CRF1 receptor antagonists: treatment of stress-related disorders

Drug Discovery Today: Therapeutic Strategies

Vol. 5, No. 3 2008

Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY

TODAY THERAPEUTIC

STRATEGIES

Psychiatric disorders

CRF1 receptor antagonists: treatment of stress-related disorders§ John H. Kehne*, George D. Maynard Neurogen Corporation, 35 NE Industrial Road, Branford, CT 06405, USA

Adaptive responding to stressors is of fundamental importance to the survival of the species. Aberrant hyperactivation of corticotropin releasing factor type

Section Editor: Leslie Iversen – Department of Pharmacology, University of Oxford, UK

1 (CRF1) receptors in dysfunctional stress response system (SRS) pathways may contribute to stressrelated psychopathology and therefore CRF1 receptor antagonists (CRAs) may be useful in their treatment. The status of nonpeptidic, orally active, brain-penetrating CRAs being developed for the treatment of depression, anxiety, irritable bowel syndrome and drug abuse

pathological emotional and mood states and CRF1 receptor antagonists (CRAs) are proposed as novel treatments (for reviews, see [1–3]). The status of current CRAs in development for a range of stress-related disorders (Table 1) is discussed as are the future directions based on an evolving understanding of the SRS and the impact of genetic, environmental and developmental factors.

is reviewed. Mood disorders

Introduction Evolution has crafted a complex stress response system (SRS) which mediates responses to external or internal stressors, thereby serving an essential survival function. Multiple neurochemicals comprise the SRS, but one of the great interests is the peptide corticotropin releasing factor (CRF) acting upon postsynaptic CRF1 receptors (CRF1 pathways). CRF1 pathways uniquely participate in multiple SRS components, that is behavioral limbic/cortical circuits (e.g. prefrontal, cingulate and insular cortices; amygdala, hippocampus, periaqueductal gray and monoamine pathways), endocrine hypothalamic– pituitary–adrenal (HPA) axis pathways (anterior pituitary) and brainstem autonomic circuits, which, when transiently activated by stressors, produce a coordinated hyperarousal and subsequent coping response (Fig. 1; for review, see [1]). Chronically hyperactivated CRF1 pathways contribute to § CRF1 receptor antagonists cited: antalarmin; BMS-562086 (Pexacerfont); CP154,526; CP-316,311; MJL-1-109-2; NBI-34041; NBI-135965; R121919; PF-572778; GSK561679; GSK586529; GW876008; MTIP; ONO-2333Ms; SSR-125543. *Corresponding author: J.H. Kehne ([email protected]), ([email protected])

1740-6773/$ ß 2008 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddstr.2008.09.003

Mood disorders include depressive disorders (major depressive disorder (MDD) and dysthymia) and bipolar disorders (bipolar I and II). MDD has been a primary focus as a clinical target for CRAs. Depressive episodes may have additional features that can indicate a greater degree of severity, for example the presence of psychosis, catatonia or melancholia. In humans, there are several lines of evidence for chronic hyperactivation of CRF1 pathways in MDD (for reviews [1,4]). Evidence for elevated CRF1 pituitary drive includes: (a) chronically elevated plasma cortisol levels in a subset (approximately half) of patients with MDD; (b) a corresponding blunted dexamethasone suppression of HPA axis activity, indicative of diminished feedback inhibition and (c) blunted intravenous (IV) CRF-induced stimulation of ACTH release from the anterior pituitary, indicative of downregulated pituitary CRF1 receptors. Notably, HPA axis hyperactivity is closely related to treatment response and long-term outcome in depression. Evidence for hyperactivated brain CRF1 pathways includes: (a) elevated cerebrospinal fluid (CSF) CRF 161

