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

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 CRF₁ antagonists and review recent findings concerning CRF-CRF₁ systems 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-CRF₁ activation not homologous to tested patients, (5) repeated CRF₁ activation-induced plasticity that reduces the importance of ongoing CRF₁ agonist stimulation, and (6) therapeutic silencing which may need to address CRF₂ receptor or CRF-binding protein 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.

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.