73: Monoamine Oxidase Inhibitors

HISTORY AND EPIDEMIOLOGY

Monoamine oxidase inhibitors (MAOIs) have a unique history, pharmacology, and toxic syndromes associated with their use. This drug class has fallen in and out of favor with scientists and clinicians over the last several decades. While toxicity from MAOI ingestion is becoming less common due to more limited clinical usage of the traditional nonselective MAOIs, an understanding of MAOI toxicity is fundamental to any clinician who takes care of patients with acute poisoning.

Monoamine oxidase (MAO) was discovered in 1928 and named by Zeller when the enzyme was recognized to be capable of metabolizing primary, secondary, and tertiary amines such as tyramine and norepinephrine.¹³¹ Subsequently, the “monoamine hypothesis” postulated depression as a monoamine deficiency state and MAOIs targeted monoamine metabolism for therapeutic benefit. In the early 1950s, iproniazid, a drug previously used to treat tuberculosis, was found to produce favorable behavioral adverse events. By the mid 1950s, it was demonstrated that iproniazid inhibited MAO, and it then became the first antidepressant used clinically.⁴⁶

In the late 1960s, two MAO isoforms were identified each with substrate and inhibitor specificity. This determination led to the development of selective MAOIs in attempts to minimize the many food and drug interactions that occur with the traditional nonselective MAOIs. Nonselective MAOIs proved to be potent and efficient antidepressants and became first-line therapy for depression. In the 1970s, alternative therapies for depression, such as tricyclic antidepressants, were developed and achieved clinical success without as many food interactions.

Intentional MAOI overdose is relatively uncommon and accounts for a dwindling number of annual exposures reported to the American Association of Poison Control Centers. From 2000 to 2010 there was a decreasing trend in the number of exposures with only 228 exposures reported in 2010,¹⁶ representing less than 1% of all antidepressant exposures. Of the reported exposures in 2010, there were only five cases of “major toxic effect” (defined as life-threatening signs or symptoms) and no deaths were reported. Over the past two decades, annual reported MAOI exposures have decreased 34% since 1985 (Chap. 136). Global MAOI exposure rates declined in proportion with the United States, with the possible exception of exposures to moclobemide, a drug not approved by the US Food and Drug Administration (FDA).³³

PHARMACOLOGY

Chemistry

Monoamines, also known as biogenic amines, include the neurotransmitters norepinephrine, dopamine, and serotonin, which share the presence of a single amine group and the ability to be metabolized by MAO. Monoamine oxidase is a flavin-containing enzyme present on the outer mitochondrial membrane of central nervous system (CNS) neurons, hepatocytes, and platelets. In a two-step reaction, MAO catalyzes the oxidative deamination of its various substrates. The reaction liberates H₂O₂, a reactive oxygen species. Deamination by MAO is one of two major routes of elimination of monoamines, the other being ...