Early clinical studies evaluating the potential role of orexin in depressive disorders indicated that depressed patients had a blunted diurnal variation in CSF orexin-A levels accompanied by higher orexin-A levels at night, and that these differences were improved with antidepressant treatment, suggesting a link between disrupted orexin signaling and HPA axis disruption associated with depression (Salomon et al., 2003). This evidence concerns the gene HCRT and major depressive disorder.