Search

Objectives: The relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response., Methods: In an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep., Results: HRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non-responders., Conclusions: Our data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

P-glycoprotein, encoded by the ABCB1 gene, functions as an ATP-driven efflux pump in the blood-brain barrier, extruding its substrates and thereby limiting their passage into the brain. ABCB1 polymorphisms predicted antidepressant drug response: Minor allele carriers of SNPs rs2032583 and rs2235015 had higher remission rates than major allele homozygotes. The aim of the current study was to evaluate an ABCB1 genotype-dependent efficacy of a quick dose escalation strategy. Depressed inpatients (n = 73) treated with antidepressants that are P-glycoprotein substrates were randomly assigned to a standard or high dose condition for 28 days. HAM-D scores, adverse effects and plasma antidepressant concentration were measured weekly and tested among two intronic SNPs rs2032583 and rs2235015. A treatment as usual control sample (n = 128) was retrospectively matched to the study group by gender, age, and diagnosis. There was a significant interaction of genotype x plasma antidepressant concentration: Minor allele carriers of rs2032583 [F(1,65) = 7.221, p = 0.009] and rs2235015 [F(1,65) = 4.939, p = 0.030] whose plasma drug concentration were within recommended range had a greater symptom reduction at study endpoint which exceeded the therapeutic benefit of the treatment as usual group [for rs2032583: F(1,163) = 4.366, p = 0.038]. Minor allele carriers of rs2032583 with high plasma drug levels had more sleep-related side effects than major allele homozygotes with high plasma drug levels. The treatment of MDD can be optimized by ABCB1 genotyping combined with monitoring of plasma drug concentrations: For minor allele carriers of rs2032583 and rs2235015, plasma antidepressant levels should not exceed the recommended range in order to obtain optimal treatment outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To evaluate whether prefrontal cordance in theta frequency band derived from REM sleep EEG after the first week of antidepressant medication could characterize the treatment response after 4 weeks of therapy in depressed patients., Method: 20 in-patients (15 females, 5 males) with a depressive episode and 20 healthy matched controls were recruited into 4-week, open label, case-control study. Patients were treated with various antidepressants. No significant differences in age (responders (mean ± SD): 45 ± 22) years; non-responders: 49 ± 12 years), medication or Hamilton Depression Rating Scale (HAM-D) score (responders: 23.8 ± 4.5; non-responders 24.5 ± 7.6) at inclusion into the study were found between responders and non-responders. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of four weeks of active medication. Sleep EEG of patients was recorded after the first and the fourth week of medication. Cordance was computed for prefrontal EEG channels in theta frequency band during tonic REM sleep., Results: The group of 8 responders had significantly higher prefrontal theta cordance in relation to the group of 12 non-responders after the first week of antidepressant medication. This finding was significant also when controlling for age, gender and number of previous depressive episodes (F1,15 = 6.025, P = .027). Furthermore, prefrontal cordance of all patients showed significant positive correlation (r = 0.52; P = .019) with the improvement of HAM-D score between the inclusion week and fourth week of medication., Conclusions: The results suggest that prefrontal cordance derived from REM sleep EEG could provide a biomarker for the response to antidepressant treatment in depressed patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Psychiatric disorders are caused by perturbed molecular pathways that affect brain circuitries. The identification of specific biosignatures that are the result of altered pathway activities in major depression, bipolar disorder and schizophrenia can contribute to a better understanding of disease etiology and aid in the implementation of diagnostic assays. In the present study we identified disease-specific protein biosignatures in cerebrospinal fluid of depressed (n: 36), bipolar (n: 27) and schizophrenic (n: 35) patients using the Reverse Phase Protein Microarray technology. These biosignatures were able to stratify patient groups in an objective manner according to cerebrospinal fluid protein expression patterns. Correct classification rates were over 90%. At the same time several protein sets that play a role in neuronal growth, proliferation and differentiation (NEGR1, NPDC1), neurotransmission (SEZ6) and protection from oxidative damage (GPX3) were able to distinguish diseased from healthy individuals (n: 35) indicating a molecular signature overlap for the different psychiatric phenotypes. Our study is a first step toward implementing a psychiatric patient stratification system based on molecular biosignatures. Protein signatures may eventually be of use as specific and sensitive biomarkers in clinical trials not only for patient diagnostic and subgroup stratification but also to follow treatment response., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo(15)N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent genome-wide association studies (GWAS) and metaanalyses revealed genetic associations for ANK3 (ankyrin 3) and CACNA1C (alpha 1C subunit of the L-type voltage gated calcium channel) with bipolar disorder (BPD). Several findings from clinical, epidemiological, and genetic studies point towards a common biological background of BPD and major depressive disorder (MDD). We were interested whether this also applies for ANK3 and CACNA1C and tested associations of single nucleotide polymorphisms (SNPs) in these genes with MDD in two Caucasian case-control samples. Sample 1 (Munich Antidepressant Response Signature Project/MARS - MDD) consisted of 720 depressed inpatients and 542 psychiatric healthy controls. Sample 2 (unipolar recurrent depression (URD)) consisted of 827 patients with URD and 860 psychiatric healthy controls. After stringent quality control we analyzed 262 SNPs (sample 1) and 504 SNPs (sample 2) and imputed further 5771 SNPs (sample 1) and 5534 SNPs (sample 2) from Hapmap Phase 2 data in the ANK3 and CACNA1C gene regions. Additionally, a metaanalysis of both samples was performed. Several SNPs in both genes were nominally associated with MDD with the highest association in the 3'-region of ANK3 (rs10994143, nominal p = 3.3*10(-4)) in the metaanalysis of both samples. None of these results remained significant after correction for multiple testing. No association of MDD with SNPs previously reported in BPD studies could be detected. By analyzing the LD-structure, our highest associated SNPs could not be linked to the SNPs previously reported in BPD. Regarding ANK3 and CACNA1C, our findings do not support a strong genetic link between BPD and MDD for these two genes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The identification of pathways pertinent to human diseases is critical for gaining a better understanding of their pathophysiology. Pathway knowledge in turn can provide disease marker information required for diagnosis, drug development and improved patient treatment. Psychiatric disorders including anxiety and depression are complex diseases and are caused by a combination of multiple genetic and environmental factors affecting certain brain circuits. Here we used a systems biology approach to identify molecular pathways that affect anxiety- and depression-like phenotypes. For this purpose we screened pathways for stable enrichment in a great number of publicly available transcriptome data from the Gene Expression Omnibus related to anxiety- and depression-like phenotypes. In case of anxiety our analysis implicate a dysregulation of carbohydrate metabolism, tight junction and the phosphatidylinositol signaling system, whereas for depression gap junction, gonadotropin-releasing hormone signaling and ubiquitin-mediated proteolysis pathways are affected. Furthermore, both anxiety and depression show a dysregulation of VEGF signaling, long term potentiation and the glycolysis pathway. Molecular entities that are part of the identified pathways can serve as biomarkers and potential therapeutic targets for diagnosis and treatment of depression and anxiety disorders., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Some, but not all studies in patients with posttraumatic stress disorder (PTSD), report reduced hippocampus (HPC) volume. In particular it is unclear, whether smaller hippocampal volume represents a susceptibility factor for PTSD rather than a consequence of the trauma. To gain insight into the relationship of brain morphology and trauma exposure, we investigated volumetric and molecular changes of the HPC in a mouse model of PTSD by means of in vivo Manganese Enhanced Magnetic Resonance Imaging (MEMRI) and ex vivo ultramicroscopic measurements. Exposure