Don’t stress about CRF: assessing the translational failures of CRF1antagonists

Abstract

BACKGROUND 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. METHODS We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology. RESULTS 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 were limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, 5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, 6) therapeutic silencing may need to address CRF2 receptor or CRF-BP molecules, constitutive CRF1 activity, 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 CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation. CONCLUSION The therapeutic scope of selective CRF1 antagonists 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.

Short-term block of CRH receptor in adults mitigates age-related memory impairments provoked by early-life adversity

“…While CRH is important for developmental plasticity within the hippocampus (Curran, Sandman, Poggi Davis, Glynn, & Baram, 2017;Dubé et al, 2015;Ivy et al, 2010;Sandman et al, 2018;Singh-Taylor et al, 2018), its role in affective-related disorders is less clear (Spierling & Zorrilla, 2017). This is observed in the present study with a lack of an effect of antagonist on the anxiety-or depression-related phenotypes tested.…”

Corticotropin-Releasing Factor (CRF) and Addictive Behaviors

“…Interestingly, whereas initial clinical trials with CRF 1 antagonists for alcohol use disorders have yielded disappointingly negative results so far (see (Spierling & Zorrilla, 2017) for review), a recent double-blind, placebo-controlled trial in a small sample of healthy individuals with restrained eating yielded promising results for stress-related eating that appear to warrant further study. Because the study was stopped prematurely by the NIH IRB for reasons unrelated to adverse drug effects or efficacy (reinterpretation of the Common Rule for human subject protection under HHS, 45 CFR 46A), it was underpowered (30% power) to detect a priori effect sizes of interest.…”

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…There are several recent reviews from 2016-2018 providing the details of other important stress responsive systems (like Corticotrophin Releasing Factor, Neuropeptide Y, and glucocorticoid receptor, etc.) from preclinical evidence to the recent clinical trials [Koob and Mason, 2016;Mantsch et al, 2016;Blaine and Sinha, 2017;Mason, 2017;Robinson and Thiele, 2017;Spierling and Zorrilla, 2017;Tunstall et al, 2017;Pomrenze et al, 2017]. The main focus in this mini-review is several other important stress responsive systems, which recently has not been reviewed, like arginine vasopressin/V1b receptors (Part I), and proopiomelanocortin/β-endorphin (Part II).…”