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Figure 1. CRF and the stress response system (SRS). Top: The SRS is composed of behavioral, endocrine and autonomic components which act in concert to generate an appropriate, adaptive response to a stressor. A key mediator in the SRS is CRF, acting through the CRF1 receptor, which is normally in a low state of basal activity. Stressor-induced CRF1 receptor activation facilitates physiological processes which allow the organism to evaluate the stressor and choose an adaptive response, while in parallel activating effector systems. Execution of a successful response will minimize the impact of the stressor and in parallel feedback inhibitory systems will ensure that the SRS will return to normal, prestress levels. Bottom: Abnormal hyperactivation of CRF pathways and CRF1 receptors can result in a dysfunctional SRS in which normal alarm reactions may be maladaptive. A complex interplay of genetic risk factors, vulnerability factors (prior history) and stressor factors (intensity, duration and chronicity), may be expressed neuronally as imbalances in different CRF1 receptor pathways in the brain and functionally, as different alterations in the alarm reaction. Thus, CRF1 receptor hyperactivity seen in different disorders may be manifested as alarm reactions with exaggerated or diminished amplitude and/or prolonged or shortened duration. Different functional effects may reflect sensitization versus desensitization of CRF1 receptors in the same or different CRF pathways in the SRS. Transient acute or repeated exposures to intense stressors may sensitize certain components giving rise to heightened or prolonged alarm reactions, whereas more chronic stressors may desensitize CRF1 receptors and give rise to blunted responses and decreased reactivity. Tonic elevations in stress hormones and anxiety levels may be the expressions of extensive failure of adaptation of the SRS. CRF1 receptor antagonists may act to restore normal balance and reactivity in the stress response across several stress-related disorders (from [1], reprinted with permission from Bentham publishers).

levels that correlate with blunted ACTH response to IV CRF, indicative of a coordinated hyperdrive of HPA and non-HPA axis CRF pathways and (b) downregulated CRF1 receptors in multiple regions of postmortem brains of depressed suicide victims, including frontal cortex. Desensitization of CRF1 receptors could reduce a restraining effect of frontal cortex on subcortical structures such as the amygdala and the periventricular nucleus of the hypothalamus, important components of the SRS. In summary, these data indicating excessive drive on CRF1 receptors provide a rationale for using CRAs for treatment in depression. Postmortem studies in depressed suicide victims have also demonstrated elevated CRF levels in brainstem monoaminergic nuclei, including norepinephrine (NE) cells of the locus coeruleus and serotonin (5HT) cells of the dorsal raphe, pathways that are affected by classic reuptake inhibitor anti162

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depressants. These interactions may be functionally relevant, because elevated NE activity [5] or decreased 5HT activity [6] can stimulate CSF CRF in humans. Notably, hyperactivation of CRF1 pathways may be particularly evident in certain subpopulations of depressed patients (for reviews, see [1,7]). Severe melancholic depression is associated with high CRF and NE levels, and HPA axis hyperactivity. Depressives with psychotic features demonstrate profound exaggerations of HPA axis activity and hypercortisolemia and electroconvulsive therapy decreased CSF CRF. Excessive HPA axis dysfunction in adult depression has been noted in individuals with a prior history of severe trauma early in life (for reviews, see [8,9]). In animals, exposure to early life stressors produces hyperactivated CRF1 pathways and evidence for affective disturbance in adulthood. Importantly, a recent genetic study reports that the presence

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Drug Discovery Today: Therapeutic Strategies | Psychiatric disorders

Table 1. Recently investigated small molecule CRF1 receptor antagonists (CRAs). Target

Pros

Depression – Clinical evidence for the MDD role of hyperactivated CRF1 pathways in depressed patients (HPA axis; postmortem CRF levels and CRF1 receptors) Preclinical evidence for CRF1 hyperactivity. Antidepressant effect reported in open label trial CRAs activity in certain ‘high stress’ or ‘high anxiety’ animal models Safety versus HPA axis demonstrated

Anxiety – SAD

Anxiety – GAD

Cons

Compound identifier – reported clinical status

R121919 – efficacy in open-label depression trial Development stopped because of abnormal liver function tests CP-316,311 – showed no difference versus placebo in Phase II trial Pexacerfont (BMS-562086) – Phase II Some evidence that subtypes of MDD may be listed as completed 10/07 but more sensitive to CRAs results not yet released GSK561679 – Phase II trial registered 08/08 CRAs not generally GSK586529 – Phase I active in antidepressant screens under low stress conditions ONO-2333Ms – program discontinued because of lack of efficacy (07/08)

JNJ/ Neurocrine

[15]

Pfizer

[16]

BMS

www.clinicaltrials.gov/

GSK/ Neurocrine GSK/ Neurocrine

www.clinicaltrials.gov/

ONO Pharm.

www.clinicaltrials.gov/

SSR-125543 – Phase I (no data available)

Sanofi-Aventis

http://en.sanofi-aventis.com/ www.ono.co.jp/eng/ii/f_ii.htm

GW876008 – Phase II SAD study showed no difference versus placebo

GSK/ Neurocrine

www.neurocrine.com/

NBI-34041 – Phase I

GSK/ Neurocrine

[49]

