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An Update on MAOIs: Dietary Restrictions and Drug Interactions

David A. Flockhart, MD, PhD

Indiana Institute for Personalized Medicine and the Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis

Some MAOIs are approved by the FDA for the treatment of depression, but dietary restrictions and potential drug interactions have limited the use of these agents. Although the current depression treatment guidelines from the APA1 and BAP2 recommend using older MAOIs for atypical or treatment-resistant depression, newer formulations of these medications that have a different mechanism of action than older MAOIs and that lessen the risk for serious adverse effects make them worth considering for these patients with depression as well.

Mechanism of Action of MAOIs

MAOIs prevent MAO enzymes from deaminating and, thus, inactivating excess dopamine, serotonin, and norepinephrine neurotransmitters, thereby allowing these neurotransmitters to accumulate in the brain and other tissues. Owing to their selectivity and reversibility, relatively newer MAOIs, such as transdermal selegiline and moclobemide, have mechanisms of action that avoid some of the problems associated with older MAOIs, such as isocarboxazid, phenelzine, and tranylcypromine. (For an in-depth review of the mechanism of action of MAOIs, see "MAOIs and Transdermal Delivery" by Chad M. VanDenBerg, PharmD, BCPP.3)

Selectivity of MAOIs. The 2 isomers of MAO enzymes are MAO-A and MAO-B. An MAOI either inhibits only 1 isomer (selective) or it inhibits both isomers (nonselective); the inhibition of MAO-A appears to be necessary for antidepressant effects to occur.4

Isocarboxazid, phenelzine, and tranylcypromine are all nonselective MAOIs. Oral and transdermal selegiline formulations are selective inhibitors of MAO-B at low doses. However, at higher doses (≥20 mg/d for oral selegiline and ≥9 mg/24 h for transdermal selegiline), selectivity is lost and both MAO-A and MAO-B are inhibited, which is when the antidepressant effects occur. Moclobemide is a selective inhibitor of MAO-A, but it is not available in the United States.

Reversibility of MAOIs. MAOIs can be either reversible or irreversible. Irreversible MAOIs bind to the MAO enzyme(s) for its lifetime, a duration of 2 to 4 weeks. Intestinal MAO-A is responsible for metabolizing dietary tyramine during digestion; when this MAO-A is irreversibly inhibited, tyramine cannot be metabolized efficiently.4 Reversible MAOIs can be displaced from MAO-A and may not inhibit tyramine breakdown during digestion. Therefore, reversibility is a favorable characteristic of MAOIs because some side effects resulting from excess tyramine can be avoided.

Isocarboxazid, phenelzine, tranylcypromine, and oral and transdermal selegiline are irreversible MAOIs. Moclobemide is a reversible inhibitor of MAO-A (RIMA).

Dietary Restrictions of Tyramine

Tyramine is a trace amine derived from tyrosine, an amino acid, that has sympathomimetic effects. It occurs naturally in a range of foods and, when ingested, is metabolized by MAO-A in the gut. When an inhibitor binds to MAO-A, this degradation is prevented, allowing an excess of tyramine to enter the blood stream. Too much tyramine increases levels of norepinephrine, thereby stimulating the cardiovascular sympathetic nervous system and constricting the blood vessels, which leads to a rapid increase in blood pressure and possibly a hypertensive crisis (>180/120 mmHg). This can cause permanent damage to bodily organs, stroke, aneurysm, and, potentially (although rarely), death.5

A high-tyramine meal consists of about 40 mg of tyramine—an amount substantially lower than the amount the typical person can digest (around 400 mg of tyramine before experiencing an increase in blood pressure).5 However, a person who is taking an MAOI has compromised tyramine metabolization and can experience a mild reaction after ingesting only 6 mg to 10 mg of tyramine and a severe reaction with 10 mg to 25 mg.6

AV 1. Foods Restricted and Allowed When Taking an MAOI (00:32)

Based on Gardner et al7 and transdermal selegiline8 and phenelzine9 package inserts
Abbreviations are defined before the References

To avoid a dangerous rise in blood pressure, people taking irreversible MAOIs must limit the amount of tyramine in their diets. Particularly high levels of tyramine (>6 mg/serving) are found in foods such as aged cheeses and meats, draft beer, soy products, and some yeast extracts as well as spoiled foods (AV 1; see also Foods to Avoid With MAOI Administration).7–9 These dietary restrictions have played a large role in the perception that MAOIs are difficult to administer and have limited the use of MAOIs since other antidepressants with more favorable safety profiles became available.

The mechanisms of action of newer MAOIs, such as moclobemide and transdermal selegiline, lessen the need for diet modification when these medications are used at low doses. Although moclobemide selectively inhibits MAO-A, its reversibility still allows tyramine to be metabolized.5 Regarding transdermal selegiline, the mechanism of delivery by means of the patch avoids first-pass metabolism in the gut, eliminating the need for dietary restrictions at the lowest dosage. At doses greater than 6 mg/24 hours, however, the dietary restrictions are still required due to insufficient safety data.8

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Drug Interactions

In addition to reactions with tyramine, MAOIs can also negatively interact with other medications causing a multitude of adverse events, including hypertensive crisis and serotonin syndrome (see Agents That Are Contraindicated With MAOIs and the Corresponding Adverse Events). Therefore, when prescribing MAOIs, clinicians should always tell patients to inform their other physicians about the MAOI regimen.

