ReviewCentral CRH system in depression and anxiety — Evidence from clinical studies with CRH1 receptor antagonists
Introduction
Stress and its neurobiological correlates are substantially involved in causation and development of depression and anxiety disorders. Chronic and acute stressors contribute to disease liability and trigger the onset of these disorders (Heim and Nemeroff, 2001, Charney and Manji, 2004, de Kloet et al., 2005).
In response to any kind of stress the pituitary gland secretes corticotrophin (ACTH), which leads to increased synthesis and release of cortisol (corticosterone in rodents) at the level of the adrenal cortex. Corticotrophin releasing hormone (CRH) and vasopressin are the key central neuropeptides accounting for peripheral increase of stress hormones. Both neuropeptides are synthesized in specialized neurons in the hypothalamus (paraventricular nuclei), from which they reach the anterior pituitary via portal vessels. These neuroendocrine activities are closely associated with a large number of other neural projections resulting in neuropeptide release in many brain areas implicated in the neuroanatomy of depression and anxiety, including the central nucleus amygdala, hippocampus, locus coeruleus and cortical structures, such as the prefrontal cortex.
Both neuropeptides, CRH and vasopressin, are involved in the adaptation of stress as they elicit a number of behavioral responses that are suited to cope optimally with a threat. When hypersecreted over extended periods of time these initially beneficial effects reverse into increased liability for anxiety- and depression-like behavior (Landgraf, 2006). Central administration of CRH to rats or mice as well as CRH overexpression in transgenic mice resulted in behavioral changes including anxiety and depression related symptoms (Britton et al., 1986, Pepin et al., 1992, Stenzel-Poore et al., 1994, Ströhle et al., 1998; Deussing, personal communication).
Many clinical research reports agreed that CRH is elevated in depression, but also in anxiety disorders. For instance, the cerebrospinal fluid of depressed patients contained elevated levels of the CRH (Nemeroff et al., 1984, Landgraf, 2006), which, if extrapolated to the situation in the brain, is consistent with reduced CRH binding in forebrains of depressed suicide victims (Merali et al., 2004, Nemeroff et al., 1988) and elevated numbers of CRH-producing neurons in the paraventricular hypothalamic nucleus of patients with depression (Raadsheer et al., 1994). Elevated CRH was also observed in the cerebrospinal fluid of patients with posttraumatic stress disorders (Bremner et al., 1997). The ACTH response to exogenous CRH was blunted among depressed patients indicating desensitized CRH receptors secondary to central hypersecretion (Gold et al., 1984, Holsboer et al., 1984, Holsboer et al., 1986). If dexamethasone pretreated patients with depression receive a test dose of CRH, an excessive release of ACTH and cortisol can be observed (Heuser et al., 1994, Ising et al., 2005). Similar results have been described for patients suffering from panic disorder (Erhardt et al., 2006, Schreiber et al., 1996). These findings can be explained by elevated secretion of the hypothalamic neuropeptides CRH and vasopressin, which are negatively regulated by endogenous corticosteroids. As a result, endogenously elevated neuropeptides in combination with exogenously administered CRH amplify each others effects at the level of anterior pituitary to produce excessive ACTH and cortisol secretions.
These findings are major pillars of the corticosteroid receptor hypothesis, submitting that impaired intracellular signaling of steroid-activated hormone receptors (glucocorticoid receptor and mineralocorticosteroid receptor) results in inappropriately high and enduring secretions of both, CRH and vasopressin in the brain and ACTH and cortisol in the periphery (Holsboer, 2000). The latter stress hormone is easily crossing the blood-brain barrier. Because a host of genes expressed in the brain are activated or repressed by corticosteroids, mostly via regulatory response elements, it is not surprising that continuous overexposure of the brain to this stress hormone also produces behavioral changes (McEwen, 2007). These include labile, mostly depressed, mood. Similarly, depressed mood is the most frequent psychopathological change among patients with M. Cushing, characterized by unrestrained hypophyseal-adrenal cortex activity. Another behavioral sequel of hypercortisolism is cognitive deficits, well known to be associated with depression. Many experiments suggested that excessive corticosteroid secretion endangers hippocampal neurons by increasing their vulnerability to noxious agents such as excitatory aminoacids and oxidative stress (Behl et al., 1997, Sapolsky, 2000). A current hypothesis submits that chronic glucocorticoid overexposure increases hippocampal vulnerability, which may render an individual susceptible for pathological stress response, i.e., for the development of a stress-related disorder. Antidepressants probably also work via restoration of this deficit by enhancing hippocampal neurogenesis (Nestler et al., 2002). Some of the depressed patients also show psychotic features. Since hypercortisolism either via a hormone secreting tumor or via corticosteroid medications also often produces psychotic features, it was submitted that the psychotic symptoms are mainly produced by corticosteroid excess (Schatzberg et al., 1985).
