Desipramine-Yohimbine Combination Treatment of Refractory Depression: Implications for the β-Adrenergic Receptor Hypothesis of Antidepressant Action

Preclinical investigations have shown that combined administration of the α₂-adrenergic receptor antagonist yohimbine hydrochloride and the tricyclic antidepressant desipramine hydrochloride produces a reduction in brain β-adrenergic receptor function within four days. Since the ability of antidepressant treatments to reduce β-adrenergic receptor function has been hypothesized to mediate antidepressant efficacy, it was predicted that combined desipramine-yohimbine treatment would be a more rapid-acting and potent antidepressant regimen than desipramine alone. In the present investigation, the effects of desipramine (N=11) and desipramine-yohimbine (N=10) treatment on depressive symptoms, norepinephrine turnover, and blood pressure were determined in patients with major depression who had a history of nonresponse to standard antidepressant treatments. Neither desipramine nor desipramine-yohimbine proved to be an effective treatment, although concomitant yohimbine administration did attenuate the ability of desipramine to decrease plasma free and 24-hour urinary 3-methoxy-4-hydroxyphenylethyleneglycol levels and blood pressure. Fifteen of the 21 patients eventually had a good response to pharmacologic treatments, particularly a desipramine—lithium carbonate or lithium carbonate—tranylcypromine sulfate combination treatment (11 of 14 responded). This study provides evidence against the β-adrenergic receptor hypothesis of antidepressant action.