MAO inhibitors: Risks, benefits, and lore
ABSTRACTMonoamine oxidase (MAO) inhibitors were the first antidepressants introduced, but their use has dwindled because of their reported side effects, their food and drug interactions, and the introduction of other classes of agents. However, interest in MAO inhibitors is reviving. Here, we discuss their use, risks, and benefits in clinical medicine.
KEY POINTS
- Data from multiple studies suggest the efficacy of MAO inhibitors in the management of major depressive disorder and, in particular, major depressive disorder with atypical features and in treatment-resistant depression.
- When using oral MAO inhibitors, patients must follow a low-tyramine diet to avoid the “cheese reaction,” ie, tyramine-induced hypertensive crisis. However, recent studies suggest that traditional dietary advice may be unnecessarily restrictive.
- The selegiline transdermal system (Emsam) is the first approved transdermal patch for treatment of major depression. Unlike oral MAO inhibitors, the patch can be used without the dietary restrictions at its lowest effective dose of 6 mg/24 hours. Because of its transdermal delivery, it has the advantage of not inhibiting the metabolism of dietary tyramine by MAO subtype A in the gut, while providing antidepressant effect in the brain. The patch may be a promising alternative to existing strategies for the management of major depressive disorder.
Side effects of the selegiline patch
The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.25 It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.24
Observe a washout period when switching between serotonergic drugs
Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.26 Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),27,28 their physiologic effects are long-lasting.14
Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.29 Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.30 A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.31
Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.
Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.
Drugs to avoid due to interactions
Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.36,37
Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.
Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.14
Beware of worsening depression
Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.
Diet can be more lenient than in the past
The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,38 and evidence from more recent studies suggests that they are unnecessarily strict39 and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.14 There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.39
To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.40
The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.39,41 The results of these investigations have led to more lenient dietary guidelines.39
Absolute dietary restrictions include39:
- Aged cheeses and meats
- Banana peels
- Broad bean (fava) pods
- Spoiled meats
- Marmite
- Sauerkraut
- Soybean products
- Draft beers.
Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).39
Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.
Dietary restrictions for the selegiline patch
Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies42 show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.
