving remission. In this subgroup, TNF-alpha levels at discharge were also positively correlated with dex/CRH test response at discharge. CONCLUSIONS: Our results suggest that elevated HPA axis activity in acute depression suppresses TNF-alpha system activity, while after remission, when HPA axis activity has normalized, the TNF-alpha system seems to gain influence on the HPA system.

Hypothalamus-pituitary-adrenal system regulation and suicidal behavior in depression.

BACKGROUND: One of the most demanding tasks in psychiatry is to protect patients from suicidal attempts. Preventive strategies could be improved by increasing our knowledge on the pathophysiologic disturbances underlying this behavior. More than 70-80% of suicides occur in the context of depressive disorders, in which dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most prominent neurobiological findings. So far data on the involvement of the HPA axis in the pathophysiology of suicidal behavior in depressed patients are controversial. METHODS: In this retrospective study, we administered the combined dexamethasone-suppression/CRH stimulation (Dex/CRH) test to 310 patients with a depressive syndrome characterized at admission for acute and past suicidal behavior within the first 10 days after hospitalization. RESULTS: Suicidal behavior in depressed patients, including past and recent suicide attempts as well as suicidal ideation, was associated with a lower adrenocorticotropin and cortisol response in the combined Dex/CRH test, with lowest hormone levels observed in patients with a recent suicide attempt. DISCUSSION: The findings suggest that suicidal behavior may alter HPA axis regulation in depressed patients. Large-scale prospective studies assessing neuroendocrine changes may help to develop predictors for an early identification of patients at risk for committing suicide.

Treatment with a CRH-1-receptor antagonist (R121919) does not affect weight or plasma leptin concentration in patients with major depression.

Weight gain during treatment with psychotropic drugs is frequently observed and is assumed to be responsible for non-compliance and for an elevated risk to develop a number of somatic co-morbidities including cardiovascular disorders and type 2 diabetes. Absence of weight inducing effects is therefore a major objective for the development of new compounds. Recently, R121919, the first corticotropin releasing hormone receptor 1 (CRH1R) antagonist, was tested in major depression. Clinical efficacy, safety, and tolerability of this compound could be demonstrated. Since CRH is discussed to be involved in the regulation of appetite and weight, directly and via interaction with leptin, CRH1R antagonists are suspected to influence body weight. Effects of 30 days of treatment with the CRH1R antagonist R121919 on weight and leptin levels in 20 patients suffering from major depression were investigated. No significant weight changes during treatment with R121919 were observed. Furthermore, noeffects on plasma leptin concentrations were found. We conclude that treatment with the CRH1R antagonist R121919 does not affect weight or plasma leptin concentrations in patients with major depression. Together with previous findings indicating safety, tolerability, and clinical efficacy CRH1R antagonists are highly promising as a new treatment option in depression.

The combined dexamethasone/CRH test as a potential surrogate marker in depression.

There is compelling evidence that impaired corticosteroid receptor function is the key mechanism in the pathogenesis of depression resulting in a dysfunctional stress hormone regulation, which can be most sensitively detected with the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. Treatment with different kinds of antidepressants is associated with a reduction of the hormonal responses to the combined dex/CRH test suggesting normalization of impaired corticosteroid receptor signaling as the final common pathway of these drugs. Consequently, the combined dex/CRH test is suggested as a screening tool to decide whether new compounds designed as antidepressants provide sufficient efficacy to normalize corticoid receptor signaling in depressed patients. We summarize own data and findings from the literature suggesting that (1) the neuroendocrine response to the combined dex/CRH test is elevated during a major depressive episode, but (2) tends to normalize after successful treatment. (3) Favorable response to antidepressant treatment can be predicted by determining the dex suppresser status on admission. For optimal prediction of non-response to antidepressant treatment, however, the results of a second dex/CRH test are necessary. These findings, together with the fact that impaired corticosteroid receptor signaling is considered as key mechanism of the pathogenesis in depression, support the suitability of the combined dex/CHR test as a surrogate marker for treatment response in depression. In conclusion, the combined dex/CRH test is a promising candidate to serve as a screening tool for the antidepressive effects of new compounds in clinical drug trials. Furthermore, the test appears to be capable of predicting the individual likelihood to respond to a current antidepressant treatment. If a drug treatment fails to normalize the outcome of the combined dex/CRH test, a change of the treatment strategy is recommended. Further systematic research is required and already ongoing to confirm the suitability of the combined dex/CRH test as a surrogate marker in depression.

Cost-Effectiveness of Screening for Primary Aldosteronism and Subtype Diagnosis in the Resistant Hypertensive Patients.

