A concise guide to monoamine oxidase inhibitors
A better understanding of the risks can lead to increased use of these highly effective agents. First of 2 parts.
VIDEO: Listen to Dr. Meyer discuss what to tell patients about diet and monoamine oxidase inhibitors.
Within the CNS, norepinephrine and dopamine neurons possess both MAO forms, with the MAO-A content greater than MAO-B. Serotonergic neurons only contain MAO-B.11 Outside of the CNS, MAO-A predominates, with only platelets and lymphocytes possessing MAO-B activity.11 The overall relative tissue proportions of MAO-A to MAO-B activity are: brain, 25% MAO-A, 75% MAO-B; liver, 50% MAO-A, 50% MAO-B; intestine, 80% MAO-A, 20% MAO-B; and peripheral adrenergic neurons, 90% MAO-A, 10% MAO-B.
Because of its specificity for serotonin and norepinephrine, CNS MAO-A inhibition is necessary for antidepressant effects. MAO-B inhibition by itself does not appear to raise CNS dopamine levels unless exogenous dopamine is supplied.11 All MAOIs used in the United States to treat depression are irreversible, nonselective inhibitors of MAO-A and MAO-B.
Selegiline in oral form generates low plasma levels and primarily inhibits MAO-B. The transdermal form of selegiline achieves significantly greater systemic exposure, and at these higher plasma levels selegiline is a nonselective, irreversible MAOI effective for MDD (Figure 112). Administering selegiline systemically via a transdermal patch avoids clinically significant MAOI effects in the gut, so no dietary warnings exist for the lowest dose (6 mg/24 hours), although there are warnings for the higher dosages (9 mg/24 hours and 12 mg/24 hours).
Differentiation of MAOIs by chemical class. The earliest MAOI, iproniazid, was a hydrazine derivative and exhibited hepatotoxicity,13 as did certain other hydrazine MAOIs. This lead to a search for safer hydrazine and nonhydrazine alternatives. Isocarboxazid and phenelzine are the 2 hydrazine MAOIs available in the United States, while tranylcypromine and selegiline transdermal are nonhydrazines (Figure 2).
What distinguishes the nonhydrazine medication selegiline is that its metabolism generates L-amphetamine metabolites (Figure 314). This property was thought to be shared by other nonhydrazines, but recent studies indicate than neither tranylcypromine15 nor the MAO-B–selective rasagiline possess amphetamine metabolites.16 Unlike the dextro isomers, L-amphetamine structures do not inhibit dopamine reuptake or cause euphoria, but can cause stimulation (eg, sleep disturbance) by inhibiting norepinephrine reuptake, and also by interacting with the trace amine-associated receptor 1 (TAAR1), an intracellular receptor expressed within the presynaptic terminal of monoamine neurons. Activation of TAAR1 by tyramine is an important part of the hypertensive effects related to excessive tyramine exposure.17 (The importance of TAAR1 and the interaction with tyramine is discussed in the next section.) Importantly, patients taking selegiline must be warned that certain drug screens may not discriminate between levo and dextro isomers of amphetamines, and that the use of selegiline should be disclosed prior to drug testing procedures.
MAOIs and tyramine: Dietary requirements
Clinicians who are familiar with MAOIs recognize that there are dietary restrictions to minimize patients’ exposure to tyramine. As most clinicians know, significant tyramine ingestion may cause an increase in blood pressure (BP) in patients taking an MAOI, but many overestimate the prevalence of foods high in tyramine content since the original reports emerged in the early 1960s.18 In a recent monograph, one of the leading experts on MAOIs, Professor Ken Gillman, stated:
Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required.19
