α2-Adrenergic Receptor Function in Depression: The Cortisol Response to Yohimbine

There is evidence that the abnormalities in hypothalamicpituitary-adrenal (HPA) axis function observed in patients with depression may be related to changes in central neurotransmitter receptor function. To evaluate this possibility further, the α₂-adrenergic receptor antagonist yohimbine hydrochloride, which increases brain norepinephrine turnover, was administered to 40 patients with DSM-III major depression (18 melancholic, 22 nonmelancholic) and 16 healthy controls. Plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) level was measured as an index of noradrenergic function, and plasma cortisol level was used to assess the HPA response. Baseline cortisol levels were elevated in melancholic depressed patients, but not in nonmelancholic patients, when compared with healthy controls. The cortisol response to yohimbine was significantly greater in depressed patients than in controls, despite similar MHPG responses between groups. Since there is evidence that stimulation of postsynaptic α₂-adrenergic receptors inhibits HPA axis function, the abnormally increased cortisol response to the α₂-antagonist yohimbine suggests a relative subsensitivity of postsynaptic α₂-adrenergic receptors in depression.