AV 2. Common Products Containing Sympathomimetics (00:33)

Based on Wimbiscus et al4

Sympathomimetic Agents. Medications that have sympathomimetic effects are those that mimic the effects of sympathetic nervous stimulation, like speeding up the heart rate or constricting blood vessels. Sympathomimetic drugs can be used over the short term to treat severe asthma, hypotension, or myocardial infarction, for example, and include a range of medications, from antihypertensive agents to illicit drugs to over-the-counter medications containing vasoconstrictors like cough and cold remedies and weight-reducing preparations (AV 2).4 When co-administered with MAOIs, sympathomimetics can dangerously elevate blood pressure, causing a hypertensive crisis.

AV 3. Signs and Symptoms of Serotonin Syndrome (00:30)

Based on Sternbach10

Serotonergic Agents. Part of the antidepressant effect of MAOIs includes inhibiting the MAO enzymes that deactivate serotonin in the synapse, which in turn enhances serotonin availability. Agents that enhance serotonin’s effects, such as antidepressants that inhibit serotonin reuptake or amphetamines that release serotonin, should be avoided with MAOIs because an accumulation of too much serotonin will result in serotonin syndrome, which can be fatal. Serotonin syndrome is characterized by autonomic, neuromotor, and cognitive-behavioral symptoms (AV 3).10 Because of the serious nature of serotonin syndrome and to ensure that unnecessary serotonergic activity does not occur, a washout period of at least 14 days must be observed after discontinuing an MAOI and beginning a serotonergic agent, and vice versa. Although dietary restrictions are lessened with transdermal selegiline and moclobemide, the drug interaction precautions for MAOIs remain in effect.

Personalizing Therapy

An armamentarium of antidepressants are available to treat depression, including MAOIs, and the future of medicine is being able to predict which patients are most likely to respond to particular agents—that is, personalizing therapy. Developing a predictive panel of pharmacogenetic biomarkers can guide the stratification of depression therapy for particular patients, which should improve their treatment outcomes and quality of life. So far, a single, first, genome-wide association study11 has shown nonsignificant results, although genetic testing may eventually be available to inform treatment selection.

Conclusion

MAOIs are effective treatments for depression, but because of dietary restrictions and drug interactions, they are relatively underused in psychiatry. The selectivity and reversibility of each MAOI depends on the need for dietary restrictions of tyramine. For example, selective MAO-B inhibitors, like the transdermal system of delivery at low dosages, and reversible MAO-A inhibitors may avoid the need for dietary modifications in some situations. However, all MAOIs have drug interactions with sympathomimetics, serotonergic agents, and other medications, so a washout period and careful monitoring are necessary. As the field of medicine moves toward personalized therapy, pharmacogenetic biomarkers may eventually allow practitioners to stratify depression treatment and thereby optimize outcome for patients.

For Clinical Use

 

  • Inform patients taking MAOIs about dietary restrictions and drug interactions
  • Observe a washout period when switching between an MAOI and a contraindicated agent
  • Advise patients to inform other physicians that they are taking an MAOI

 

Drug Names

isocarboxazid (Marplan), phenelzine (Nardil and others), selegiline oral formulation (Eldepryl, Zelapar, and others), selegiline transdermal system (EMSAM), tranylcypromine (Parnate and others)

Abbreviations

APA = American Psychiatric Association, BAP = British Association of Psychopharmacology, FDA = US Food and Drug Administration, MAO = monoamine oxidase, MAOI = MAO inhibitor, RIMA = reversible inhibitor of MAO-A

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References

  1. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. Washington, DC: American Psychiatric Association; 2010. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1667485. Accessed April 13, 2012.
  2. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22(4):343–396. http://www.bap.org.uk/pdfs/antidepressants.pdf. Accessed April 13, 2012.
  3. VanDenBerg CM. MAOIs and transdermal delivery. J Clin Psychiatry. 2012;doi:10.4088/JCP.11096tx6c. http://www.cmeinstitute.com/newcme/launcher.asp?test=1557. Accessed April 13, 2012.
  4. Wimbiscus M, Kostenko O, Malone D. MAO inhibitors: risks, benefits, and lore. Cleve Clin J Med. 2010;77(12):859–882. PubMed
  5. Stahl MS. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York, NY: Cambridge University Press; 2008.
  6. McCabe BJ. Dietary tyramine and other pressor amines in MAOI regimens: a review. J Am Diet Assoc. 1986;86(8):1059–1064. PubMed
  7. Gardner DM, Shulman KI, Walker SE, et al. The making of a user friendly MAOI diet. J Clin Psychiatry. 1996;57(3):99–104. PubMed
  8. EMSAM (selegiline patch) [package insert]. Napa, CA: Dey Pharma LP; 2010. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b891bd9f-fdb8-4862-89c5-ecdd700398a3. Accessed April 13, 2012.
  9. Nardil (phenelzine sulfate) [package insert]. New York, NY: Pfizer, Inc; 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=513a41d0-37d4-4355-8a6d-a2c643bce6fa. Accessed April 13, 2012.
  10. Sternbach H. Serotonin syndrome: how to avoid, identify, and treat drug interactions. J Fam Pract. 2003;2(5). Abstract
  11. Garriock HA, Kraft JB, Shyn SI, et al. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry. 2010;67(2):133–138. PubMed