OBJECTIVE To compare the cardiac safety and therapeutic efficacy of trimipramine and doxepin. METHODS A 1-week single-blind placebo period followed by a 5-week randomized double-blind parallel group clinical trial. METHODS Psychiatric out-patient clinic of a general hospital. METHODS 37 young-elderly patients with a diagnosis of Major Depressive Episode (DSM-III criteria). METHODS Placebo for 1 week, 2 weeks of titration with either drug in the dosage range of 75 mg/day up to a maximum of 200 mg/day. METHODS We measured the psychiatric effects with the Hamilton Rating Scale for Depression, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression Scale. Cardiovascular effects were assessed on 12-lead standard electrocardiograms plus 1-minute rhythm and high speed recordings; orthostatic (lying/standing) blood pressures were also taken. Physical exams, lab tests, cognitive functions (Buschke Selective Reminding Test, Hierarchic Dementia Scale, Word Fluency) and adverse reactions were also noted. RESULTS Both drugs were equally effective in relieving symptoms of depression and anxiety. The cardiovascular effects of both drugs were minimal. Trimipramine did lower blood pressure but this was without clinical significance. Three trimipramine patients and five doxepin patients developed occasional premature ventricular or atrial contractions. Of these, two trimipramine patients and one doxepin patient were among those with abnormal ECG's at entry. The doxepin patient was withdrawn from the study after 21 days of treatment when the PVC's became increasingly frequent. CONCLUSIONS Trimipramine and doxepin are equally safe and effective antidepressants in the young-elderly.