5-HT4R agonism is a promising target in MDD, because rodent models suggest that direct stimulation of the 5-HT4R leads to rapid antidepressant effects (Lucas et al., 2007), appears to protect against stress (Chen et al., 2020), and is crucial for efficacy of SSRIs to rescue depressive- and anxiety-like behaviors (Mendez-David et al., 2014). Here, HTR4 is linked to major depressive disorder.