Adjunctive yohimbine for treatment in refractory depression

Although yohimbine (YOH) has been available for the treatment of male erectile dysfunction (ED) for longer than Viagra^®, there is a perception that little is known about the clinical performance of the drug. This review attempts, by comprehensive analysis of the literature, to cover the clinical, pharmacological, and therapeutic profiles of YOH, relevant to its potential utility in the management of patients with ED. Relatively few well-designed studies have been completed. From these, however, it can be concluded that YOH as monotherapy possesses only modest efficacy in ED patients. In acute and chronic (long-term) studies, YOH has been found to be relatively free of side effects over the dose range predicted to be effective in ED. At much higher doses, the most frequently observed effects, consistent with the primary pharmacological action of the drug, are elevation of blood pressure, a slight anxiogenic action, and increased frequency of urination. These side effects are all easily reversible on termination of YOH therapy. There is increasing evidence that the erectogenic action of YOH can be augmented by concomitant administration of agents that augment the release and/or action of nitric oxide in the corpus cavernosum. YOH has yet to be studied in female sexual dysfunction. Overall, the benefit risk profile of YOH would indicate that it has potential, more probably as part of a combination strategy, e.g., with a drug that enhances the nitric oxide pathway, in the treatment of ED.

Although “treatment-resistant depression” is a widely used and empirically useful concept, varying interpretations of its operational definition in the literature and an absence of well-designed placebo-controlled trials have resulted in a confusing landscape in which the direction to be taken in an individual case is likely to be influenced as much by anecdote or theoretic speculation as by published data. Treatment resistance is most simply defined as the persistence of clinically meaningful depressive symptoms after 6 weeks of antidepressant treatment, given at therapeutic dosages and taken by the patient as prescribed. More stringent definitions require a similar lack of response to one or more subsequent structurally different antidepressants, and some investigators have suggested that no patient should be considered resistant until a course of electroconvulsive therapy (ECT) has been administered.2, 6, 9, 22, 34

The definition of outcome, like that of an adequate pharmacologic trial, has varied. In some studies, it is dependent on a percentage change from baseline in objective behavioral ratings of mood, whereas in others, it is linked to global assessments of overall functional ability and complete remission.37, 43, 85, 86 Most early attempts at definition of treatment resistance presumed a homogenous population; more recently, investigators such as Nierenberg and others 76, 77 have suggested that treatment resistance might best be defined in the context of a continuum in which the degree of treatment resistance is ascertained by taking into account such things as the total number of antidepressant trials and their quality, the number of failed treatments, and the degree of lack of response.