Florian Holsboer

..To extract significantly regulated genes from a genome-wide microarray data set and to deduce underlying CRHR1-dependent signaling networks, we combined supervised and unsupervised algorithms...

..Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days...

..Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses...

..The results of the clinical studies underscore that CRH(1) receptor antagonists represent promising novel therapeutics in the psychopharmacology of depression and anxiety...

..This process will require many further steps and collaboration between basic and clinical neuroscience...

..These could be a first step into personalized medicine using treatments tailored to the specific pathology of the patients...

..Recent findings obtained with this mouse model and its usefulness in the context of the CRH-dependent, region-specific changes in depression will be discussed...

..The application of a personalized depression therapy supported by genetic testing and biomarkers raises the possibility of early recognition of the risk of disease and a targeted intervention before the symptoms of disease emerge...

..Once these goals are achieved notorious undertreatment of depression may come to an end...

....

..Thus, patients with clinical conditions that are causally related to HPA hyperactivity may profit from treatment with a CRH1 receptor antagonist...

..All these strategies are not yet fully clinically developed, but preliminary data from basic and clinical research strongly underscore that such strategies may lead to innovative treatment modalities...

..Furthermore, the potential of drugs that interfere more directly with stress hormone regulation, such as corticosteroid receptor antagonists and corticotropin-releasing hormone receptor antagonists, is discussed...

..In this sense, biotechnology opens up new chances for drug development through serendipity by providing new data bases on which systematic biological research in psychiatry and psychology can be conducted...

..The reported associations in independent samples of AD and MDD support an estrogen-dependent function of GAL in pathophysiology of anxiety and depression, affecting response to antidepressant treatment...

..Chronic paroxetine enhanced the presynaptic responsivity in HAB rats, but not LAB rats, pointing to a preferential efficacy of paroxetine in rats with enhanced anxiety/depression-related behaviour...

..Taken together, our results demonstrate a role for an AVP gene polymorphism and CBF-A in elevated AVP expression in the PVN of HAB rats likely to contribute to their behavioral and neuroendocrine phenotype...

..In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories...

....

..Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve--indicating the involvement of effects distant from reuptake inhibition...

..In addition, our study highlights the use of in vivo microdialysis to assess the neuroendocrine endophenotype of animal models via profiling of stimulus-response patterns of stress hormones...

..These associations, however, are not unidimensional, but dependent on the kind of sleep parameters as well as on the selection of the subjects...

..In addition, differential regulation of dynein association and nuclear translocation contributes to the effects of the two immunophilins on the glucocorticoid receptor in mammals...

..Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition...

..This finding can be viewed as a further step into personalized antidepressant treatment...

..This region contains two candidate genes for purinergic ligand-gated ion channels, P2RX7 and P2RX4, and one gene coding for calmodulin-dependent protein kinase kinase b (CaMKKb)...

..Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome...

..Furthermore, we provide evidence for a new role of limbic Crhr1 in neuroendocrine adaptation to stress...

..Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses...

..Therefore, we investigated in CNS-specific CRH receptor type 1 deficient mice whether centrally administered CRH could induce its sleep-wake modulatory effects without peripheral induction of HPA activity...

..This reaction pattern suggests that subjects carrying these variants are at risk of displaying chronically elevated cortisol levels after repeated stress constituting a risk factor for stress-related diseases...

..This so-called 'stress reactivity' (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors...

..Furthermore, GAL is involved in hypothalamic-hypophysiotropic signalling and cosecreted with luteinizing hormone-releasing hormone (LHRH), possibly acting as a mediator of estrogen action...

..Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression...

..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...

..Results resonate with a role of the PCC/RspC for the regulation of consciousness. We further submit that preserved corticocortical synchronization could represent a prerequisite for maintaining internal and external awareness...

..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...

....

..In conclusion, these data suggest a novel, previously unknown role of the CRH/CRH-R1 system in modulating neurovascular gene expression and function...

..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...

....

..Ongoing follow up investigations of HRPs will clarify whether the observed increase in sigma EEG activity during nonREM sleep is of clinical relevance with respect to the likelihood to develop an affective disorder...

..Glucocorticoids themselves are reported to increase leptin synthesis and secretion in humans...

..Additional studies will examine whether glyoxalase-I has an impact beyond that of a biomarker to predict the genetic predisposition to anxiety- and depression-like behavior...

..Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported...

..Our data demonstrate that the high anxiety-related behavior and low anxiety-related behavior mouse model is a valuable tool for anxiety disorder drug discovery efforts...

