Glucocorticoid Receptor Antagonist for PTSD
(SEVEN Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
TC
Overseen byThomas C. Neylan, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: VA Office of Research and Development
Must be taking: SSRIs, SNRIs, Trazodone, Opiates
Must not be taking: Tricyclics, Lithium, Antipsychotics, Corticosteroids
Disqualifiers: Alcohol, Substance use, Bipolar, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This trial tests a drug called CORT108297 that blocks the stress hormone cortisol to help Veterans with chronic PTSD. The study will check if the drug is safe and effective over a short period. Veterans will receive either the drug or an inactive substance, and their symptoms will be monitored regularly.
Do I have to stop taking my current medications for the trial?
You may need to stop certain medications, like some antidepressants, mood stabilizers, antipsychotics, and corticosteroids, as they are not allowed in the trial. However, if you are on a stable dose of SSRIs, SNRIs, trazodone, or opiate pain medications, you can continue taking them. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug CORT108297 for PTSD?
Is the glucocorticoid receptor antagonist treatment safe for humans?
How is the drug CORT108297 different from other PTSD treatments?
CORT108297 is unique because it works by blocking glucocorticoid receptors, which are involved in the body's stress response, potentially helping to reduce PTSD symptoms like anxiety and fear memory disruption. This mechanism is different from most current PTSD medications, which were originally developed for other conditions like depression.2351011
Research Team
TC
Thomas C. Neylan, MD
Principal Investigator
San Francisco VA Medical Center, San Francisco, CA
Eligibility Criteria
This trial is for US veterans with PTSD from military service, including combat or sexual trauma. They must have had symptoms for over 3 months and agree to use two forms of contraception if applicable. Participants can be on stable doses of certain medications like trazodone or SSRIs/SNRIs but not others that affect the study drug's metabolism or increase suicide risk.Inclusion Criteria
Criterion A event meets DSM-5 criteria and occurred during military service, including combat and military sexual trauma
I have been on a stable dose of medication for PTSD for at least 8 weeks.
I agree to use two reliable birth control methods, including a barrier method.
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Exclusion Criteria
You have been diagnosed with alcohol, marijuana, or drug addiction in the last 3 months according to the DSM-5 guidelines.
I am not taking certain antidepressants, mood stabilizers, antipsychotics, or benzodiazepines.
You have experienced any kind of injury or accident within the past 3 months.
See 7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive CORT108297 or placebo for 7 days
1 week
Several visits (in-person and virtual)
Follow-up
Participants are monitored for safety and effectiveness after treatment
8 weeks
Visits at day 7, 28, and 56
Treatment Details
Interventions
- CORT108297 (Corticosteroid)
- Placebo (Other)
Trial OverviewThe trial is testing CORT108297, a new medication that blocks cortisol without affecting progesterone, which could help treat PTSD. It compares this drug to a placebo (a substance with no active drug). The goal is to see if it's effective and safe for treating PTSD in veterans.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: CORT108297Experimental Treatment1 Intervention
CORT108297- 180mg daily for 7 days
Group II: PlaceboPlacebo Group1 Intervention
Placebo- 180mg daily for 7 days
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Tuscaloosa VA Medical Center, Tuscaloosa, ALTuscaloosa, AL
San Francisco VA Medical Center, San Francisco, CASan Francisco, CA
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Who Is Running the Clinical Trial?
VA Office of Research and Development
Lead Sponsor
Trials
1691
Patients Recruited
3,759,000+
References
Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone. [2013]Alterations of mineralocorticoid receptor (MR) mediated negative feedback inhibition of cortisol might contribute to abnormalities of hypothalamic-pituitary adrenal (HPA) activity in posttraumatic stress disorder (PTSD).
Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial. [2022]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.
Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder. [2013]The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD).
Mineralocorticoid receptor function in patients with posttraumatic stress disorder. [2015]The study examined whether enhanced limbic mineralocorticoid receptor activity resulting in negative glucocorticoid feedback could contribute to the diminished basal and stress-induced cortisol output reported in patients with posttraumatic stress disorder (PTSD).
