Venlafaxine is a new nontricyclic antidepressant inhibiting the reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine without antagonizing cholinergic, histaminergic, or noradrenergic receptors. Significantly, in a first placebo-controlled safety and efficacy study, high doses of venlafaxine increased blood pressure in some study subjects. In order to investigate further the effect of subchronic antidepressant drug treatment on blood pressure and heart rate, the effects of a conventional tricyclic (imipramine) and a structurally different phenethylamine antidepressant (venlafaxine) were compared. Sixteen inpatients with major depression (melancholic type) were treated for six weeks with imipramine or venlafaxine in a randomized parallel double-blind design. Blood pressure was monitored for 24 hours before treatment and at days 14 and 28 by means of a portable, automatic blood-pressure monitoring system. Both compounds lowered systolic blood pressure by about 5% on average, while diastolic pressure was influenced neither by imipramine nor by venlafaxine. Imipramine treatment resulted in a significant 15% increase in heart rate on both day 14 and day 28, whereas heart rate tended to decrease under venlafaxine. When the data of individual patients were evaluated, a clinically significant increase in blood pressure was apparent in one venlafaxine-treated patient; a marked increase in blood pressure in one patient treated with imipramine proved to be reversible with continued treatment. Due to the relatively small sample sizes, the present data do not allow a definitive judgement as to whether venlafaxine may cause differential blood pressure alterations in comparison with imipramine. However, our results demonstrate that the blood pressure-increasing effect reported for venlafaxine from first clinical studies might be clinically significant in individual patients. Furthermore, our study shows that 24-hour monitoring of blood pressure and heart rate is a powerful tool in safety evaluations of new drugs, even in relatively small samples.