BACKGROUND: Primary aldosteronism (PA) is a common and underdiagnosed disease with significant morbidity potentially cured by surgery. We aim to assess if the long-term cardiovascular benefits of identifying and treating surgically correctable PA outweigh the upfront increased costs in patients at the time patients are diagnosed with resistant hypertension (RH). METHODS AND RESULTS: A decision-analytic model compares aggregate costs and systolic blood pressure changes of 6 recommended or implemented diagnostic strategies for PA in a simulated population of at-risk RH patients. We also evaluate a 7th "treat all" strategy wherein all patients with RH are treated with a mineralocorticoid-receptor antagonist without further testing at RH diagnosis. Changes in systolic blood pressure are subsequently converted into gains in quality-adjusted life years (QALYs) by applying National Health and Nutrition Examination Survey data on concomitant risk factors to an existing cardiovascular disease simulation model. QALYs and lifetime costs were then used to calculate incremental cost-effectiveness ratios for the competing strategies. The incremental cost-effectiveness ratio for the strategy of computerized tomography (CT) followed by adrenal venous sampling (AVS) was $82,000/QALY compared with treat all. Incremental cost-effectiveness ratios for CT alone and AVS alone were $200,000/QALY and $492,000/QALY; the other strategies were more costly and less effective. Integrating differential patient-reported health-related quality of life adjustments for patients with PA, and incremental cost-effectiveness ratios for screening patients with CT followed by AVS, CT alone, and AVS alone were $52,000/QALY, $114,000/QALY, and $269,000/QALY gained. CONCLUSIONS: CT scanning followed by AVS was a cost-effective strategy to screen for PA among patients with RH.

Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects.

A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5-40 mg vs. 40-80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic-pituitary-gonadal system, the hypothalamic-pituitary-thyroid axis, the renin-angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs.

Gender differences in anxiety and depressive symptoms in patients with primary hyperaldosteronism: a cross-sectional study.

OBJECTIVE: The renin-angiotensin-aldosterone-system (RAAS) has gained increasing attention in the investigation of the pathogenesis of depression. Primary hyperaldosteronism (PA) is associated with a marked aldosterone excess. Prior studies on PA describe an increased prevalence of anxiety and sub-threshold depressive symptoms in these patients. METHODS: In a cross-sectional exploratory study we investigated 132 patients with PA. Twenty-seven patients were studied before initiation of specific treatment (U = untreated), 56 were studied 5.4 years after initiation of mineralocorticoid antagonist treatment (MRA) and 49 patients were studied 4.3 years after unilateral adrenalectomy (ADX). GAD-7 and PHQD self-rating questionnaires were used to assess symptoms for anxiety and depression. RESULTS: No significant difference was found between the three investigated groups. A higher prevalence for depression and anxiety compared to the normal population was found. Women of all groups had higher mean values compared to men, for depression in untreated patients this difference was found to be significant. Correlations between the psychopathology and hormones were only found for renin. Plasma renin concentration correlated significantly with anxious symptoms of untreated females. CONCLUSIONS: This study supports the RAAS to be involved in the pathogenesis of depression as patients with PA seem to be more depressive and anxious compared to the normal population. Gender differences in the regulation of the RAAS seem to be apparent, as females were more affected by the dysregulation than males.

Quality of life in patients with primary aldosteronism: gender differences in untreated and long-term treated patients and associations with treatment and aldosterone.

Psychopathological symptoms in patients with primary aldosteronism (PA) have been reported. In a cross-sectional design the self-reported physical and mental condition among patients with PA of the German Conn's Registry differently treated during the course of the disease were analysed. 27 patients were investigated before initiation of specific therapy (U), 56 patients were on chronic mineralocorticoid antagonist treatment (MRA) and 49 patients had undergone adrenalectomy (ADX). Patient's quality of life was analysed with the SF-12 for a Physical (PCS) and a Mental Component (MCS). Statistically significant lower scores for PCS were found for female PA patients treated with MRA in comparison to ADX patients and the German reference population (36.4 ± 11.1 vs. 49.1 ± 10.9 (p = 0.024) vs. 47.9 ± 9.7 (p = 0.001)), respectively. Concerning MCS, untreated female patients scored significantly lower (36.5 ± 7.4) than females from the German population (51.3 ± 8.4, p = 0.000). Furthermore, untreated females appear to differ significantly from MRA and ADX females, scoring the lowest reading (U vs. MRA: p = 0.029; U vs. ADX: p = 0.005). Significant correlations were found between plasma aldosterone (r = -0.819, p = 0.013) and the MCS and between plasma renin concentration and MCS (r = -0.938, p = 0.001) in female MRA patients. In summary, PA patients report a worse physical and mental condition than the one reported for the German reference population. Untreated and mineralocorticoid antagonist treated patients report the lowest readings. Females were found to be more impaired than males in QoL. MRA treatment seems to affect the MCS of female patients.

Changes in the sleep electroencephalogram (EEG) during male to female transgender therapy.

