oxadiazoles and Stress-Disorders--Post-Traumatic

After exposure to a traumatic event, a subset of people develop post-traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear-potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear-potentiated startle during a conditional discrimination fear-conditioning paradigm, termed AX+/BX-. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double-blind, placebo-controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre- and 29 post-treatment) and patients taking a placebo pill (n = 52 pre- and 30 post-treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre-post-treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX- transfer test (p < 0.05). While all PTSD participants showed typical impairments in fear inhibition prior to treatment, GSK561679 enhanced fear inhibition post-treatment, independent of clinical effects. The current study suggests that CRF receptor 1 antagonism may have specific effects within neural circuitry mediating fear inhibition responses, but not overall symptom presentation, in PTSD.

Topics: Adult; Azabicyclo Compounds; Conditioning, Classical; Double-Blind Method; Fear; Female; Humans; Inhibition, Psychological; Middle Aged; Oxadiazoles; Receptors, Corticotropin-Releasing Hormone; Reflex, Startle; Stress Disorders, Post-Traumatic; Treatment Outcome

For a drug to acquire Food and Drug Administration approval, it must significantly outperform placebo treatment. In recent years, the placebo effect seems to be increasing in neuropsychiatric conditions. Here, we examine placebo effects across self-reported, clinically rated, and performance-based data from a trial using a corticotropin-releasing hormone receptor type 1 (CRHR1) antagonist for treatment of post-traumatic stress disorder (PTSD).. Women with chronic PTSD were randomized to treatment with either GSK561679, a CRHR1 antagonist, or placebo. Before randomization, participants completed self-report scales, clinician-rated measures of PTSD and depression symptoms, and objective tests of cognition and functioning. Differences in change scores on measures were compared between GSK561679 and placebo-treated participants.. GSK561679 failed to produce any significant improvement in the participants. A substantial placebo effect was observed in both self-report and clinical rating scales, with effect sizes up to 1.5 SD. No single variable predicted placebo-related changes. Notably, there was an improvement on objective performance measures of cognition that exceeded previous standards for practice effects.. Participants in this trial manifested retest effects on performance-based measures of cognition. Notably, they had minimal prior experience with performance-based assessments. Experiencing the structure and support of a clinical trial may have contributed to significant reductions in subject-reported and clinician-rated PTSD symptom levels. The improvement seen across all assessment domains was consistent with that seen in previous studies where the active treatments separated from placebo. Investigators conducting clinical trials treating PTSD patients should expect placebo effects and design studies accordingly.

Topics: Adult; Azabicyclo Compounds; Cognition; Female; Humans; Middle Aged; Oxadiazoles; Placebo Effect; Psychiatric Status Rating Scales; Receptors, Corticotropin-Releasing Hormone; Research Design; Self Report; Stress Disorders, Post-Traumatic; Treatment Outcome

We have previously evaluated the efficacy of the CRF. Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment.. Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF. NCT01018992 . Registered 6 November 2009.

Topics: Adult; Azabicyclo Compounds; DNA Methylation; Epigenesis, Genetic; Female; Humans; Middle Aged; Oxadiazoles; Polymorphism, Single Nucleotide; Receptors, Corticotropin-Releasing Hormone; Receptors, Glucocorticoid; Stress Disorders, Post-Traumatic; Tacrolimus Binding Proteins; Treatment Outcome; Young Adult

Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD.. We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF. In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF. The results of this trial, the first evaluating a CRF

Topics: Adult; Adult Survivors of Child Abuse; Azabicyclo Compounds; Double-Blind Method; Female; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Oxadiazoles; Polymorphism, Single Nucleotide; Psychotropic Drugs; Receptors, Corticotropin-Releasing Hormone; Stress Disorders, Post-Traumatic; Treatment Failure

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.. Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010.

Topics: Adolescent; Adult; Aged; Azabicyclo Compounds; Clinical Protocols; Conditioning, Psychological; Diagnostic Techniques, Endocrine; Double-Blind Method; Extinction, Psychological; Fear; Female; Gene Expression Profiling; Hormone Antagonists; Humans; Hypothalamo-Hypophyseal System; Middle Aged; Oxadiazoles; Pituitary-Adrenal System; Psychiatric Status Rating Scales; Receptors, Corticotropin-Releasing Hormone; Research Design; Stress Disorders, Post-Traumatic; Time Factors; Treatment Outcome; United States; Young Adult

Physical exercise is well-established paradigm for improving adult neurogenesis and brain functions. As considered as an alternative therapeutic strategy, treadmill running could reduce cognitive impairment and psychiatric abnormalities associating post-traumatic stress disorder (PTSD), which might associate with the promote effects to adult neurogenesis. In current study, we aimed to address how treadmill exercise benefit adult hippocampal neurogenesis in PTSD model and the underlying molecular mechanism related with Akt signaling. PTSD was induced by exposure to aggressor and treatments were conducted with different intensity of compulsory treadmill running. We observed treadmill running improved hippocampal neurogenesis including proliferation and neural differentiation of neural stem cells (NSCs). Moreover, behavioral tests showed treadmill could attenuate the cognitive deficit and depressive/anxiety like behaviors in correlating with PTSD model. Moreover, treadmill running recovered the Akt activity in hippocampus. Interrupting treadmill running administrated mice with Akt inhibitor GSK690693 resulted in the blocked the effects of treadmill running to hippocampal neurogenesis and behavioral improvement in PTSD mice model. In conclusion, treadmill running could mediate behavioral functions and improve hippocampal neurogenesis in PTSD model by regulating Akt signaling.

Topics: Animals; Anxiety; Behavior, Animal; Cognitive Dysfunction; Depression; Disease Models, Animal; Exercise Therapy; Hippocampus; Male; Memory, Short-Term; Mice; Mice, Inbred C57BL; Neurogenesis; Oxadiazoles; Proto-Oncogene Proteins c-akt; Running; Signal Transduction; Stress Disorders, Post-Traumatic