In the 1950s, monoamine oxidase inhibitors (MAOIs) were one of the first drugs to be utilized as antidepressants in clinical practice.[1] To this day, the available literature shows that MAOIs remain a useful and efficacious tool in the treatment of atypical depression, panic, and social anxiety disorders, treatment-resistant depression, and to some extent, in bipolar disorder.[2][3] Four MAOIs are FDA approved for the treatment of depression in the US; these are isocarboxazid, phenelzine, tranylcypromine, and selegiline.

That said, due to their broad adverse effect profile and multiple drug-drug as well as drug-food interactions, MAOIs are not first or second-line drugs in the management of depression.[4][5] Nevertheless, in cases of treatment-resistant unipolar depression, a double-blind crossover study of imipramine and phenelzine found that response to treatment occurred more frequently in patients switched to phenelzine than those switched to imipramine.[6] Additionally, there is a preferential response to MAOIs in patients diagnosed with atypical depression (a subtype of depression featuring a pattern of mood reactivity, hypersomnia, increased appetite or weight gain, leaden paralysis, and interpersonal rejection sensitivity.)[7]

In addition to the indications mentioned above, selective MAO-B inhibitors (MAOBIs) have shown some effectiveness in the symptomatic treatment of mild Parkinson disease (PD) early in its course. Patients with early PD symptoms given MAOBIs show reductions in motor symptoms, and a lower need for levodopa without a substantial increase in morbidity or mortality.[8] These therapeutic effects occur whether patients are given MAOBIs as an adjunctive treatment with levodopa, or as monotherapy.[9]

Monoamine oxidases function as catalysts for the oxidative deamination of monoamines, including the neurotransmitters serotonin and histamine, as well as the catecholamines dopamine, norepinephrine and epinephrine. There are two main isoenzymes of monoamine oxidases: MAO-A and MAO-B. Norepinephrine, epinephrine, dopamine, tryptamine, and tyramine are all oxidized by both isoenzymes. On the other hand, serotonin is mainly oxidized by MAO-A.[10]

MAOs are present in most of our body’s tissues, but their distribution is not even. In the brain, most of the MAOs are present in the striatum of the basal ganglia and the hypothalamus.[11] The main form being MAO-B in the basal ganglia. In the intestines, however, MAO-B is only found in trace amounts, leaving MAO-A the dominant of both isoenzymes.

Inhibitors of monoamine oxidases function, as the name implies, by inhibiting the enzyme MAO, and thus result in the accumulation of its substrates (the monoamine and catecholamine neurotransmitters, as well as tyramine ingested in some foods.) The accumulation of serotonin, norepinephrine, and dopamine in the synaptic clefts in the CNS is then responsible for MAOIs’ antidepressant effect. It’s important to state that this is mainly dependent on the inhibition of MAO-A, with MAO-B inhibitors being devoid of antidepressant activity. This effect is likely due to the heterogenicity of isoenzyme distribution in the brain. Conversely, the motor symptom alleviation effects of MAOIs are mainly achievable via the selective inhibition of MAO-B (as this is the dominant isoenzyme in the basal ganglia). L-deprenyl (selegiline), being one of the selective MAO-B inhibitors (at low doses), is effective in treating early Parkinson disease symptoms.[12]

The four most commonly prescribed MAOIs are selegiline, isocarboxazid, phenelzine, and tranylcypromine. Their administration is discussed below:

Selegiline’s now preferred method of administration is through a transdermal patch. The drug’s extensive “first pass” metabolism through the liver results in a low bioavailability when taken orally; this necessitates the administration of a relatively large oral dose which predisposes patients for the “cheese reaction” side effect of MAOIs (discussed later) through the inhibition of MAO-A in the intestines. The transdermal patch avoids the “first pass” metabolism, eliminating the need for a large bolus dose and decreasing the chances of developing the “cheese reaction” side effect.[13][14] In fact, dietary restrictions are not necessary when using the 6mg/24 hour patch.  Selegiline is also available in tablet form. Isocarboxazid, phenelzine, and tranylcypromine, on the other hand, are only available in oral tablet form.

