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Cited by 96Posttraumatic Stress Disorder ResearchStress Responses and CortisolPsychoanalysis and Psychopathology Research

Corticotropin-releasing factor receptor 1 antagonism is ineffective for women with posttraumatic stress disorder

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Dunlop, Boadie W., Binder, Elisabeth B., Iosifescu, Dan, Mathew, Sanjay J., Neylan, Thomas C., Pape, Julius C., Carrillo-Roa, Tania, Green, Charles +5 more·2017·Biological Psychiatry
DOI 10.1016/j.biopsych.2017.06.024PMC PMC5683912
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Abstract

Background 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.Methods We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF 1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period.Results 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 1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n = 6) but not with placebo (n = 7) on the PTSD Symptom Scale-Self-Report.Conclusions The results of this trial, the first evaluating a CRF 1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF 1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF 1 receptor antagonists lack efficacy as monotherapy agents for these conditions.

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  • No clinical studies to date have found efficacy of CRF1 antagonists for other stress-related psychiatric disorders.

    “Additionally, no clinical studies to date have found efficacy of CRF 1 receptor antagonists for the treatment of other stress-related psychiatric disorders, such as major depression, generalized anxiety disorder, social anxiety, or posttraumatic stress disorder (Griebel and Holsboer, 2012;Dunlop et al., 2017).”

    From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Dunlop et al., 2017

    The Introduction reports that larger trials found no efficacy for major depression, generalized anxiety disorder, or social anxiety disorder, and the Abstract’s Conclusions report a negative PTSD trial. But the Introduction also says an early human trial suggested efficacy for major depression, so the absolute claim that no clinical study had found efficacy overstates the source. (LLM, conf=0.88)

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  • In a double-blind, randomized, placebo-controlled trial with women suffering from PTSD, Verucerfont could not reveal a significant improvement of PTSD symptoms.

    “While this trial could not reveal a significant improvement of PTSD symptoms,”

    From The HPA Axis as Target for Depression (2024) · cites this paper as [106]

  • Patients with a history of childhood trauma and a certain CRH1 receptor SNP genotype did only respond to Verucerfont, and not to placebo.

    “patients with a history of childhood trauma and a certain CRH1 receptor single nucleotide polymorphism (SNP) genotype did only respond to Verucerfont, and not to placebo [106].”

    From The HPA Axis as Target for Depression (2024) · cites this paper as [106]

  • Monotherapy with CRHR1 receptor antagonists including verucerfont, R121919 and pexacerfont does not exhibit greater efficacy than placebo for the treatment of PTSD, GAD, SAD and major depressive disorder, despite good tolerability.

    “However, since monotherapy with CRHR 1 receptor antagonists including verucerfont (GSK-561679, NBI-77860), R121919 (NBI-30775) and pexacerfont (BMS-562086) does not exhibit greater efficacy than placebo for the treatment of PTSD (Dunlop et al., 2017), GAD, SAD and major depressive disorder, despite good tolerability of these drugs in all of these clinical trials (Griebel & Holsboer, 2012),”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Dunlop et al., 2017

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Authors
Dunlop, B. W., Binder, E. B., Iosifescu, D., Mathew, S. J., Neylan, T. C., Pape, J. C., Carrillo-Roa, T., Green, C., Kinkead, B., Grigoriadis, D., Rothbaum, B. O., Nemeroff, C. B., & Mayberg, H. S.
Affiliations
  • Emory University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Michael E. DeBakey VA Medical Center (US)
  • San Francisco VA Medical Center (US)
  • Max Planck Institute of Psychiatry (DE)
  • Neurocrine Biosciences (United States) (US)
  • University of Miami (US)
Corresponding author
Dunlop, Boadie W.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2017-12
Volume
82
Issue
12
Pages
866-874
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2017.06.024
PMC
PMC5683912
OpenAlex
W2726808213
Cited by
96
References
75
Citations by year
2026: 9 · 2025: 8 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 11 · 2020: 11 · 2019: 18 · 2018: 11 · 2017: 2 · 2013: 1
FWCI
14.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (acceptedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Max Planck Digital Library (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • National Institute of Mental Health (U19 MH069056, K23 MH086690)
  • Veterans Affairs Clinical Science Research and Development (09S-NIMH-002)
  • Acadia
  • Assurex
  • Axsome
  • Bristol-Myers Squibb
  • Janssen
  • GlaxoSmithKline
  • NIMH
  • Otsuka
  • Pfizer
  • Takeda
  • National Institutes of Health
  • European Community
  • German Ministry of Health
  • Böhringer-Ingelheim Inc
  • Icahn School of Medicine at Mount Sinai
  • Alkermes
  • Astra Zeneca
  • Brainsway
  • Euthymics
  • Neosync
  • Roche
  • Shire
  • NIH
  • Department of Veterans Affairs
  • Johnson Family Chair
  • Janssen Research and Development
  • Department of Defense
  • Cancer Prevention Institute of Texas
  • Stryker
  • Wounded Warrior Project, Department of Defense
  • Brain and Behavior Research Foundation
  • McCormick Foundation
  • Stanley Medical Research Institute
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
Keywords
post-traumatic stress disorder, corticotropin-releasing hormone receptor 1, CRF1 receptor antagonist, women, hypothalamic-pituitary-adrenal axis, childhood abuse, treatment response, pharmacotherapy efficacy
MeSH terms
CRF Receptor, Type 1, Adult, Double-Blind Method, Female, Humans, Oxadiazoles, Psychotropic Drugs, Stress Disorders, Post-Traumatic, Treatment Failure, Receptors, Corticotropin-Releasing Hormone, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Kaplan-Meier Estimate, Azabicyclo Compounds, Adult Survivors of Child Abuse

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