..Gene expression and regulation was determined by microarray analyses and further evaluated by bioinformatics tools including pathway and cluster analyses...

..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...

..These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder...

..We conclude that the interaction between CRH and MR presents a novel mechanism involved in the adaptation of the brain to psychologically stressful events...

..These results further underline a possible important role of genetic variations within the system controlling serotonergic neurotransmission for the development and course of disease in PD...

..An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood...

....

..Thus, the SNP-associated deficit in plasma and central AVP contributes to signs of cDI and, at least partially, to low trait anxiety, both features being typical of LAB animals...

....

....

..These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders...

....

..Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system...

....

..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...

..However, data from expression studies imply that these polymorphisms could tag functional effects on the neighboring gene MYO3A, which is also expressed in the brain, including the cingulate cortex and the amygdala...

..Polymorphisms in the gene encoding the glucocorticoid receptor (GR) regulating co-chaperone FKBP5 have been shown to alter GR sensitivity and are associated with an increased risk to develop posttraumatic stress disorder (PTSD)...

..Importantly, similar results were obtained with a constitutively active GR. Thus, the action of p23 on the nuclear stage of GR regulation requires its Hsp90 co-chaperone function, but not its chaperone activity...

..To elucidate the impact of weight on the course of depression beyond comorbidity, we investigated psychopathology, attention, neuroendocrinology, weight change, and treatment response in MDD patients, depending on their weight...

..In the context of an anxiety-inhibiting role of the dmPFC, we propose that failure to sufficiently activate this region in stressful situations may contribute to high trait anxiety...

..Our results confirm that dex/CRH tests can be used as predictors of clinical course also under mirtazapine treatment...

....

....

..We conclude that trimipramine is an antidepressant with sleep-improving qualities that possibly acts through inhibition of hypothalamic-pituitary-adrenocortical system activity by a yet unknown mechanism...

..These data provide further evidence for the intricate relationship between corticotropin-releasing hormone and serotonin and the important role of the CRH-R1 herein...

....

..Whereas it is well established that the endocrine and thermoregulatory systems are very sensitive to endotoxin, this study shows that human sleep-wake behavior is even more sensitive to activation of host defense mechanisms...

..This indicates that extrapolation from LTP in a single brain structure to complex behaviours such as learning and memory may not be justified...

..Taken together, our data reveal a selective compensatory activation of the hypothalamic vasopressinergic, but not the oxytocinergic system, to maintain basal ACTH secretion and HPA system activity in Crhr1-/- mutants...

..We conclude that pharmacological blockade of CB1 signaling shares antidepressant-like behavioral effects with desipramine, but reveals opposite effects on HPA axis activity...

..This polymorphism results in an amino acid exchange in the C-terminal cytosolic domain of the P2RX7 channel protein, suggesting that the observed P2RX7 polymorphism might play a causal role in the development of depression...

..Whether the relatives with the neurobiological and psychometric abnormalities we identified have a higher risk for developing an affective disorder than those without has to be answered by the still ongoing prospective part of the study...

..Within the intraadrenal CRH/ACTH system, our data suggest different roles for CRHR1 and CRHR2 in fine-tuning of adrenocortical corticosterone release...

..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...

....

....

..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...

..The aim of this study was to differentiate between healthy members of unipolar and bipolar families without a previous history of any psychiatric disorder according to the neurobiological and psychometric findings...

..In view of the GABAergic inhibition of HPA system activity and the anxiogenic effect of CRH, benzodiazepine withdrawal symptoms may be partly due to a disinhibition of the HPA system during discontinuation of benzodiazepines...

..e. CRH hypersecretion) condition only...

....

..Whereas the levels of TNF-alpha and sTNF-R p75 were reduced, the levels of sTNF-R p55 increased after a transient decrease...

....

..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...

..This essay also briefly reviews the status of knowledge regarding GC actions on neuronal birth, survival and death from the perspective of the importance of these phenomena in depression...

..As this effect could imply an antidepressive potency we studied the effect of intravenous galanin administration on psychopathology and sleep EEG in patients with depression...

..Furthermore, there are no data on the effects of age and gender on nocturnal renin and the interaction between these variables, sleep, growth hormone (GH) and cortisol...

..Moreover, it is predictive for the onset of a psychiatric disorder. Therefore, it can be recommended as a possible endophenotype of these diseases...

....

..The existence of an intra-adrenal CRH/CRHR1 regulatory system which contributes to the corticosteroid secretory activity adds to the complexity of HPA system regulation and stress hormone homeostasis...