MAO Inhibitors

Mechanism of Action

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. However, in the intestines, 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]

Administration

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 6 mg/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 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.

Adverse Effects

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 worth mentioning 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, manifesting 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.

Contraindications

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 since 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, 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 ever 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.

Monitoring

It is essential to evaluate the mood and mental status of adolescent recipients of MAOIs, as with any other antidepressant; these medications may increase the risk for suicide in those aged 18 to 24 years.[29]

Baseline and periodic monitoring of renal and hepatic functions and blood pressure measurements should be taken for those on MAOIs. Blood glucose also requires monitoring, as noradrenergic effects of MAOIs lead to a decrease in insulin production and an increase in glucagon secretion.[30] This is of particular concern in diabetic patients.

For those on MAO-B inhibitors such as selegiline, periodic evaluation for parkinsonism is advisable.

Toxicity

There is no specific antidote for MAOI toxicity, and dialysis is unhelpful in removing the drug. An overdose of MAOIs, or use in combination with other serotonergic agents, may lead to serotonin toxicity. Likewise, the use of MAOIs with sympathomimetic agents may lead to the development of a hypertensive crisis.

When managing serotonin syndrome, early transfer to a medical ICU and consultation with a toxicologist is strongly advised. Diagnosis of serotonin toxicity is possible using the “Hunter criteria” or the “Sternbach criteria” based on physical manifestations.[22] The mainstay of management is the discontinuation of the serotonergic agent and supportive care, where most patients improve within 24 hours.[31]

In cases of hypertensive crisis, immediate admission to the ICU for prompt blood pressure control with a parenteral, titratable antihypertensive agent while the patient remains on a vitals monitor is necessary. Urine output measurements and a neurologic examination should also take place. BP correction should be slowly achieved over several minutes to an hour, and not immediately. The goal is to lower the BP to no less than 20% to 25% during the first hour.[32]

Enhancing Healthcare Team Outcomes

Patients requiring MAOI administration often are refractory to other medications and require an interprofessional team of healthcare professionals, including a nurse, laboratory technologists, pharmacists, and several physicians in different specialties. Without proper monitoring, there is a risk of developing potentially fatal adverse effects such as serotonin syndrome or a hypertensive crisis.

An MAOI prescription will require the patient to follow up with a dietitian to ensure a safe diet that does not trigger a food-drug interaction with the medication. Moreover, patients who have Parkinson disease may be put on an MAOI as part of early management by a neurologist. PD patients often develop depressive episodes as the disease progresses and may benefit from follow-up with a psychiatrist.

Only by working as an interprofessional team can we reduce the likelihood of and monitor potential side effects of MAOIs. Data available from published literature shows that the use of rasagiline improves motor fluctuations and PD symptoms in early course Parkinson’s disease patients on levodopa.[12] [Level 1] Furthermore, research also shows that treatment with the MAOI phenelzine is more effective in alleviating symptoms in chronically ill patients of major depressive disorder in contrast to treatment with the TCA imipramine.[6] [Level 2]