The first hint of a potential link between the orexin system and major depression was derived from the clinical observation that the oscillating amplitude of the OX-A concentration in the cerebrospinal fluid (CSF) during the diurnal cycle was significantly reduced in patients with major depression compared with that in healthy controls, but the mean OX-A level tended to be higher in patients with depression than in controls [11]. This evidence concerns the gene HCRT and depressive disorder.