Two double blind, placebo-controlled trials with active comparator reported no efficacy (only one published)

Lack of efficacy in Genetic link in children with behavioral inhibition; Phase II trial, but findings not published CRF studies in socially housed monkeys Imaging studies demonstrate dysfunctional SRS in humans Safety versus HPA axis demonstrated in Phase I trial CRAs not typically active in ‘low stress’ animal models sensitive to benzodiazepines

Reduced stress-induced ACTH release and corticosterone in ‘Trier Social Stress Test’ BMS Pexacerfont (BMS-562086) – Phase II (completed 03/08; results not reported) PF-572778 – Phase I program Pfizer discontinued

http://www.clinicaltrials.gov/

www.pfizer.com/research/ pipeline/pipeline.jsp www.clinicaltrials.gov/

Anxiety – PTSD

Key role of traumatic stress in etiology

IBS

CRAs active in animal models of IBS

GW876008 – Phase II trial in progress

GSK/ Neurocrine

Peptidic CRF antagonist active in human experimental medicine model

Pexacerfont (BMS-562086) – Phase II study listed as completed in January 2008 but results not yet released

BMS

www.neurocrine.com/ www.clinicaltrials.gov/

Reversed anxiety-like behavior and reduced alcohol self administration in preclinical models

MTIP – preclinical

NIAAA/ Eli Lilly

[44] www.niaaa.nih.gov/

Alcohol abuse

No clinical data to evaluate hypothesis

Currently Refs researched by

No PTSD trials listed

www.clinicaltrials.gov/ www.clinicaltrials.gov/

CRF, corticotropin releasing factor; HPA, hypothalamic–pituitary–adrenal; MDD, major depressive disorder; SAD, social anxiety disorder; GAD, generalized anxiety disorder; PTSD, posttraumatic stress disorder; IBS, irritable bowel syndrome; SRS, stress response system; JNJ, Johnson & Johnson; BMS, Bristol Myers Squibb; GSK, GlaxoSmithKline; NIAAA, National Institute on Alcohol Abuse and Alcoholism.

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of certain CRF1 gene polymorphisms is associated with increased probability that individuals exposed to early life trauma develop depression as adults [10]. In summary, these data suggest that CRAs might be particularly suitable for certain subpopulations of depressed patients in which CRF1 pathways show the greatest dysfunction. Studies in animal models of depression (see [1,11] for reviews) have generally reported that CRAs, unlike classic antidepressants, are not active in standard acute models (forced swim test and tail suspension test) run in normal rodents, but are active in certain genetic lines such as the Flinders Sensitive Line rat which have been selectively bred to exhibit a high degree of depressive traits. In the chronic mild stress model of depression in rats, there are elevated CRF levels in key limbic (bed nucleus of the stria terminalis) and HPA axis (periventricular nucleus of the hypothalamus) structures of the SRS. In mice, SSR125543A or antalarmin given for 30 days is efficacious in ameliorating the deficits produced by chronic mild stress. Antidepressants may exert their therapeutic effects in part by stimulating hippocampal neurogenesis and by decreasing stress induced decreases in hippocampal neurogenesis. SSR125543 ameliorated stressinduced decreases in hippocampal neurogenesis and improved behavior in mice exposed to seven weeks of chronic mild stress. Overall, these data indicate that CRAs can have antidepressant effects under conditions of chronic stress which give rise to excessive stimulation of CRF1 pathways. In genetic models, CRF overexpressing mice show neuroendocrine and autonomic changes similar to those seen with chronic stress as well as CRF1 receptor downregulation. CRF overexpression in the amygdala results in impaired HPA axis feedback inhibition and depressive- and anxious-like symptoms in rats [12]. The functional consequences of aberrant, sustained glucocorticoid output from chronic stress may be profound [13,14]. Corticosterone can stimulate neuronal activity in limbic areas such as the amygdala and detrimental changes in hippocampal organization and volume can be seen following the chronic administration of synthetic glucocorticoids, changes that resemble alterations observed in depression. CRAs may be useful in preventing these long-term deleterious effects. There are two published clinical trial results for CRAs in depression [15,16]. In a Phase II open-label clinical trial in MDD, R121919 demonstrated antidepressant activity. This occurred without diminishing basal levels of ACTH or cortisol, nor did it prevent reactivity of the HPA axis, in that ACTH responses to an IV CRF challenge were not eliminated [15]. This study indicated that chronic dosing with a CRA could produce efficacy without compromising HPA axis function but R121919 was halted in development, because of concerns about hepatotoxicity. Recently, CP-316,311 was evaluated in MDD in a double-blind, placebo-controlled trial with an 164

