A concise guide to monoamine oxidase inhibitors: A better understanding of the risks can lead to increased use of these highly effective agents

Despite an abundance of evidenced-based literature supporting monoamine oxidase inhibitors (MAOIs) as an effective treatment for depression, use of these agents has decreased drastically in the past 3 decades. A lack of industry support and the ease of use of other agents are contributing factors, but the biggest impediments to routine use of MAOIs are unfamiliarity with their efficacy advantages and concerns about adverse effects, particularly the risk of hypertensive crises and serotonin syndrome. Many misconceptions regarding these medications are based on outdated data and studies that are no longer reliable.

The goal of this 2-part review is to provide clinicians with updated information regarding MAOIs. Part 1 provides a brief description of:

* the pharmacology of nonselective irreversible MAOIs

* the mechanism by which tyramine induces hypertension

* sources of clinically significant tyramine exposure

* what to tell patients about dietary restrictions and MAOIs.

Part 2 of this guide will cover the risk of serotonin syndrome when MAOIs are combined with inhibitors of serotonin reuptake, how to initiate MAOI therapy, and augmenting MAOIs with other agents.

The pharmacology of MAOIs

First used clinically in the 1950s to treat tuberculosis, MAOIs have a long and interesting history (see the Box "Abrief history of monoamine oxidase inhibitors" on CurrentPsychiatry.com). Table 1 (1) (page 16) lists MAOIs currently available in the United States, including the MAO-B-specific agent rasagiline, which is used for Parkinson's disease.

Manipulation of the monoamines serotonin, norepinephrine, and dopamine is fundamental to managing major depressive disorder (MDD), yet only nonselective MAOIs directly promote neurotransmission of all 3 by inhibiting MAO-A and MAO-B. (2) The Sequenced Treatment Alternatives to Relieve Depression (STARED) study demonstrated that <50% of MDD patients achieve remission in monotherapy trials of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, mirtazapine, or bupropion, necessitating consideration of antidepressant combinations, augmentation options, and eventually irreversible, nonselective MAOIs such as phenelzine, tranylcypromine, or isocarboxazid. (3,4) Nonselective MAOIs thus offer a therapeutic opportunity for patients who do not respond to single or dual-mechanism strategies; moreover, nonselective MAOIs have compelling effectiveness data for other conditions, including panic disorder and social phobia. (5) Although MAOIs are among the most effective pharmacologic agents for MDD, (6) they are underutilized because of an inadequate understanding of risk mechanisms and resultant fear of catastrophic outcomes. Because of the difficulties encountered in achieving clinical remission for MDD, the nonselective MAOIs deserve a second look.

Differentiation of MAO-A from MAO-B. It is essential to understand the mechanism of action of MAOIs, specifically the impact of MAO-A inhibition. Although the enzyme MAO was known in the 1950s, it wasn't until 1968 that Johnston (7) postulated the existence of >1 form. In 1971, Goridis and Neff (8) used clorgyline to examine the deamination rate by MAO of tyramine and norepinephrine. They found that tyramine appeared to be a substrate of both MAO isoforms, but only 1 of the MAO types was sensitive to the inhibitory effects of clorgyline. They also discerned that norepinephrine was only a substrate for MAO-A, and that this form of...