to a brief inescapable foot shock led to a volume reduction in both left HPC and right central amygdala two months later. This volume loss was mirrored by a down-regulation of growth-associated protein-43 (GAP43) in the HPC. Enriched housing decreased the intensity of trauma-associated contextual fear, independently of whether it was provided before or after the shock. Beyond that, enriched housing led to an increase in intracranial volume, including the lateral ventricles and the hippocampus, and to an up-regulation of GAP43 as revealed by MEMRI and Western blot analysis, thus partially compensating for trauma-related HPC volume loss and down-regulation of GAP43 expression. Together these data demonstrate that traumatic experience in mice causes a reduction in HPC and central amygdala volume possibly due to a shrinkage of axonal protrusions. Enriched housing might induce trophic changes, which may contribute to the amelioration of trauma-associated PTSD-like symptoms at behavioural, morphological and molecular levels., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Corticotropin-releasing hormone (CRH) is thought to play an important role in the pathophysiology of stress-related psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). However, knowledge about the actions of CRH at the neuronal network level is only scarce. Here, we examined whether CRH affects neuronal activity propagation through the hippocampal formation (HF), a brain region which is likely to be involved in MDD and PTSD. For this purpose, we applied voltage-sensitive dye imaging (VSDI) to specifically cut hippocampal brain slices obtained from adult mice. This approach allowed us to investigate evoked neuronal activity propagation through the HF with micrometer spatial and millisecond temporal resolution. Application of CRH (50 nM) to slices increased neuronal activity propagation from the dentate gyrus (DG) to the CA1 subfield. This effect of CRH was caused by amplification of neuronal excitation on its passage through the HF and absent in mice lacking the CRH receptor type 1 (CRHR1). In conclusion, our study presents a VSDI assay for the investigation of neuronal activity propagation through the HF and demonstrates that CRH, via CRHR1, enhances this activity propagation. This effect of CRH might contribute to alterations of memory formation seen in MDD and PTSD. Moreover, it could influence hippocampal regulation of hypothalamic-pituitary-adrenal axis (HPA-axis) activity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The dexamethasone-corticotropin releasing hormone (Dex-CRH) test may differentially predict which depressed patients will respond to antidepressant medication. However, a comprehensive analysis of the safety of this test in psychiatric patients has not previously been performed., Methods: We conducted a pooled analysis of depressed patients in four clinical studies. Observed and subjectively reported side-effects in 454 patients were collected for 90 minutes following CRH administration. Pre-test electrocardiograms were available in 250 patients to assess cardiac safety. Descriptive statistics were performed to evaluate these safety data., Results: Eight-six (18.9%) subjects experienced no side-effects from the procedure. The mean number of side-effects per subject was 1.4±1.0. The most frequent adverse events were: flushing (n=216, 47.6%), feeling of warmth (144, 31.7%), hyperpnea/tachypnea (108, 23.8%), palpitations (37, 8.1%), and tachycardia (28, 6.2%). Side-effects were consistently mild and brief in duration. There were no serious adverse events., Conclusion: The Dex-CRH test produces a mild, predictable side-effect profile, characterized by flushing, feelings of warmth, hyperpnea/tachypnea, palpitations, and tachycardia. These results provide reassurance that the Dex-CRH test is well tolerated in psychiatric patients., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Consolidation of extinction learning is a primary mechanism disrupted in posttraumatic stress disorder (PTSD), associated with hypoactivity of the ventromedial prefrontal cortex and hippocampus. A role for rapid eye movement (REM) sleep disturbances in this failure to consolidate extinction learning has been proposed. We performed functional magnetic resonance imaging (fMRI) with simultaneous skin conductance response (SCR) measurements in 16 healthy participants during conditioning/extinction and later recall of extinction. The visual stimuli were basic geometric forms and electrical shocks functioned as the unconditioned stimulus. Between the conditioning/extinction and recall sessions, participants received a 90-min sleep window in the sleep laboratory. This daytime sleep was polysomnographically recorded and scored by professionals blind to the study design. Only seven out of 16 participants had REM sleep; participants without REM sleep had a significantly slower decline of both SCR and neural activity of the laterodorsal tegmentum in response to electrical shocks during conditioning. At recall of fear extinction, participants with preceding REM sleep had a reduced SCR and stronger activation of the left ventromedial prefrontal cortex and bilateral lingual gyrus in response to the extinguished stimulus than participants lacking REM sleep. This study indicates that trait-like differences in shock reactivity/habituation (mediated by the brainstem) are predictive of REM sleep disruption, which in turn is associated with impaired consolidation of extinction (mediated by the ventromedial prefrontal cortex). These findings help understand the neurobiological basis and the temporal sequence of the relationship between shock exposure, disturbed sleep and impaired consolidation of extinction, as observed in PTSD., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Adenosine A(2A) receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. A variant within the corresponding ADORA2A gene (rs5751876) increased the risk for panic disorder (PD), for elevated anxiety during challenge tests in healthy probands and for anxiety-related arousal in blood-injury phobia. These multiple effects may mirror a more general effect of the SNP on basic personality traits. In the present study we therefore aimed to replicate the original finding in a large PD sample and extend it by investigating an additional proband sample characterized for different anxiety-related personality scores. In addition, as rs5751876 is assumed not to be the disease variant itself but to be in linkage disequilibrium (LD) with the true functional polymorphism other SNPs of potentially functional relevance were identified by re-sequencing the whole gene including several newly identified regions of putative regulatory potential and analysed for their impact on PD and anxious personality. We were indeed able to replicate rs5751876 as risk factor for PD, particularly PD with agoraphobia. Rs5751876 and several other variants in high LD (rs5751862, rs2298383 and rs3761422) as well as the corresponding haplotypes were also associated with different anxiety-related personality scores (Bonferroni corrected P(all) < 0.05). Of these variants, rs2298383 shows functional potential based on in silico analyses and might therefore represent the true underlying causal variant. Our data provide further support for an important role of ADORA2A variants in the pathogenesis of anxiety disorders and anxious personality reflecting their potential as basic susceptibility factors., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Cognitive deficits are a common feature of major depression (MD), with largely unknown biological underpinnings. In addition to the affective and cognitive symptoms of MD, a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is commonly observed in these patients. Increased plasma glucocorticoid levels are known to render the hippocampus susceptible to neuronal damage. This structure is important for learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. In order to further elucidate how altered stress responsiveness may contribute to the etiology of MD, three mouse lines with high (HR), intermediate (IR), or low (LR) stress reactivity were generated by selective breeding. The aim of the present study was to investigate whether increased stress reactivity is associated with deficits in hippocampus-dependent memory tests. To this end, we subjected mice from the HR, IR, and LR breeding lines to tests of recognition memory, spatial memory, and depression-like behavior. In addition, measurements of brain-derived neurotrophic factor (BDNF) in the hippocampus and plasma of these animals were conducted. Our results demonstrate that HR mice exhibit hippocampus-dependent memory deficits along with decreased hippocampal, but not plasma, BDNF levels. Thus, the stress reactivity mouse lines are a promising animal model of the cognitive deficits in MD with the unique feature of a genetic predisposition for an altered HPA axis reactivity, which provides the opportunity to explore the progression of the symptoms of MD, predisposing genetic factors as well as new treatment strategies., (Copyright 2009 Elsevier Ltd. All rights reserved.)

