title: Don't stress about CRF: assessing the translational failures of CRF1antagonists.
abstract: Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts.
  
  
  
  We explore potential causes for the failure of CRF1antagonists and review recent findings concerning CRF-CRF1systems in psychopathology.
  
  
  
  Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF1activation not homologous to tested patients, (5) repeated CRF1activation-induced plasticity that reduces the importance of ongoing CRF1agonist stimulation, and (6) therapeutic silencing which may need to address CRF2receptor or CRF-binding protein molecules, constitutive CRF1activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF1systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1antagonists in food craving and CRF-driven HPA-axis overactivation.
  
  
  
  The therapeutic scope of selective CRF1antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF's role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA. samspier@scripps.edu.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Spierling
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA. ezorrilla@scripps.edu.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D057170:Translational Research, Biomedical / Q000379:methods*; D000099052:CRF Receptor, Type 1
chemical_list: C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: Alcohol dependence; Alcohol use disorder; Alcoholism; Antidepressant or anxiolytic; Binge drinking; Binge eating; CRF; CRF1 receptor antagonist; CRH; CRH1 receptor antagonist; Clinical trial; Corticotropin-releasing factor; Corticotropin-releasing hormone; Drug addiction; Food addiction; Generalized anxiety disorder; Irritable bowel syndrome; Major depression; Panic disorder; Post-traumatic stress disorder; Translation; Treatment