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active comparator (sertraline) and reported to be safe and well tolerated, but lacking efficacy [16]. Although sufficient plasma levels were claimed based on animal receptor occupancy studies, the lack of data in an appropriate animal model of depression makes it unclear if sufficient plasma levels were achieved for efficacy. These data highlight the general need for predictive animal assays and, in humans, suitable biomarkers to assess for the central blockade of CRF1 receptors. Blockade of stress-induced HPA axis activity is not an adequate biomarker because it reflects peripheral CRF1 receptor blockade in the pituitary. Measurement of in vivo receptor occupancy has been impeded by the lack of a suitable, high potency PET ligand for CRF1 receptors. Development of an adequate biomarker will be an important step in facilitating further assessment of the CRA approach. Results in other ongoing clinical studies (Table 1) will be important in helping further assess the potential utility of CRAs in MDD.

Anxiety disorders Anxiety disorders include generalized anxiety disorder (GAD, persistent, excessive worry occurring for at least six months), specific phobias (e.g. anxiety provoked by specific feared situations or objects), social anxiety disorder (SAD, also social phobia, provoked by exposure to certain types of social or performance situations, often accompanied by avoidance), panic disorder (characterized by unexpected panic attacks, with or without agoraphobia, or anxiety about being in places or situations lacking escape), post-traumatic stress disorder (PTSD, characterized by re-experiencing of highly traumatic events, hyperarousal and avoidance of stimuli associated with trauma), acute stress disorder (PTSD symptoms that occur shortly after the trauma) and obsessive compulsive disorder (OCD, characterized by anxiety-provoking obsessions and anxiety-relieving compulsions). Given the demonstrated role of CRF1 pathways in the SRS, CRAs may be best suited for anxiety disorders which are most closely linked to traumatic stressors, such as PTSD. As noted in the depression section above, CRAs do not profile like classic anxiolytics in standard screening models, but are active in models in which high levels of prior stress have presumably sensitized CRF1 receptors (for reviews, see [17,18]). Direct infusion of CRF into the brain, or genetic models in which CRF1 receptors are hyperstimulated produce anxiogenic symptoms, whereas conditional knockouts of CRF1 receptors in limbic system structures have anxiolyticlike effects [19].

PTSD Evidence for hyperactive CRF1 pathways in PTSD includes increases in CSF levels of CRF (for reviews, see [1,7,20]) and a dysfunctional HPA axis, for example low plasma cortisol but exaggerated stress-induced release [21]. There is also evidence

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for increased NE activity (for review, see [7]) and pharmacological challenge studies using the a2-adrenergic antagonist yohimbine to produce NE release reported that the drugevoked PTSD symptoms [21,22], HPA axis activation and increases in CRF and NE in the CSF [5], suggestive of a coordinated NE–CRF interaction. As with depressed patients, additional features of psychosis in PTSD are associated with heightened CSF CRF levels relative to nonpsychotic PTSD [23], suggesting particularly severe CRF imbalances in this subpopulation. There are no reports of clinical studies evaluating the effects of CRAs in patients with PTSD which is unfortunate because prior exposure to an intense stressor is the sine qua non of the disorder. Notably, the nature and timing of the stressor(s) can vary considerably, ranging from a single event (natural disaster, rape and autoaccident) to repeated events. The ability to precisely define the causal trauma gives rise to the possibility of treating the trauma shortly after its occurrence, thereby possibly preventing the long-term development of permanent dysfunctional changes (e.g. traumatic memories) that give rise to chronic pathology. Also, a novel pharmacological intervention using b-NE blockers to prevent reconsolidation of established traumatic memories is being explored [24]. Such approaches may be relevant for the clinical evaluation of CRAs in PTSD. Finally, imaging studies in patients with chronic PTSD have demonstrated decreased hippocampal volume (possibly because of stressorinduced cell death) and associated deficits in hippocampally mediated memory which can be ameliorated by antidepressant treatment [21]. If CRF1 pathways are involved in this cascade, then CRAs might be effective in decreasing the longterm deleterious effects of stress on hippocampal structure and function.