In laboratory rats and mice, differences in maternal care during the first week of life have been shown to exert long-lasting consequences on cognitive functioning and stress processing of the offspring. Such epigenetic programming is also assumed to play an important role in the transgenerational transmission of PTSD in humans. Here we studied whether even subtle within-subject differences in maternal care - caused by increasing mothering experience from the first to the second litter - can determine subsequent vulnerability for PTSD-like behaviour. To assess the influence of maternal experience on different components of fear, we analysed the adult male offspring of two subsequent litters (offspring 1, 2) from the same parental C57BL/6NCrl (B6N) and C57BL/6JOla (B6JOla) mice for (i) their innate anxiety behaviour on a modified hole board and (ii) their vulnerability to develop long-lasting PTSD-like fear symptoms ("hyperarousal", contextually conditioned fear) following perception of an inescapable foot shock. Increasing maternal experience reduced the animals' innate fear on the modified hole board (more exploration, less inhibition), the acute stress reaction to the shock and - one month after trauma - the levels of hyperarousal-like behaviour in the PTSD-prone B6N strain. In contrast, both acquisition and extinction of contextually conditioned fear were increased in the second offspring, representing cognitive flexibility. A factor analysis showed that innate fear, "hyperarousal" and conditioned fear represent independent behavioural dimensions. In conclusion, the present study identifies maternal inexperience as a risk factor for the development of PTSD-like symptoms. This effect - occurring in inbred mice on an almost identical genetic background - emphasizes the impact of epigenetic factors in PTSD-like behaviour.

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

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.

