It has been hypothesized that the mechanism of action of antidepressant treatments is related to their ability to decrease the sensitivity of the alpha-2 adrenergic autoreceptor. In order to assess alpha-adrenergic autoreceptor sensitivity, the effects of clonidine, the alpha-2 adrenergic receptor agonist, on plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), blood pressure (BP) and patient-rated sedation were measured in nine depressed patients before and during amitripytline treatment. Postsynaptic alpha-2 adrenergic receptor sensitivity was assessed by determining the growth hormone (GH) response to clonidine before and during treatment. Amitriptyline significantly attenuated the effects of clonidine on plasma MHPG, standing systolic BP, and sedation, indicating that alpha-2 adrenergic autoreceptors had become subsensitive. In addition, baseline plasma MHPG levels were significantly reduced. Amitriptyline had no effect on the GH response to clonidine.