AGT and major depressive disorder: ARB blocking of the AT1 receptor leads to greater circulation of angiotensin II in the brain, which increases levels of substance P in brain tissue.21,22 Higher concentrations of substance P are correlated with hyperactivity of the hypothalamic pituitary-axis, which is indicative of a heightened stress response and is common among patients diagnosed with depression.23 In the same pathway, ACEIs would have the opposite effect, decreasing angiotensin II production and dysregulation of the hypothalamic pituitary-axis.