GRM2 and major depressive disorder: The possible reasons might be: (I) these drugs have poor gastrointestinal permeability resulting in low oral bioavailability (Holly, LaCrosse, & Hillhouse); (II) both mGluR2/3 antagonists and NAMs selectively target at specific sites (mainly mGluR2/3), but the pathogenesis of depression is multifactorial, thus limiting the antidepressant effects of these agents.