Steroids, including estrogens, participate in sleep regulation. For example estrogen replacement therapy improved sleep quality in postmenopausal women. Patients, who undergo a cross-gender hormone therapy, receive high doses of estrogens. The effects of this treatment on sleep are unknown. To clarify this issue, we examined seven male to female transsexual patients (age range 31-44 years, mean±SD 35.9±4.2 years). The patients spent two nights on 2 separate occasions in our sleep laboratory. The first night of each session served for adaptation to laboratory conditions. In the second night sleep electroencephalogram [EEG] was recorded from 2300h to 0700h. The first examination was performed before and the second about 3 months after initiation of cross-gender hormone therapy with a dose of 80-100mg estrogen applied every 2 weeks. Additionally patients were treated with a starting dose of the anti-androgen cyproteronacetate of 100mg/day and after about 6 weeks with a maintenance therapy of 50mg/d in order to suppress androgenic effects. Statistical analysis was performed with the Wilcoxon rank test. Under this estrogen therapy we found a significant increase in stage 1 sleep during the whole night (at baseline [b]: 33.29±9.94min; treatment [t]: 51.57±24.26min; p<0.05) Beta activity in nonREM sleep was significantly increased (p=0.02) during hormone therapy compared to before treatment. Other sleep EEG parameters showed no significant changes. Administration of estrogen and anti-androgens in male to female transsexual patients had only a small influence on sleep EEG, with an increase in the duration of shallow sleep.

Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol--a double-blind multicenter trial.

BACKGROUND: Patients with delusional depression are difficult to treat. The atypical antidepressant trimipramine was effective in a previous 4-week open label pilot study in patients with this disorder. The major neurobiological effect of trimipramine is the inhibition of the hypothalamic-pituitary-adrenocortical (HPA) system. In delusional depression HPA overactivity is more distinct than in other subtypes of depression. HPA suppression is thought to contribute to the action of trimipramine. METHODS: In a double-blind, randomized, placebo controlled multicenter trial we compared the effects of trimipramine monotherapy versus a combination of amitriptyline and haloperidol. Dosage was increased stepwise from 100mg up to 400mg trimipramine and from 100mg up to 200mg amitriptyline combined with 2mg up to 7.5mg haloperidol. The average dose of trimipramine was higher than that of amitriptyline throughout the trial. During sixth week mean dosage (+/-standard deviation) were 356.1+/-61.2mg trimipramine, 184.0+/-23.6 mg amitriptyline and 6.3+/-1.8 mg haloperidol. During six weeks psychometric assessments were performed weekly. For HPA monitoring a dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed before active medication and at the end of treatment. Additionally tolerability was monitored by ECG, EEG assessment of extrapyramidal symptoms and akathisia, clinical laboratory routine and recording of blood pressure and heart rate. Adverse events were documented. RESULTS: 94 patients were enclosed into the study. The per protocol sample consisted of 33 patients of the trimipramine group and of 24 patients of the amitriptyline/haloperidol group. The decrease of the Hamilton depression (HAMD) score (24 items) showed non-inferiority of trimipramine compared to amitriptyline/haloperidol. Twenty-eight patients (84.84%) in the trimipramine arm and 17 patients (70.83%) in the amitriptyline/haloperidol arm were responders (HAMD

Changes in the hypothalamic-pituitary-adrenal axis and leptin levels during antidepressant treatment.

BACKGROUND: In depressed patients, overstimulation of the hypothalamo-pituitary-adrenocortical (HPA) system, probably caused by glucocorticoid receptor resistance, is the most consistent neurobiological finding. Glucocorticoids themselves are reported to increase leptin synthesis and secretion in humans. METHODS: We examined alterations in plasma levels of leptin as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 74 depressed inpatients. RESULTS: Mean leptin concentration did not change significantly between admission and discharge. However, changes in ACTH response and partial cortisol response to the combined dex/CRH test between admission and discharge were significantly correlated with leptin levels at discharge. CONCLUSIONS: Leptin levels at discharge rise as the HPA axis normalizes. These findings may be explained by an improvement in glucocorticoid receptor sensitivity among depressed patients during antidepressant therapy and a consecutively increased influence of glucocorticoids on leptin levels via the glucocorticoid receptor.

Ghrelin plasma levels during psychopharmacological treatment.

The mechanisms underlying weight gain induced by psychopharmacological agents are poorly understood. Because the recently discovered enteric hormone, ghrelin, stimulates food intake, we hypothesized that increases in circulating ghrelin levels might mediate the weight gain caused by certain antidepressants and atypical antipsychotic drugs. Fifty-two patients receiving psychopharmacological treatments were included in the study: 16 patients received antidepressants that are not known to induce weight gain, and 13 patients received mirtazapine or trimipramine, which are antidepressants known to lead to weight gain; 6 patients received clozapine and olanzapine, which have the highest liability among the antipsychotics to cause weight gain, and 17 patients received other antipsychotics. Fasting venous blood samples for the measurement of ghrelin were drawn in the morning between 06:00 and 08:00 a.m. in the second week of treatment. Although psychopharmacological treatment induced significant weight changes in the expected directions (most prominent in the clozapine or olanzapine treatment group), ghrelin levels did not differ significantly between groups. Psychotropic drugs with different propensities to induce body weight gain are associated with similar concentrations of plasma ghrelin in psychiatric patients after a short period of treatment.