CRF1 Receptor Agonists as an Adjunct Treatment for Major Depression and Treatment-Resistant Depression

Major depressive disorder (MDD) affects ~16% of the global population, yet existing treatments like SSRIs/SNRIs are slow to act and leave ~30% of patients treatment-resistant. Although ketamine offers rapid antidepressant effects, its efficacy varies widely. Our preclinical work demonstrates that acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, particularly through corticotropin-releasing factor (CRF), is essential for ketamine’s behavioral and synaptic efficacy. We show that CRF facilitates ketamine’s behavioral and cellular effects, while CRF1 receptor (CRF1R) antagonism blocks them, highlighting the therapeutic potential of transient CRF1R activation, a largely unexplored strategy. We propose a novel approach using CRF1R agonists as adjuncts to enhance antidepressant response. Aim 1 will validate the efficacy of CRF1R agonists in combination with ketamine, examining behavior, pharmacokinetics, and circuit-level engagement. Aim 2 will test whether CRF1R agonists can accelerate or enhance SSRI response in a chronic stress model. Aim 3 will generate a detailed safety profile of CRF1R agonists, including CNS and gastrointestinal effects, and use bioinformatic tools to assess translational relevance through human data. Our multidisciplinary team integrates expertise in neuropsychopharmacology, bioinformatics, and drug discovery. This work will advance CRF1R agonists as promising fast-acting, adjunctive treatments for early intervention in treatment-resistant depression.