SAD A risk factor for developing panic and phobic disorders is a heritable phenotype in children referred to as ‘behavioral inhibition to the unfamiliar’ involving fearful or avoidant behavior in novel situations [25]. Genetic studies indicate an association between behavioral inhibition and the CRF gene [25,26] and imaging studies indicate abnormal activity in cortical and HPA limbs of the SRS [27]. Rhesus monkeys with an anxious temperament (excessive anxiety and exaggerated defensive behavioral responses) have an abnormal EEG profile (asymmetric right frontal brain activity) and increased CRF in the CSF and cortisol in the plasma [28]. GW876008 has been evaluated in a Phase II clinical trial in SAD, but announced that it was discontinued because of lack of efficacy. No further details are currently available.

Panic disorder Hyperactivation of CRF1 pathways has been implicated in panic disorder (for review, see [29]) though evidence for HPA axis dysfunction in patients with panic disorder is mixed (e.g.

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see [30]). Recent genetic studies associate CRF1 receptor gene polymorphisms with panic disorder [31]. In a rodent model of panic disorder involving the basolateral nucleus of the amygdala [32], the direct injection of the peptide agonist urocortin produced an anxiogenic response as measured with the social interaction test, and this effect was blocked by a CRA. Notably, repeated urocortin administration appeared to sensitize CRF1 receptors such that the rat eventually developed a panic-prone state, plasticity that may be relevant to the changes that underlie the development of panic disorder. There are no published reports of the effects of CRAs in panic patients or in experimentally induced panic models in humans and no evidence for ongoing clinical trials.

Generalized anxiety disorder Clinical measures of CSF CRF levels in GAD demonstrated no differences from placebo [33]. To date, CRAs are being evaluated in one clinical trial and the results of a second trial have yet to be announced.

Comorbid anxiety and depression Anxiety is also seen in approximately 30% of patients with depression, and this comorbid population shows heightened resistance to drug treatment [34]. Greater HPA axis activation in response to social stress is seen in patients with comorbid depression and anxiety [35]. To date, no measures of CSF CRF have been reported in this population, nor have there been any reports of clinical trials with CRAs.

Irritable bowel syndrome Irritable bowel syndrome (IBS) is a stress-related gastrointestinal disorder characterized by disturbed bowel habits (diarrhea and/or constipation) and visceral abdominal pain and is frequently comorbid with anxiety [36]. CRAs blocking both central and peripheral CRF1 receptors are being proposed as a novel pharmacological treatment for IBS (for reviews, see [37]). In animals, CRAs ameliorate the stimulatory effects of exogenous CRF on colonic motility and colonic bowel function, and reduce stress-induced increases in visceral sensitivity (for reviews, see [38]). NBI35965 blunted intracerebroventricular CRF or water avoidance stress-induced visceral hyperalgesia and colonic motor function in rats. Heightened visceral hypersensitivity in adult rats exposed to early life stressors (maternal separation) was reversed by CP154526 or NBI35965. In humans, functional imaging studies in IBS patients demonstrated heightened responsiveness of the ‘emotional motor system’ to painful peripheral gut stimulation [39]. IV infusion of the nonselective peptidic CRF1/2 receptor antagonist, a-helical-CRF to IBS patients improved gut-stimulationinduced changes in gastrointestinal motility, visceral pain perception and negative mood without affecting the HPA axis [40]. Two compounds, GW876008 and pexacerfont, are being www.drugdiscoverytoday.com

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evaluated in Phase II trial in patients with IBS though results have not yet been released. Functional imaging is being used to study the effects of GW876008 on emotional reactivity in the amygdala in IBS patients (see http://clinicaltrials.gov). While clinical data are needed to evaluate the potential of CRAs in IBS, these studies support the notion that dysfunctions of the CRF1 receptor in its crucial role in the SRS can have wide ranging impacts on central (psychiatric) as well as on peripheral (gastrointestinal) functions.