Acute administration of cortisol increases non-rapid-eye movement (non-REM) sleep, suppresses rapid-eye movement (REM) sleep and stimulates growth hormone (GH) release in healthy subjects. This study investigates whether cortisol has similar endocrine and electrophysiological effects in patients with depression who typically show a pathological overactivity of the hypothalamus-pituitary-adrenal (HPA) system. Fifteen depressed inpatients underwent the combined dexamethasone/corticotropin-releasing hormone test followed by three consecutive sleep EEG recordings in which the patients received placebo (saline) and hourly injections of cortisol (1mg/KG BW). Cortisol increased duration and intensity of non-REM sleep in particular in male patients and stimulated GH release. The activity of the HPA axis appeared to influence the cortisol-induced effects on non-REM sleep and GH levels. Stimulation of delta sleep was less pronounced in patients with dexamethasone nonsuppression. In contrast, REM sleep parameters were not affected by the treatment. These data demonstrate that the non-REM sleep-promoting effects of acute cortisol injections observed in healthy controls could be replicated in patients with depression. Our results suggest that non-REM and REM sleep abnormalities during the acute state of the disease are differentially linked to the activity of the HPA axis.

Sleep electroencephalographic (EEG) abnormalities and increased hypothalamo-pituitary-adrenal (HPA) axis activity are the most prominent neurobiological findings in depression and were suggested as potential biomarker for depression. In particular, increased rapid eye movement sleep (REM) density, deficit in slow wave sleep and excessive stress hormone response are associated with an unfavorable long-term outcome of depression. Recent studies indicate that the sleep and endocrine parameters are related to each other. This study investigated the association of sleep structure including a quantitative EEG analysis with the results of the combined dexamethasone (Dex)/corticotropin-releasing hormone (CRH)-test in 14 patients with a severe major depression, 21 healthy probands with a positive family history of depression (HRPs) and 12 healthy control subjects without personal and family history for psychiatric disorders. As expected patients with depression showed an overactivity of the HPA axis, disturbed sleep continuity and prolonged latency until slow wave sleep in the first sleep cycle. Differences in microarchitecture of sleep were less prominent and restricted to a higher NonREM sigma power in the HRP group. Dexamethasone suppressed cortisol levels were positively associated with higher NonREM sigma power after merging the three groups. We also observed an inverse association between the ACTH response to the Dex/CRH-test and rapid eye movement sleep (REM) density in HRPs, with suggestive evidence also in patients, but not in controls. This contra-intuitive finding might be a result of the subject selection (unaffected HRPs, severely depressed patients) and the complementarity of the two markers. HRPs and patients with high disease vulnerability, indicated by an elevated REM density, seem to have a lower threshold until an actual disease process affecting the HPA axis translates into depression, and vice versa. To summarize, our findings provide further evidence that the HPA axis is involved in the sleep regulation in depression. These associations, however, are not unidimensional, but dependent on the kind of sleep parameters as well as on the selection of the subjects.

Previous studies have suggested that patients with posttraumatic stress disorder (PTSD) have an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) system and a blunted ACTH response to corticotropin releasing hormone (CRH). The effects of two dexamethasone dosages (0.75 and 1.5 mg) on the ACTH and cortisol concentrations after CRH stimulation (100 microg) were studied in eight patients with PTSD and matched healthy control subjects. Compared to healthy subjects, patients with PTSD have a blunted ACTH response to CRH. Cortisol concentrations were only significantly influenced by dexamethasone dosage. Our results give further evidence for a central role of the pituitary in reflecting changes of the negative feedback sensitivity of the HPA system in patients with PTSD.

Several lines of evidence suggest that anxiety disorders have a strong genetic component, but so far only few susceptibility genes have been identified. There is preclinical and clinical evidence for a dysregulation of the central gamma-aminobutyric acid (GABA)-ergic tone in the pathophysiology of anxiety disorders. Diazepam binding inhibitor (DBI) has been suggested to play a pivotal role in anxiety disorders through direct and indirect, i.e. via synthesis of neuroactive steroids, modulation of GABA(A) receptor function. These findings suggest that the DBI gene can be postulated as a candidate for a genetic association study in this disorder. Thus, single nucleotide polymorphisms (SNPs) of the DBI gene were investigated for putative disease associations in a German sample of anxiety disorder patients suffering from panic attacks and matched controls. We were able to detect a significant association between a non-synonymous coding variant of DBI with anxiety disorders with panic attacks. The rare allele of this polymorphism was more frequent in controls than in patients (OR=0.43; 95% CI: 0.19-0.95). In conclusion, these results suggest a central role of DBI genetic variants in the susceptibility for the development of anxiety disorders that are characterized by the occurrence of panic attacks.

Objective: An impaired hypothalamic-pituitary-adrenocortical (HPA) function is a well-established finding in major depression (MD), but it is still unclear how this dysfunction affects immune responses in this disorder., Method: To further examine the relationship between immune and endocrine responses in MD, 0.4ng/kg body weight endotoxin [LPS] or 100mug hCRH were sequentially applied to 12 patients with MD and to 12 age- and gender-matched healthy controls after pre-treatment with 1.5mg dexamethasone (DEX). Immune (TNF-alpha, IL-6, rectal temperature) and endocrine (ACTH, cortisol) parameters were examined as area under the curve (AUC) levels., Results: After pre-treatment with DEX, LPS evoked an immune response in all participants of the study with most immune parameters significantly related to the endotoxin challenge. However, only a marked immune response resulted in an additional endocrine reaction. Subsequently, the quantitative extent of the endocrine reaction was related to the extent of the immune response after DEX/LPS challenge. Pre-LPS AUC levels of cortisol, ACTH and post-LPS levels of IL-6 as well as the post-CRH AUC levels of cortisol and ACTH were related to the depressive symptomatology as measured by the Beck depression inventory (BDI). In depressive patients who showed increased cortisol plasma levels before LPS, the later increase in IL-6 was reduced., Conclusions: The challenge with DEX/LPS did not reveal major impairments of evoked immune functions in MD. Only the endocrine parameters and the IL-6 response were related to the depressive symptomatology, suggesting a limited interaction between immune and endocrine dysfunctions in MD.

