Reboxetine is a selective noradrenaline reuptake inhibitor, whereas mirtazapine acts as an antagonist at noradrenergic alpha(2), serotonin (5-HT(2)), 5-HT(3) and histamine H(1) receptors. In a former study we could demonstrate an inhibitory impact of mirtazapine on cortisol secretion. In the present investigation, the influence of combined administration of 15 mg mirtazapine and 4 mg reboxetine on the cortisol (COR), adrenocorticotropin (ACTH), growth hormone (GH), and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to reboxetine alone (4 mg). In a randomized order, the subjects received reboxetine (4 mg) alone or the combination of reboxetine (4 mg) and mirtazapine (15 mg) at 8:00 a.m. on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to the administration of single reboxetine or the combination (reboxetine and mirtazapine), at time of administration, and during the time of 5 h thereafter in periods of 30 min. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. For statistical evaluation, the Wilcoxon signed-ranks test was performed. There was a pronounced stimulation of COR, ACTH, GH, and PRL concentrations after single administration of reboxetine. When reboxetine was given in combination with mirtazapine, a significant reduction of the COR, ACTH, and PRL stimulation was observed whereas GH secretion patterns remained unchanged, compared to single administration of reboxetine. Apparently, the stimulatory effects of reboxetine on pituitary hormone secretion via noradrenergic mechanisms are counteracted in part by the alpha(2)-blocking properties of mirtazapine and its inhibitory influence on cortisol secretion.