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.
TYPES OF MAO INHIBITORS
MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.
Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.
Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.
A reversible MAO inhibitor is moclobemide (not available in the United States).
Do selectivity and reversibility matter?
Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.
Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.12 At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.
Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.13
SELEGILINE TRANSDERMAL SYSTEM
The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.
Pharmacokinetics of the selegiline patch
With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.
The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.1 About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.
This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.
Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.1 Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.1
Advantages of the patch system
Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.1 Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.1
Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.2
Disadvantage of the selegiline patch: Cost
The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.
SAFETY, TOLERABILITY OF MAO INHIBITORS
Side effects of oral agents
Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.14 Phenelzine has the strongest association with sedation.14
Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.15
Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.19 The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.19–21
Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.22 Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.23 The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.23
