Intriguingly, if 5-HT4R is an inverse proxy for cerebral 5-HT levels [22, 38], our observations suggest that high anxiety levels in depression are associated with higher-than-normal brain 5-HT levels and may correspond to the observation of serotonin-increase caused engagement of anxiety and fear-promoting circuit in the brain [48] and the well-known transiently increased anxiety following initiation of SSRI treatment. This evidence concerns the gene HTR4 and major depressive disorder.