Drug abuse Drug addiction disorders have been linked to hyperactivation of CRF1 receptors and CRAs have been proposed as potential treatments (for reviews, see [41,42]). Withdrawal symptoms, including anxiety, are a major risk factor for relapse to drug abuse. In animals, anxiety-like symptoms seen during withdrawal from drugs of abuse, such as cocaine, amphetamine and morphine, have been associated with heightened CRF release and are attenuated by CRAs. Antalarmin reversed the conditioned place aversion produced by naloxone-precipitated opiate withdrawal in rats [43]. By decreasing vulnerability to relapse during prolonged abstinence from drugs of abuse, CRAs may be useful as treatments for drug addictions. Alcohol dependency has also been linked to the hyperactivation of CRF1 receptors (for review, see [44]). An association between the CRF1 receptor gene and excessive drinking has been reported in alcohol-dependent adults. In animal studies, increased ethanol self-administration during acute withdrawal in ethanol-dependent rats was attenuated by R121919 and MJL-1-109-2. Alcohol-dependent rats in a chronic withdrawal state manifest enhanced sensitivity to stress-induced drinking, heightened anxiety (conflict test) and CRF1 receptor upregulation in the basolateral and medial amygdala [45]. MTIP blocked withdrawal anxiety in dependent rats and in rats genetically bred for high alcohol intake [44]. No effects of MTIP were seen on anxiety or on ethanol intake in normal (nondependent) rats, consistent with the idea that CRAs do not alter behavior in a basal, unstressed state. Rats genetically bred for high alcohol preference show a dysfunctional upregulation of CRF1 receptors and antalarmin selectively reversed the lowered threshold for stress-induced reinstatement of alcohol seeking [46]. These preclinical studies support the potential of CRAs in the treatment of chronic alcohol abuse; however, data on clinical validation of this concept are not yet available (Table 1).

Conclusions CRAs have been pursued as a novel approach for the treatment of stress-related disorders, driven by preclinical and clinical neurobiological data and reinforced by positive results of an early open-label trial in MDD [15]. Efforts to develop compounds, hindered in the past by hurdles such as suboptimal physicochemical properties and/or limited struc166

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tural diversity [18,47,48], have resulted in several CRAs reaching Phase II for MDD, SAD, GAD and IBS (Table 1). Limited data from these trials are currently available, but some interim assessments can be made. Regarding safety, CRAs given chronically to humans have not produced adrenal insufficiency, an important finding for continued evaluation of this class of compounds. Regarding efficacy, recent data have been published on only one compound indicating the lack of efficacy in MDD [16]. In other Phase II trials (Table 1), press releases have indicated the lack of efficacy in SAD and GAD, and additional studies in MDD, GAD and IBS have yet to be reported. While the negative outcomes reported thus far indicate that CRAs might lack efficacy in these indications, the following should be considered as additional data become available: (a) It is challenging to predict the dose required for clinical efficacy. CRAs do not consistently profile like classic antidepressants or anxiolytics in animal models, making it difficult to predict efficacious plasma concentrations. Furthermore, there are currently no validated biomarkers (e.g. imaging with a suitable PET ligand) to demonstrate in humans that a targeted level of CNS occupancy has been achieved. Progress in addressing these hurdles is needed. (b) CRAs may be useful in particular disorders (e.g. those with clearly defined traumatic stressors such as PTSD) and/or in patient subpopulations. Hyperactive CRF1 pathways are not evident in all patients with MDD, and may be especially prominent in severely affected subpopulations such as depressed or PTSD patients with psychotic features, or in melancholia. Hyperactive CRF1 pathways seen in a variety of adult psychopathologies have been linked to a prior history of early life trauma and recent findings of a CRF1 receptor gene  environment (early life trauma) interaction in depression may help define CRA-sensitive subpopulations. (c) Because excessive activation of CRF1 receptors is required for a CRA to work, one must define when hyperactivation occurs and its impact on brain function and symptomotology. A better understanding of the contribution of hyperactivated CRF1 pathways to dysfunctional sensitization and learning processes (overlearning of traumatic memories; failure of extinction) and the implications for treating trauma-related pathology is needed. CRAs given early post-trauma might prevent the development of PTSD, or in chronic PTSD, might prevent reconsolidation or enhance extinction of disabling traumatic memories. (d) Because stress can be an important precipitating or exacerbating factor in many disorders not discussed herein, CRAs may be of benefit in these populations. (e) The potential utility of CRAs in reversing the long-term detrimental anatomical and functional impacts of excessive stress-induced HPA axis activation on structures such as the hippocampus should be explored. (f) CRAs may be useful as adjunctive agents in dampening the potential deleterious effects of chronic traumatic stress and improving treatment response.

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A half-century after Hans Selye’s groundbreaking work on stress, we are beginning to elucidate the inner workings of a complex and dynamic SRS with CRF1 pathways as a key component though, clearly, much work remains before we fully understand the impact of CRAs on this system and their therapeutic utility in treating stress-related disorders.

Conflict of interest The authors have been project leaders in a CRF1 receptor antagonist pharmaceutical program at Neurogen Corporation, Branford, CT.

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