Effects of RU486 in Treatment of Traumatic Stress-Induced Glucocorticoid Dysregulation and Fear-Related Abnormalities: Early versus Late Intervention. [2022]Central glucocorticoid receptor (GR) activity is enhanced following traumatic events, playing a key role in the stress-related cognitive abnormalities of posttraumatic stress disorder (PTSD). GR antagonists are expected to have potential as pharmacological agents to treat PTSD-related symptoms such as anxiety and fear memory disruption. However, an incubation period is usually required and stress-induced abnormalities do not develop immediately following the trauma; thus, the optimal intervention timing should be considered. Single prolonged stress (SPS) was employed as a rodent PTSD model to examine the effects of early or late (1-7 versus 8-14 days after the SPS) sub-chronic RU486 (a GR antagonist) administration. Behaviorally, fear conditioning and anxiety behavior were assessed using the fear-conditioning test and elevated T-maze (ETM), respectively. Neurochemically, the expressions of GR, FK506-binding proteins 4 and 5 (FKBP4 and FKBP5), and early growth response-1 (Egr-1) were assessed in the hippocampus, medial prefrontal cortex (mPFC), amygdala, and hypothalamus, together with the level of plasma corticosterone. Early RU486 administration could inhibit SPS-induced behavioral abnormalities and glucocorticoid system dysregulation by reversing the SPS-induced fear extinction deficit, and preventing SPS-reduced plasma corticosterone levels and SPS-induced Egr-1 overexpression in the hippocampus. Early RU486 administration following SPS also increased the FKBP5 level in the hippocampus and hypothalamus. Finally, both early and late RU486 administration inhibited the elevated hippocampal FKBP4 level and hypothalamus GR level in the SPS rats. Early intervention with a GR antagonist aids in the correction of traumatic stress-induced fear and anxiety dysregulation.
High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response. [2014]Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory.
Corticosterone mitigates the stress response in an animal model of PTSD. [2014]Activation of glucocorticoid receptor signaling in the stress response to traumatic events has been implicated in the pathogenesis of stress-associated psychiatric disorders such as post-traumatic stress disorder (PTSD). Elevated startle response and hyperarousal are hallmarks of PTSD, and are generally considered to evince fear (DSM V). To further examine the efficacy of corticosterone in treating hyperarousal and elevated fear, the present study utilized a learned helplessness stress model in which rats are restrained and subjected to tail shock for three days. These stressed rats develop a delayed long-lasting exaggeration of the acoustic startle response (ASR) and retarded body weight growth, similar to symptoms of PTSD patients (Myers et al., 2005; Speed et al., 1989). We demonstrate that both pre-stress and post-stress administration of corticosterone (3 mg/kg/day) mitigates a subsequent exaggeration of the ASR measured 14 days after cessation of the stress protocol. Furthermore, the mitigating efficacy of pre-stress administration of corticosterone (3 mg/kg/day for three days) appeared to last significantly longer, up to 21 days after the cessation of the stress protocol, in comparison to that of post-stress administration of corticosterone. However, pre-stress administration of corticosterone at 0.3 mg/kg/day for three days did not mitigate stress-induced exaggeration of the ASR measured at both 14 and 21 days after the cessation of the stress protocol. In addition, pre-stress administration of corticosterone (3 mg/kg/day for three days) mitigates the retardation of body weight growth otherwise resulting from the stress protocol. Congruently, co-administration of the corticosterone antagonist RU486 (40 mg/kg/day for three days) with corticosterone (3 mg/kg/day) prior to stress diminished the mitigating efficacy of the exogenous corticosterone on exaggerated ASR and stress-retarded body weight. The relative efficacy of pre versus post administration of corticosterone and high versus low dose of corticosterone on stress-induced exaggeration of innate fear response and stress-retarded body weight growth indicate that exogenous corticosterone administration within an appropriate time window and dosage are efficacious in diminishing traumatic stress induced pathophysiological processes. Clinical implications associated with the efficacy of prophylactic and therapeutic corticosterone therapy for mitigating symptoms of PTSD are discussed, particularly in relation to diminishing hyperarousal and exaggerated innate fear response.
Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. [2022]Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS- skin conductance response (SCR) compared to placebo (b = -0.19, CI = -0.01 to -37, p = 0.042 and b = -0.25, CI = -08 to -0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS- SCR in the DCS group, compared to placebo, (b = -0.25, CI = 0.04 to -0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.
Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study. [2021]Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p
The relationship between glucocorticoid receptor polymorphisms, stressful life events, social support, and post-traumatic stress disorder. [2021]It is debatable whether or not glucocorticoid receptor (GR) polymorphisms moderate susceptibility to PTSD. Our objective was to examine the effects of stressful life events, social support, GR genotypes, and gene-environment interactions on the etiology of PTSD.
Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD. [2015]Posttraumatic stress disorder (PTSD) has been shown to be associated with altered glucocorticoid receptor (GR) activity. We studied the expression and functional properties of the receptor in peripheral blood mononuclear cells (PBMCs) from non-traumatized healthy individuals (healthy controls; n=85), and war trauma-exposed individuals with current PTSD (n=113), with life-time PTSD (n=61) and without PTSD (trauma controls; n=88). The aim of the study was to distinguish the receptor alterations related to PTSD from those related to trauma itself or to resilience to PTSD.