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.

One of the most characteristic alterations in depression is a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. A function test combining the pre-treatment of 1.5 mg dexamethasone (DEX) with a challenge of 100 microg corticotropin-releasing hormone (CRH) reveals a pathological increase in the adrenocorticotropin and cortisol release in patients with major depression. These changes partially persist after successful treatment with remission and therefore, might represent trait or vulnerability markers. To further address this question, we were investigating the premorbid neuroendocrine profile of 74 healthy high-risk probands (HRPs) with a positive family history for affective disorders. The aim was to identify premorbid vulnerability factors. During the observation period, 19 HRPs developed an affective disorder. Their premorbid DEX/CRH test results were compared with 19 age- and sex matched controls. No significant differences could be observed between these two groups. Our results suggest that a dysregulated HPA system indicated by this function test can rather be regarded as a neurobiological scar developing during the course of affective disorders.

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic-pituitary-adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.

Well documented changes of sleep electroencephalogram (EEG) in patients with depression include rapid eye movement (REM) sleep disinhibition, decreases of slow-wave-sleep (SWS) and increase in wakefulness. Twenty-seven inpatients with major depression were admitted subsequently to a clinical trial with the CRH(1)-receptor-antagonist R121919 administered in two different dose escalation panels. A random subgroup of 10 patients underwent three sleep-EEG recordings (baseline before treatment, at the end of the first week and at the end of the fourth week of active treatment). SWS time increased significantly compared with baseline after 1 week and after 4 weeks. The number of awakenings and REM density showed a trend toward a decrease during the same time period. Separate evaluation of these changes for both panels showed no significant effect at lower doses, whereas in the higher doses after R121919 REM density decreased and SWS increased significantly between baseline and week 4. Furthermore positive associations between HAMD scores and SWS at the end of active treatment were found. Although these data might indicate that R121919 has a normalizing influence on the sleep EEG, the design of the study does not allow to differentiate genuine drug effects from those of clinical improvement and habituation to the clinical setting.

Dysfunction of the hyopthalamo-pituitary adrenal (HPA) system is frequently found in major depression. In addition, signs of non-specific inflammatory system activation have been reported. However, very little is known about interactions between the HPA and immune systems in depressive patients. To assess HPA system function, we performed a combined dexamethasone suppression and corticotropin-releasing hormone stimulation (DEX/CRH) test in 14 depressive patients. Moreover, baseline nocturnal plasma levels of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha were measured. In addition, the system was challenged with an intraveneous pulsatile injection of hydrocortisone (1 mg/kg body weight in total) and again cytokine levels were measured across one night. Baseline TNF-alpha levels were negatively correlated with the amount of ACTH released upon CRH stimulation during the DEX/CRH test. Acute hydrocortisone administration suppressed TNF-alpha and IL-6 levels independently of baseline HPA system activity. We conclude that chronic HPA system overactivity in depressed patients might compromise the production of inflammatory cytokines under baseline conditions. However, the responsivity of the cytokine production to acutely administered glucocorticoids does not seem to correlate with the state of the HPA system.

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.

Excessive corticotropin-releasing hormone (CRH) secretion in limbic and prefrontal brain areas has been postulated to underly stress-related clinical conditions. Studies in mice with deleted or pharmacologically compromised CRH type 1 receptors (CRH-R1) point to a key role of the CRH/CRH-R1 signaling cascade as a potential drug target. Therefore, we compared the effect of a selective high affinity CRH-R1 antagonist (R121919) on sleep-wake behavior in two rat lines selectively bred for either high or low innate anxiety. We found that the subcutaneous injection of the solvent of R121919, a citrate buffer solution, transiently increased circulating levels of the stress hormones ACTH and corticosterone and reduced sleep, especially in high-anxiety animals. When R121919 was added to the solvent, hormone levels and sleep patterns returned to baseline and were indistinguishable between the rat lines. This finding is in accord with previous observations from a clinical trial in depressed patients and studies in rats with high innate anxiety that suggested major effects of CRH-R1 antagonism in the presence of a pathological (i.e. CRH hypersecretion) condition only., (Copyright 2002 Elsevier Science Ltd.)

Antidepressants are widely used for the treatment of psychiatric disorders, including depression and anxiety. Although they are efficient drugs, there are several unsolved questions regarding their clinical pharmacology. Furthermore, the molecular mechanisms of action of antidepressants are still poorly understood and the molecular targets and pathways remain to be identified. To address these issues, we performed a gene expression analysis in mice treated with two commonly used antidepressants with differing pharmacology (paroxetine or mirtazapine) for 1, 7 or 28 days. We quantified the effects of these treatments on gene expression in the mouse brain with cDNA-microarrays containing 3624 expressed sequence tags (ESTs) representing murine genes expressed in the brain. We found that both drugs led to downregulation of four common genes. In addition, although it was possible to identify common targets for the two drugs, the expression profiles of the drugs differed in a fundamental manner, and the longer the treatment duration, the greater the difference in the profiles. These findings suggest that antidepressants with different pharmacologies can share molecular targets even though the primary pathways at which they act are different.

