The rapid onset of response to depression treatment by Yueju pill: From discovery of a novel treatment target to clinical perspective

Depression, marked by persistent low mood and anhedonia, poses significant global health challenges, whereas mainstream antidepressants like SSRIs often have delayed onset and limited efficacy. Yueju Pill, a traditional Chinese herbal medicine formulated 800 years ago to treat “stagnation syndrome”, which overlaps with depression. Yueju pill has been shown to have the rapid onset and sustained antidepressant potential since 2013. It has been revealed to have similarities to the prototype rapid antidepressant ketamine in neuroplasticity mechanisms, including instant stimulation of protein synthesis signaling in the hippocampus and prefrontal cortex, subsequently enhancing expressions of BDNF and synaptic proteins. More recently, some targets and compound substrates that were not known before have been revealed from Yueju pill, and some clinical evidence has been provided. This review will focus on the advances in the discovery of a novel target, the neuropeptide PACAP in the hippocampus for the onset of depression treatment, the study paradigm employed to identify the synergism of the composing compounds in Yueju pill targeting PACAP, the mechanisms of neuroinflammation and gut-brain axis, and clinical trials showing fast alleviation of depression symptoms by adjunct or monotherapy with Yueju pill, in relationship to the improvement in serum BDNF levels. The perspective for a broader use of Yueju pill as a therapeutic avenue for depression and further mechanistic and clinical research directions is also provided. • Yueju Pill is the first herbal medicine identified with rapid antidepressant potential, comparable to ketamine. • The hippocampal PACAP is a novel target for depression discovered from Yueju pill. • The compound synergism key for Yueju pill’s efficacy is revealed via PACAP. • Clinic studies show Yueju pill quickly alleviate depression symptoms and improve serum BDNF levels.