CRHR1 and major depressive disorder: We hypothesize that hyperactivation of the neuro-endocrine CRH-norepinephrine (NE)-CRH system (CRH-NE-CRH), mediated by CRHR1 variants, underlies MDD and may increase the risk for T2D, and thus, inherited CRHR1 variants involved in stress responses might account, at least in part, for the comorbidity of MDD with T2D [28, 29].