Development of CRF1 Receptor Antagonists as Antidepressants and Anxiolytics

Department of Psychology, Grand Valley State University, Allendale, MI 49401, USA.
CNS Drugs (Impact Factor: 5.11). 02/2006; 20(11):887-96. DOI: 10.2165/00023210-200620110-00002
Source: PubMed


Depression and anxiety disorders are highly prevalent forms of mental illness that are considered to be stress-related disorders because some form of stressful life event often triggers their symptoms. Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioural responses to stress, and clinical studies provide evidence for the role of CRF in the development of depression and anxiety disorders. Two CRF receptor subtypes have been identified to date - the CRF(1) receptor and the CRF(2) receptor. Preclinical models provide evidence of a role for CRF(1) receptors in the activation of the stress response. Data from these experiments suggest that antagonism of CRF(1) receptor activity may provide an effective pharmacological treatment for stress-related psychiatric disorders. This review highlights progress to date with the development of CRF(1) receptor antagonists as potential pharmacotherapies for depression and anxiety disorders. Although additional research is needed to fully investigate the efficacy and safety profiles of CRF(1) receptor antagonists as candidate medications for these disorders, the results of preclinical experiments and clinical trials are encouraging. Further development of these compounds is warranted.

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    • "Intracerebroventricular administration of CRH produces anxiety-like behaviors in animal models, including features particularly relevant to PTSD such as sleep disturbance, enhanced acoustic startle response, and increased conditioned fear responses. CRH type 1 receptor (CRHR1) antagonists reverse stress-related behaviors in preclinical models, including the elevated plus-maze, defensive withdrawal, light/dark transfer, and conditioned fear paradigms [11]. Animal models of early life stress have been associated with hyperactivity of CRH neurons, with chronic activation of CRHR1 in limbic brain regions [12,13]. "
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    ABSTRACT: Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months’ duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks’ exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects. Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD. Trial registration Identifier: NCT01018992. Registered 6 November 2009. First patient randomized 14 January 2010.
    Trials 06/2014; 15(1):240. DOI:10.1186/1745-6215-15-240 · 1.73 Impact Factor
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    • "Stress not only increases glucocorticoid levels through the cellular actions of CRF in the hypothalamic-pituitary-adrenal axis, but also induces the release of CRF in extrahypothalamic brain regions, such as VTA [135, 136], where stimulates CRFR1 on VTA dopamine neurons and activates a protein-kinase-C- (PKC-) dependent enhancement of Ih, which led to increased cell firing [137]. This activation may be implicated in the interaction between stress, dopamine, and motivation which is important for many behaviors and psychiatric disorders such as depression [138–140] drug abuse [136, 141], and schizophrenia [138, 142]. "
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    ABSTRACT: Obesity has become one of the leading causes of illness and mortality in the developed world. Preclinical and clinical data provide compelling evidence for ghrelin as a relevant regulator of appetite, food intake, and energy homeostasis. In addition, ghrelin has recently emerged as one of the major contributing factors to reward-driven feeding that can override the state of satiation. The corticotropin-releasing-factor system is also directly implicated in the regulation of energy balance and may participate in the pathophysiology of obesity and eating disorders. This paper focuses on the role of ghrelin in the regulation of appetite, on its possible role as a hedonic signal involved in food reward, and on its interaction with the corticotropin-releasing-factor system and chronic stress.
    International Journal of Peptides 09/2011; 2011(1687-9767):898450. DOI:10.1155/2011/898450
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    • "This report demonstrates this concept in action using a novel compound that shows a good anxiolytic profile in animal models. Preclinical and some clinical evidence suggests that drugs that act at the corticotrophin-releasing factor (CRF) system may be useful for the treatment of psychiatric disorders, such as anxiety and depression or other stress-related disorders (Valdez, 2006). CRF is a 41 amino acid peptide produced by the paraventricular nucleus (PVN). "
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    ABSTRACT: We have validated the use of prolonged inhalation of 7.5% carbon dioxide (CO(2)) as a human model of anxiety and have shown that drugs from two prototypical classes of anxiolytics, benzodiazepines and a serotonin reuptake inhibitor, attenuate CO(2)-induced symptoms (Bailey et al., 2007a). Preclinical evidence suggests that drugs acting at the corticotropin-releasing factor (CRF) system may be useful for the treatment of depression, anxiety, and other stress-related disorders (Valdez, 2006), hence we have now examined the effects of a CRF(1) receptor antagonist in the 7.5% CO(2) model. In a randomized double-blind, placebo-controlled, study in 32 healthy participants we examined the effects of 7 days of treatment with the CRF(1) receptor antagonist, R317573, at a dose that shows a favourable safety profile and is comparable with those effective in preclinical models (40 mg). On day 8, eight of the placebo-treated group received lorazepam (LZP) 2 mg as a positive control. All participants underwent 20 min inhalation of 7.5% CO(2)-enriched air. Subjective reports of peak gas effects were assessed using visual analogue scales and questionnaires. The mean age of participants was 26 years, and 13 were male. The peak effects of CO(2) were expressed as a difference from baseline scores obtained while breathing air alone. Compared with placebo (PLAC), both drug groups showed a decrease in all subjective symptoms, total score on the panic symptom inventory (CRF 11 [2.6], PLAC 16.4 [3.1], LZP 2.9 [3.0]) and a generalized anxiety disorder symptom scale (CRF 2.2 [1.5], PLAC 8.2 [2.2], LZP 1.1 [1.5]). We have shown that a drug that acts to inhibit the CRF(1) receptor shows efficacy in the 7.5% CO(2) model of anxiety in healthy participants.
    Journal of Psychopharmacology 05/2011; 25(9):1199-206. DOI:10.1177/0269881111400650 · 3.59 Impact Factor
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