A variety of test procedures are used in preclinical research on behavioral pharmacology and to dissociate behavioral differences or pharmacologically induced behavioral alterations several independent tests are usually performed. In the present study we introduce a modified hole board procedure for mice which allows us to investigate a variety of behavioral parameters such as anxiety, risk assessment, exploration, locomotion, food-intake inhibition, novelty seeking, and arousal by using only one test. The modified hole board was established by investigating the behavior of two inbred mouse strains, C57BL/6 and BALB. Significant differences in terms of locomotor activity, general exploration, and other parameters were found. Moreover, strain-specific exploration strategies could be detected in the modified hole board. Further, the test was validated by investigating the effects of diazepam as standard anxiolytic on the behavior in both mouse strains. Acute administration of diazepam (1 and 3 mg/kg) induced strong sedative effects in a dose-dependent manner in C57BL/6 mice. In BALB mice, the lower dosage of diazepam showed an activating and anxiolytic action while the 3 mg dosage revealed a slight sedative but still anxiolytic effect in these animals. Taken together, the results demonstrate that the modified hole board enables to differentially investigate behavioral phenotypes and also pharmacologically-induced behavioral alterations in mice. Therefore, this new strategy allows to reduce the number of experimental animals and the time needed, thus, representing an effective screening-tool for behavioral investigations.

The development and course of depression is causally linked to impairment of central regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Previous research documented that the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test identifies HPA dysfunction with high sensitivity. We evaluated the predictive validity for medium-term outcome of the cortisol response in the combined DEX/CRH test in 74 remitted patients previously suffering from major depressive disorder. Of the 74 patients, 61 remained in stable remission and 13 relapsed during the first 6 months after discharge from the hospital. Although the cortisol and ACTH responses in the DEX/CRH test did not differ between the two groups of patients on admission, the responses differed significantly just before discharge (P< 0.05). We defined two dichotomous variables as prediction rules indicating (1) the change between admission and discharge in the cortisol response to the DEX/CRH test, and (2) the effect of the CRH infusion on cortisol as compared to the baseline level in the DEX/CRH test prior to discharge only. An elevated cortisol response in the DEX/CRH test was correlated with a four- to six-fold higher risk for relapse than in individuals with a normal cortisol response. The two proposed rules for predicting relapse within the first 6 months after discharge could be optimized by including age and gender. Hence, an exaggerated cortisol response in the combined DEX/CRH test predicts the recurrence of depressive psychopathology. The test performance can be further optimized if gender and age are taken into account.

A reduction in glucocorticoid receptor (GR) function leads to hippocampus-dependent allocentric spatial learning deficits, altered novelty exploration and disrupted hippocampal long-term potentiation (LTP) in transgenic mice expressing a GR antisense construct. After continuous long-term treatment of these mice with moclobemide (a reversible inhibitor of monoamine oxidase A), spatial navigation performance but not accuracy improved during initial acquisition. These changes were associated with a shift of the threshold for the induction of hippocampal LTP at low stimulation frequencies. Moreover, novel object exploration increased in both control and transgenic animals following long-term treatment with moclobemide. These findings open the possibility that antidepressants might improve hippocampal function under conditions of impaired stress hormone regulation, and that these drugs might in part act through this mechanism to attenuate cognitive deficiency in disorders such as depression.

Clinical and preclinical data suggest that unrestrained secretion of corticoctropin-releasing hormone (CRH) in the CNS produces several signs and symptoms of depression and anxiety disorders through continuous activation of CRH(1) receptors. This led to the development of drugs that selectively antagonize CRH(1) receptors suppressing anxiety-like behavior in rats and also in monkey models of anxiety. These findings led to a clinical development program exploring the antidepressive potential of R121919, a water-soluble pyrrolopyrimidine that binds with high affinity to human CRH(1) receptors and is well absorbed in humans. This compound was administered to 24 patients with a major depressive episode primarily in order to investigate whether its endocrine mode of action compromises the stress-hormone system or whether other safety and tolerability issues exist. The patients were enrolled in two dose-escalation panels: one group (n=10) where the dose range increased from 5-40 mg and another group (n=10) where the dose escalated from 40 to 80 mg within 30 days each. Four patients dropped out because of withdrawal of consent to participate (three cases) or worsening of depressive symptomatoloy in one case. We found that R121919 was safe and well tolerated by the patients during the observation period. Moreover, the data suggested that CRH(1)-receptor blockade does not impair the corticotropin and cortisol secretory activity either at baseline or following an exogenous CRH challenge. We also observed significant reductions in depression and anxiety scores using both, patient and clinician ratings. These findings, along with the observed worsening of affective symptomatology after drug discontinuation, suggests that the pharmacological principle of CRH(1)-receptor antagonism has considerable therapeutic potential in the treatment and the prevention of diseases where exaggerated central CRH activity is present at baseline or following stress exposure.

