The Role of Mixed Action Antidepressants in Therapeutics

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Recently marketed non-SSRI antidepressants are considered by most clinicians as second-line therapeutic options for treatment refractory patients or as augmenting agents. Since these antidepressant medications act on different neuronal systems, they are a rational choice in non-responders (182). They are also used as adjunctive agents to augment SSRIs in partial responders. Their overall efficacy as antidepres-sants is comparable to that of the standard antidepressant classes such as SSRIs, TCAs, and MAOIs, and some data indicate superiority compared to SSRI in depression with melancholic or endogenous features. They are second-line agents because the SSRI are easier to dose, are available in generic form, and have few medically serious adverse effects.

In addition to the efficacy of non-SSRI agents in depression, studies support efficacy in anxiety disorders (especially venlafaxine, mirtazapine, nefazodone) and ADHD (venlafaxine, bupropion). Bupropion's role in smoking cessation is well recognized (211) but it has also been used to treat neuropathic pain (212). Duloxetine and milnacipram are the preferred antidepressant agents in fibromy-algia. Bupropion and mirtazapine have become the agents of choice if SSRI-induced sexual dysfunction limits continued treatment with that class of drugs.

Trazodone has a limited role, but may be useful in promoting sleep in patients taking energizing antidepressants, or as an augmentation agent. Nefazodone is a very effective antidepressant but its use has declined since reports of hepatotoxicity have appeared. Mirtazapine is also an effective antidepressant and antianxiety agent that is frequently used in combination with other antidepressants as an augmentation strategy and to improve sleep, although with higher doses its hypnotic actions are eliminated.

The possibility of a more rapid onset of clinical effect for agents that have mixed actions, mirtazapine and venlafaxine in particular, has been the subject of much debate. At present, there are insufficient data to support such a claim.

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