The effects of the optically active enantiomers of oxaprotiline (OXP), R(-) OXP and S(+) OXP, on depressive symptomatology and the sleep EEG were investigated in two separate exploratory studies. In addition, the neuroendocrine profile of both compounds was characterized in normal controls. In the patients treated with a daily oral dose of 150 mg S(+) OXP we found a Hamilton depression score that decreased from 29.1 +/- 1.8 (SEM) on day 0 to 14.7 +/- 3.2 on day 28 (P < 0.01). Six patients were judged to be full responders (HAMD score 0-7 points), three were improved (HAMD score 8-15) and four were nonresponders (HAMD score > 16). The therapeutic effect achieved with 150 mg R(-) OXP daily was less pronounced: the HAMD score decreased from 27.8 +/- 2.5 on day 0 to 19.4 +/- 3.2 on day 28 (P < 0.05). There were two full responders, one improved patient and seven nonresponders. The sleep EEG scoring revealed a marked suppression of REM sleep among patients treated with S(+) OXP but not with R(-) OXP. In the normal controls, a single oral dose of 75 mg S(+) OXP prompted an increase in the secretion of cortisol and growth hormone, whereas 75 mg R(-) OXP did not. Neither enantiomer influenced the secretion of testosterone or prolactin.