As a consequence of these abnormalities induced by various stress hormones their potential role in the pathogenesis of depression has been hypothesized and therefore three complementary lines of pharmacological interventions are currently in the focus of antidepressant drug discovery and development programs (see Fig. 1).
In the following, we focus on the CRH system, discuss CRH receptors as drug targets, and present clinical findings obtained with CRH1 receptor antagonists.
Section snippets
CRH receptors as drug targets
CRH exerts its actions through two different G-protein-coupled receptors (GPGR), CRH1 and CRH2 receptors. Both receptors are unequally expressed in the brain, where they not only bind CRH but also three other CRH related peptides: Urocortin I (UCN I), stresscopin-related peptide (also termed UCN II) and stresscopin (UCN III). UCN I binds with equal affinity at both CRH1 and CRH2 receptors, while UCN II and III preferentially bind at CRH2 receptors and have poor affinity for CRH1 receptors (
Open-label dose-escalation trial with NBI-30775/R121919
The first clinical study published was an open-label trial designed to assess the safety of NBI-30775/R121919. This drug is a nonpeptide tricyclic high-affinity CRH1 receptor antagonist, which is well absorbed when given orally, penetrates the blood-brain barrier and binds specifically to cloned human CRH1 receptors with high-affinity (Ki = 3.5 nmol/L), while binding to other neurotransmitter and neuropeptide receptors or transporters is absent or more than 1000-fold lower (Chen et al., 2004,
Conclusion and future directions
The huge basic science data base contrasts with the paucity of clinical reports using CRH1 receptor antagonists. In fact, a number of unreported clinical trials were discontinued because of toxic side effects. Importantly, these adversities do not question the pharmacological principle of muting CRH/CRH1 receptor signaling, as toxicity of investigational CRH1 receptor antagonists was observed in tissues not carrying CRH1 receptors. Once a CRH1 receptor antagonist has taken all the hurdles
Conflict of interest statement
Florian Holsboer, MD, PhD, is founder and shareholder of Affectis Pharmaceuticals, and shareholder of Corcept and Neurocrine Biosciences. Marcus Ising, PhD, has nothing to disclose.
References (62)
- et al.
Activating and ‘anxiogenic’ effects of corticotropin releasing factor are not inhibited by blockade of the pituitary–adrenal system with dexamethasone
Life Sci.
(1986) - et al.
The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies
Biol. Psychiatry
(2001) - et al.
Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist
Neuropsychopharmacology
(2002) - et al.
Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression
J. Psychiatr. Res.
(2004) - et al.
The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders
J. Psychiatr. Res.
(1994) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety
J. Psychiatr. Res.
(1999)The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
(2000)- et al.
Human corticotropin-releasing hormone in depression
Biol. Psychiatry
(1986) - et al.
The combined dexamethasone/CRH test as a potential surrogate marker in depression
Prog. Neuro-psychopharmacol. Biol. Psychiatry
(2005) - et al.
Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression — a potential biomarker?
Biol. Psychiatry
(2007)
Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects
J. Psychiatr. Res.
Differential behavioural effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain
J. Psychiatr. Res.
Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders
Neurosci. Lett.
Mice with mutations in the HPA-system as models for symptoms of depression
Biol. Psychiatry
Neurobiology of depression
Neuron
A corticosteroid/dopamine hypothesis for psychotic depression and related states
J. Psychiatr. Res.
Dysregulation of the hypothalamic–pituitary–adrenocortical system in panic disorder
Neuropsychopharmacology
Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development
Neuron
Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated
J. Psychiatr. Res.
Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro
Endocrinology
Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder
Am. J. Psychiatry
Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression
J. Neurosci.
Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention
Sci. STKE
Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure–activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists
J. Med. Chem.
Stress and the brain: from adaptation to disease
Nat. Rev. Neurosci.
Dimensions of arousal: wakefulness and vigor
Hum. Factors
Regulation of the hypothalamic–pituitary–adrenocortical system in patients with panic disorder
Neuropsychopharmacology
Psychiatric implications of basic and clinical studies with corticotropin-releasing factor
Am. J. Psychiatry
The corticotropin-releasing factor receptor: a novel target for the treatment of depression and anxiety-related disorders
Expert Opin. Ther. Targets
Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists
J. Med. Chem.
HAMD Hamilton Depression Scale
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