As with other antidepressants, MAOIs require few weeks; usually, 4 weeks before there is a clinically apparent response. Also, certain considerations are necessary when switching antidepressants to and from MAOIs. The current antidepressant dose should be tapered off over 2 to 4 weeks then completely discontinued before switching to another antidepressant. Next, two weeks should elapse from the last dose of antidepressant and the first dose of an MAOI. A five-week gap should be allowed for fluoxetine, especially due to its relatively long half-life.[15] Similarly, two weeks are necessary when switching from an MAOI after tapering it off, to allow for MAO enzyme reconstitution by the cells.

MAOIs have a potent hypotensive effect, leading to almost half of their users experiencing dizziness.; this is an important adverse effect to watch for, especially in elderly patients.[16][17][18]

A significant and potentially fatal side effect of MAOIs is the hypertensive crisis or the “cheese reaction.” This adverse event occurs when taking MAOIs along with sympathomimetic amines such as tyramine found in some fermented foods like cheese.[19] It is important to note that selective MAO-B inhibitors do not have such an adverse effect, as the intestines contain very little MAO-B.[20] Another point worthy of mention is that the development of reversible, selective MAO-A inhibitors also avoided this issue. MAO-A inhibitors can successfully block enough MAO-A in the brain while having a low enough affinity to allow its displacement by dietary tyramine from intestinal MAO-A.[21]

Serotonin syndrome, or serotonin toxicity, is another potentially life-threatening condition that can be precipitated by co-administration of MAOIs with other antidepressants or serotonergic agents. Clinical features include mental status changes such as delirium, autonomic manifestations such as tachycardia, hypertension, diarrhea, and neuromuscular hyperactivity that manifests as tremors and hyperreflexia.[22][23]

Also, abrupt cessation of MAOIs can result in antidepressant discontinuation syndrome; symptoms may include anxiety, agitation, insomnia, chills, diaphoresis, headache, irritability, malaise, and nausea.[24][25] Other common side effects include sexual dysfunction, insomnia, headaches, and weight gain. Many antidepressants share these traits.

As previously stated, prescribing MAOIs with any sympathomimetic agent may precipitate a hypertensive crisis. For that reason, it is contraindicated to co-administer these agents. Moreover, preparations containing ephedrine, phenylephrine, phenylpropanolamine, or pseudoephedrine such as cold and nasal decongestion remedies should not be given concomitantly with MAOIs for the same reason. Similarly, levodopa should be utilized with caution in patients on MAOIs as it increases the levels of circulating noradrenaline.[26] Sublingual nifedipine is also absolutely contraindicated for the treatment of hypertension if the patient is on an MAOI.[27] One should also be wary of any signs and symptoms of pheochromocytoma or other catecholamine-releasing paragangliomas, as giving MAOIs to patients suffering from these conditions will most likely trigger a hypertensive crisis.

Serotonergic antidepressants cotemporally administered with MAOIs increase the chances of serotonin syndrome precipitation, and so it is generally advised against the co-prescription of those agents. If utilized, in cases of treatment-resistant depression, rigorous monitoring is necessary.[26]

For the sake of avoiding a hypertensive crisis, or the so-called “pressor response” of tyramine found in some foods, dietary restrictions require implementation. Classically, all aged cheeses are absolutely contraindicated, as well as all aged, smoked, pickled, or cured meats, fish, and poultry. A variety of other foods, including over-ripened fruit, are also contraindicated.[26] That said, reviews from food science literature on tyramine concentrations in food revealed that tyramine concentrations in modern food are less than they have ever been and that this trend is continuing. The conclusion is that in the right portions, all foods may be allowed in the MAOI diet.[28]

It also goes without saying that patients’ refusal to take the medication or severe allergy to MAOIs are absolute contraindications to their administration.