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Augmentation of Venlafaxine With Bupropion: Risks Associated With a Triple Monoamine Reuptake Inhibition Approach to Partially Responsive Depression

J Clin Psychiatry 2013;74(2):e119-e121

In patients who show partial response to venlafaxine, augmentation with a second antidepressant may be considered with bupropion as a candidate drug. Theoretically, the advantage of the venlafaxine-bupropion combination is that it results in the reuptake inhibition of serotonin and norepinephrine, as well as dopamine; such a triple neurotransmitter reuptake inhibition formula could be expected to maximize the chances of treatment response. However, there are pharmacokinetic risks associated with this antidepressant combination because bupropion is a potent inhibitor of cytochrome P450 (CYP) 2D6, the enzyme responsible for the metabolism of venlafaxine. Bupropion can substantially raise venlafaxine levels, resulting in a variety of dose-dependent serotonergic and noradrenergic adverse effects, ranging from increased anxiety and restlessness to increased blood pressure. Coping with the interaction requires awareness of the risk of such an interaction, knowledge about dose-dependent serotonergic and noradrenergic adverse effects of antidepressant drugs, down-titration of the dose of venlafaxine (or temporary withdrawal of the drug) should such adverse effects emerge during combination treatment, and the use of blood levels of venlafaxine and desvenlafaxine as a guide in down-titration, should facilities for such estimations be available. Fortunately, although venlafaxine and its active metabolite desvenlafaxine mildly inhibit CYP2D6, these drugs do not increase bupropion levels, because CYP2D6 is not involved in the metabolism of bupropion.