There is evidence for a differential alteration in the concentrations of 3 alpha-reduced neuroactive steroids in major depression. Because it has been suggested that fluoxetine may shift the activity of the 3 alpha-hydroxysteroid oxidoreductase towards the reductive direction, treatment of major depression may be accompanied by a further increase in plasma 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) concentration. We studied eight male depressed patients before and after treatment with fluoxetine and compared them to healthy age-matched control subjects. Blood samples were quantified for 3 alpha, 5 alpha-tetrahydroprogesterone, 3 alpha,5 beta-tetrahydroprogesterone (THP) and THDOC by means of a highly sensitive combined gas chromatography/mass spectrometry analysis. Compared to control subjects, concentrations of THDOC were higher in depressed patients and decreased after fluoxetine treatment. In contrast, THP concentrations were lower in depressed patients and increased after fluoxetine treatment. Our results give further evidence for a disequilibrium of 3 alpha-reduced neuroactive steroids in major depression, which is normalized by treatment with fluoxetine.

Neuroendocrine studies strongly suggest that dysregulation of the hypothalamic pituitary-adrenocortical (HPA) system plays a causal role in the development and course of depression. Whereas the initial mechanism resulting in HPA hyperdrive remains to be elucidated, evidence has emerged that corticosteroid receptor function is impaired in many patients with depression and in many healthy individuals at increased genetic risk for an depressive disorder. Assuming such impaired receptor function, then central secretion of CRH would be enhanced in many brain areas, which would account for a variety of depressive symptoms. As shown in rats and also in transgenic mice with impaired glucocorticoid receptor function, antidepressants enhance the signaling through corticosteroid receptors. This mechanism of action can be amplified through blocking central mechanisms that drive the HPA system. Animal experiments using antisense oligodeoxynucleotides directed against the mRNA of both CRH receptor subtypes identified the CRH1 receptor as the mediator of the anxiogenic effects of CRH. Studies in mouse mutants in which this receptor subtype had been deleted extended these findings as the animals were less anxious than wild-type mice when experimentally stressed. Thus, patients with clinical conditions that are causally related to HPA hyperactivity may profit from treatment with a CRH1 receptor antagonist.

The purpose of this study was to investigate the functional role the two corticotropin-releasing hormone (CRH) receptor subtypes play in regulating the behavioural performance of rats in various well-defined test situations. Antisense oligodeoxynucleotides (ODNs) corresponding to either the rat CRH1 or CRH2 receptor mRNA were infused chronically into the lateral ventricle of male rats via osmotic minipumps (5 microg/0.5 microl/h over 6 days). Control groups received infusions of either a scrambled sequence ODN or mixed bases ODN or vehicle. On day 4 after surgery, the rats were subjected to 10 min of social defeat and immediately afterwards tested on the elevated plus-maze. Compared to a scrambled sequence control ODN, CRH1 receptor antisense ODN infusion was found to exert an anxiolytic-like effect whereas CRH2 receptor antisense ODN infusion had no effect on defeat-induced anxiety-related behaviour. In contrast, the CRH2 receptor antisense ODN increased immobility in a forced swim test whereas CRH1 receptor ODN-treated rats did not differ from controls. No influence of either ODN was found on general locomotor activity in an open field or on short-term memory performance in a social discrimination test. Furthermore, the CRH2 receptor antisense ODN did not affect spatial learning in a Morris water maze task. An additional experiment comparing a mixture of both missense ODNs and a vehicle control group confirmed that the former failed to induce non-specific (toxic) side effects, further substantiating the specificity of the respective antisense effects measured in this study. The results support the hypothesis that the two CRH receptor subtypes selectively mediate differential effects of endogenous CRH or CRH-related peptides at the brain level with the CRHI receptor contributing predominantly to emotional behaviour and the CRH2 receptor being involved in the regulation of stress coping behaviour.

Background: An altered nocturnal sleep pattern and a dysfunction of the hypothalamic-pituitary-adrenocortical system are neurobiological abnormalities typical for depression. A persistence of these neurobiological alterations during remission has been shown to be associated with an increased risk for a relapse. However, it remains unclear whether these persisting abnormalities are trait markers indicative of an increased vulnerability for affective disorders or only represent 'biological scars' acquired during past episodes. Thus, respective examinations need to be performed in the premorbid state in order to answer this open question., Methods: In the present article we have summarized the various results of the index investigation of a prospectively designed study in which we investigated 54 healthy first-degree relatives (high-risk probands; HRPs) of patients with an affective disorder using polysomnography, the combined dexamethasone corticotropine-releasing hormone (DEX-CRH) test and psychometric measurements., Results: In the cross-sectional part of this study the HRPs, as a group, exhibited a 'depression-like' sleep EEG profile and DEX-CRH test result, while their psychometric profile was characterized by elevated scores on the measures 'Rigidity' and 'Autonomic lability'. On an individual level, 35% of the HRPs were identified as conspicuous in at least two of the three areas under investigation., Conclusions: The question of whether these abnormalities do indeed reflect trait markers indicative of an increased vulnerability for depression will be answered by the longitudinal part of the study that allows for the retrospective identification of the premorbid status of those HRPs who develop an affective disorder during the follow-up period.

