Neuropeptide Y as a multifaceted modulator of neuroplasticity, Neuroinflammation, and HPA axis dysregulation: Perceptions into treatment-resistant depression

Treatment-resistant depression (TRD) is a severe neurobiological and clinical category in which common antidepressants do not induce an adequate response. Neuropeptide Y (NPY), a neuropeptide highly conserved through evolution, is known to be involved in the regulation of stress responses, emotional processing, neuroinflammation, and neuroplasticity. This review synthesizes the importance of NPY in TRD by describing NPY's physiological (central nervous system) functions and roles. Experimental data suggest that NPY is dysregulated in animal models of chronic stress and TRD, which include changes in hippocampal NPY signaling, neurotrophic factor expression, and HPA axis activity. Clinical studies have, in turn, shown decreased cerebrospinal NPY concentrations in TRD patients as well as decreased expression of NPY receptors in stress-related regions of their brains. Finally, we discuss new therapeutic avenues targeting NPY pathology, such as intranasal NPY administration and receptor-selective modulation. Thus, preclinical and clinical data jointly suggest that restoration of NPY signaling pathways might offer a novel and biologically grounded intervention for TRD.