The effects of amitriptyline (n [no.] = 14) or zimelidine (n = 13) [antidepressants] on the sleep EEG of hospitalized depressed patients were assessed in a double-blind protocol involving 28 days of active dosing. Zimelidine induced no immediate improvement in sleep continuity, and even after 3 wk on zimelidine subjects tended to have longer sleep latency, more awakenings and lighter non-rapid eye movement (REM) sleep than before taking the drug. Zimelidine induced a rapid and persistent alteration of sleep architecture and selected REM measures. REM sleep, which was suppressed over the first 2 nights on zimelidine, was maximally suppressed after 1 wk, but by 3 wk there was some tolerance for selected REM measures. While zimelidine induced none of the sedative effects of amitriptyline, both were equivalent in their REM-suppressant effects. These findings are discussed in terms of the differences in uptake blockade and anticholinergic potency in these 2 drugs.