Previous studies have shown unequivocally a lack of pituitary-adrenocortical stress hormone activation during lactate-induced panic attacks despite considerable psychopathological alterations, signs of arousal and several vegetative symptoms regularly occurring during stressful conditions. To study the possible inhibitory action of atrial natriuretic hormone (ANH) on adrenocorticotrophic hormone (ACTH) and cortisol release in humans, 10 patients with panic disorder (DSM-III-R) received sodium lactate and placebo (0.9% saline) infusions and ten healthy comparison subjects additionally received a 2.5% saline infusion and the response of ANH, vasopressin, ACTH, cortisol, and several biochemical and physiological cardiovascular parameters were measured. In comparison to placebo, lactate infusion led to enhanced ANH levels in both non-panicking comparison subjects and panickers. Importantly, panickers showed significantly lower baseline levels of ANH than comparison subjects followed by a faster release. No significant concomitant changes in vasopressin, ACTH, and cortisol were observed. During lactate infusion, heart rate was accelerated considerably in the two groups; in contrast, the reduction of pCO2 indicated an enhanced ventilation only in panickers. The pattern of ANH release cannot be attributed simply to either the volume load administered, the cardiac activation or an osmotic effect since neither 0.9 nor 2.5% saline resulted in comparable effects. Additional central nervous mechanisms must be considered for the increased ANH concentrations in lactate-induced panic attacks. We propose that the release of ANH is an intrinsic mechanism contributing to the apparent unresponsiveness of the pituitary-adrenocortical system in lactate-induced panic attacks. In addition, we surmise that ANH may also play a role in the yet unknown mechanisms for termination of panic attacks, e.g. either by inhibitory actions on the locus coeruleus or by bronchiorelaxation and consecutive decatastrophization.

This report summarizes our extensive experience with the application of the DEX/CRH test to assess hypothalamic-pituitary-adrenal-system (HPA) alteration in patients with psychiatric disorders. The application of this combined dexamethasone suppression/CRH-challenge (DEX/CRH) test requires individuals to take 1.5 mg dexamethasone (DEX) at 23:00 h orally the previous night. On the day of the test, 100 micrograms human CRH are administered to the subjects under study at 15:00 h intravenously as a bolus, and blood samples for the determination of plasma cortisol and ACTH are drawn every 15 min from 14:00 h to 18:00 h. DEX/CRH-test results from 96 patients with major depression (MDE), 11 with a manic episode (MA), 9 with panic disorder (PD), 24 with a schizophrenic psychosis (SP), and 82 healthy control subjects served as the data base for this report. Three major conclusions can be drawn from statistical analysis of these data: 1. Psychiatric patients (n = 140), regardless of diagnostic classification, release significantly more cortisol and ACTH after DEX and additional CRH in comparison with age-matched controls. This hormonal release pattern (DEX CRH-test phenomenon) supports the assumption that psychiatric patients are prone to an altered glucocorticoid feedback regulation during the acute illness episode. This supports the notion that the DEX/CRH-test phenomenon constitutes a neuroendocrine sign of these various disorders and emphasizes the usefulness of the DEX/CRH test as a laboratory test to monitor the course of these disorders. 2. The sensitivity of the DEX/CRH test for MDE (about 80%) greatly exceeds that of the standard DST (1-2 mg of DEX), which has been reported to average about 44% in a meta-analysis of the literature data; in our sample the sensitivity of the DST was about 25%. 3. The sensitivity of the DEX/CRH test can be further increased to above 90% if subjects are clustered into four different age ranges: age < 35 years, age between 35 and 50 years, age between 50 and 70 years, and age above 70 years. 4. By reducing the time points of blood sampling for ACTH and cortisol to as few as five (15:00, 15:30, 15:45, 16:00, and 16:15 h), the DEX/CRH-test procedure becomes more convenient and more easily applicable without reducing its sensitivity.

Transgenic mice with impaired glucocorticoid receptor (GR) function produced by partially knocking out GR gene expression with antisense RNA were treated with increasing dosages of dexamethasone. In these mice, ten-fold higher dexamethasone dosages were required to induce full suppression of plasma corticosterone than in normal mice. This relative dexamethasone insensitivity adds to the evidence that these transgenic mice could serve as an appropriate model to study the negative feedback disturbance of the hypothalamic-pituitary-adrenocortical system in affective disorders.

Adrenal steroid hormones are capable of interfering with a variety of behavioral phenomena including sleep. The mechanisms appear to involve effects at the cell membrane as well as nuclear actions mediated by intracellular mineralo- and glucocorticosteroid receptors (MR and GR). We employed the MR agonist deoxycorticosterone (DOC) and the MR antagonist spironolactone (SP) to study the role of MRs in the regulation of human sleep. We also tested whether the effects of DOC upon the sleep EEG and nocturnal hormone secretion (growth hormone and cortisol) are compatible with those predicted for its major metabolite tetrahydro-DOC (THDOC): electrophysiological and animal experiments had suggested that THDOC would act as a hypnotic via positive modulation of the GABAA receptor. Because neither DOC nor SP affected the sleep EEG substantially, the involvement of MRs in the regulation of sleep needs further study. The sleep-endocrine data showed a suppressive effect of DOC upon plasma cortisol concentrations and an earlier occurrence of nocturnal GH maxima, which can be plausibly explained by GR or sigma receptor-mediated effects. Molecular characterization of DOC and SP confirmed a relatively strong effect of DOC upon transactivation via MR and no effect of SP on the GR-mediated transcription rate. In addition, the possibility that a low dose of the mineralocorticoid DOC may serve as a prodrug for the potential hypnotic THDOC is not supported by the current data.

Sleep EEG and the nocturnal secretion of cortisol and testosterone in 12 male patients (mean age 46.4 +/- 11.26 years) with major endogenous depression were investigated concomitantly during acute depression, before treatment and after recovery and drug cessation. Testosterone concentration increased after remission, while cortisol secretion decreased. Sleep EEG disturbances remained unchanged in remitted patients. The data suggest that a blunted testosterone and an elevated cortisol secretion are state markers of acute depression, which normalize independently from sleep structure. An interaction between the hypothalamic-pituitary-gonadal axis and the limbic-hypothalamic-pituitary-adrenocortical axis appears likely.