Irreversible Monoamine Oxidase Inhibitors Revisited

Irreversible Monoamine Oxidase Inhibitors Revisited

As with many psychiatric drugs, the discovery of irreversible MAOIs was serendipitous. While being used as an antitubercular agent in the 1950s, iproniazid—a derivative of the hydrazine compound isocarboxazid—was observed to have significant antidepressant properties. Almost at the same time as the discovery of TCAs such as amitriptyline and imipramine (which were also discovered by chance), MAOIs began to be widely used as the first effective antidepressants.

In 1957, Nathan Kline, MD, one of the pioneers of psychopharmacology, published the first report on the neuropsychiatric experiences with iproniazid, referring to it as a “psychic energizer.”1 Within a year of the original report by Kline, more than 400,000 patients with depression had received iproniazid. This development led to the discovery of other, more potent MAOIs and more effective antidepressants, including phenelzine, isocarboxazid, and the nonhydrazine derivative tranylcypromine.

The vast majority of MAOI prescriptions were for tranylcypromine and phenelzine, which largely remain the MAOIs of choice today. Thus, MAOIs became the first class of antidepressants that became widely used in the early 1960s. In the 1960s and 1970s, combination drugs that included antidepressants and neuroleptic agents became popular. One such example was Parstelin, a combination of tranylcypromine and trifluoperazine.

The success of MAOIs in the late 1950s and early 1960s suddenly changed when iproniazid was removed from the US market because of concerns regarding hepatotoxicity. MAOIs were quickly replaced by the TCAs in the 1960s. Lpez-Muoz and Alamo1 suggest that the withdrawal of these drugs because of hepatotoxicity and jaundice may have been an overreaction. They also highlight the dramatic effect that an “antidepressant” drug had on the general attitude toward depression.

The fact that a medication that altered brain monoamines could treat a psychiatric illness such as depression suggested that the mechanism of action may be a chemical imbalance and not a predominantly psychological reaction. Even though ECT had been known to have a potent antidepressant effect, it was not until a pharmacological antidepressant was discovered that the fundamental concept of a neurobiological cause for depression was crystallized.


The enzyme monoamine oxidase exists as 2 subtypes, MAO-A and MAO-B. MAO-A metabolizes serotonin and norepinephrine (NE), the monoamines most closely linked to depression. MAO-B preferentially metabolizes dopamine and trace amines, including phenethylamine. Tyramine is metabolized by both MAO-A and MAO-B. Inhibition of MAO-B is not effective as an antidepressant because there is no direct effect on either serotonin or NE metabolism. Brain MAO-A must be inhibited for an antidepressant effect to occur. The ratio of MAO-A to MAO-B varies throughout the body. In the human brain, the ratio of MAO-A to MAO-B is 25% to 75%, whereas in the liver, the ratio is 50% to 50%. The ratio is 80% to 20% in the intestine, and in the peripheral adrenergic neurons, the ratio is 90% to 10%.2

MAOIs act by inhibiting the activity of MAO and preventing the breakdown of monoamine neurotransmitters (serotonin and NE), thereby increasing their availability. Inhibition may be reversible or irreversible. When an MAOI covalently binds to the enzyme, it is irreversibly inhibited and the enzyme is permanently deactivated.3 Enzyme activity cannot be restored until the body replaces the enzyme through new enzyme synthesis. Restoration of full activity can take up to 2 weeks. Tranylcypromine and phenelzine, the most commonly prescribed MAOIs, are nonselective, irreversible inhibitors of isoforms MAO-A and MAO-B. Tranylcypromine was originally developed as an amphetamine analogue and thus also has some amphetamine-like effects.

The pharmacokinetics of both drugs are very different. Caddy and colleagues4 observed that phenelzine has a half-life of 2 hours. Weber-Grandke and colleagues5 observed that tranylcypromine exists as both a + enantiomer, with a half-life of 0.75 hours, and a − enantiomer, with a half-life of 1.5 hours. Nevertheless, since activity occurs through irreversible inhibition of MAO, the pharmacokinetics of the concentration of these drugs appears to have little relationship to effect. MAO inhibition will persist long after the drug has been eliminated from the body.


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