FIRST OF 2 PARTS Web video at CurrentPsychiatry.com Dr. Meyer: What to tell patients about diet and monoamine oxidase inhibitors A concise guide to monoamine oxidase inhibitors A better understanding of the risks can lead to increased use of these highly effective agents Jonathan M. Meyer, MD espite an abundance of evidenced-based literature supporting Psychopharmacology Consultant monoamine oxidase inhibitors (MAOIs) as an effective treat- California Department of State Hospitals Sacramento, California Dment for depression, use of these agents has decreased drasti- Assistant Clinical Professor of Psychiatry cally in the past 3 decades. A lack of industry support and the ease of University of California, San Diego use of other agents are contributing factors, but the biggest impedi- San Diego, California Deputy Editor, CURRENT PSYCHIATRY ments to routine use of MAOIs are unfamiliarity with their efficacy Disclosure advantages and concerns about adverse effects, particularly the risk Dr. Meyer is a consultant to Acadia Pharmaceuticals, of hypertensive crises and serotonin syndrome. Many misconceptions Neurocrine Biosciences, Inc., and Teva Pharmaceutical regarding these medications are based on outdated data and studies Industries; and is a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Neurocrine Biosciences, Inc., that are no longer reliable. Otsuka America, Inc., Sunovion Pharmaceuticals, and The goal of this 2-part review is to provide clinicians with updated Teva Pharmaceutical Industries. information regarding MAOIs. Part 1 provides a brief description of: • the pharmacology of nonselective irreversible MAOIs • the mechanism by which tyramine induces hypertension • sources of clinically significant tyramine exposure • what to tell patients about dietary restrictions and MAOIs. Part 2 of this guide will cover the risk of serotonin syndrome when MAOIs are combined with inhibitors of serotonin reuptake, how to initi- ate MAOI therapy, and augmenting MAOIs with other agents. The pharmacology of MAOIs First used clinically in the 1950s to treat tuberculosis, MAOIs have a long and interesting history (see the Box “A brief history of monoamine oxidase inhibitors” on CurrentPsychiatry.com). Table 11 (page 16) lists Current Psychiatry ALEX NABAUM Vol. 16, No. 12 15 Table 1 MAOIs available in the United States Drug (brand name, approval date) MAO-A/B Dose Comments, adverse effects Isocarboxazid 1:1 Start: 10 mg AEs: Sexual dysfunction, weight gain, orthostasis, (Marplan, 7/1/59) at bedtime hypertensive events, serotonin syndrome Monoamine Max: 60 mg/d oxidase inhibitors Phenelzine 1:1 Start: 15 mg AEs: Sexual dysfunction, weight gain, orthostasis, (Nardil, 6/9/61) at bedtime hypertensive events, serotonin syndrome Max: 90 mg/d Tranylcypromine 1:1 Start: 10 mg No known L-amphetamine metabolites, but can be (Parnate, 2/21/61) at bedtime stimulating at higher doses Max: 60 mg/d AEs: Sexual dysfunction, weight gain, orthostasis, hypertensive events, serotonin syndrome Selegiline 1:1 Start: No dietary restrictions at lowest dose (6 mg/24 h). Has (transdermal) 6 mg/24 h L-methamphetamine metabolites; can be stimulating Clinical Point (Emsam, 2/27/06) Max: at higher doses. Also, has potential for false-positive 12 mg/24 h drug screen Nonselective MAOIs AEs: Insomnia, site reaction, hypertensive events, offer a therapeutic serotonin syndrome opportunity for Rasagiline 1:14 (Only used for Lacks L-amphetamine metabolites. No risk (Azilect, 5/16/06) Parkinson’s of hypertensive crises. No cases of serotonin patients who do not disease) syndrome when combined with antidepressants in large review (n = 1,504),1 but the package respond to single insert warns about use with inhibitors of serotonin or dual-mechanism reuptake, including antidepressants, meperidine, tramadol, and methadone strategies AEs: Adjunctive use: orthostasis and falls, peripheral edema, dyskinesia, abnormal dreams, nausea. Risk of serotonin syndrome not seen in large samples, although the package insert includes warnings Selegiline (oral) 5 mg, (Only used for Short half-life requires multiple daily dosing. Lower (Eldepryl, 4/17/89) twice a Parkinson’s plasma levels for oral than transdermal results in day: 1:10 disease) limited MAO-A inhibition. Oral bioavailability 4% vs >20 mg/d: 75% for transdermal 1:1 AEs: Nausea, dizziness/orthostasis/falls, abdominal pain AE: adverse effect; MAO: monoamine oxidase MAOIs currently available in the United tonin norepinephrine reuptake inhibitors, States, including the MAO-B–specific mirtazapine, or bupropion, necessitating agent rasagiline, which is used for consideration of antidepressant combina- Parkinson’s disease. tions, augmentation options, and eventu- Manipulation of the monoamines sero- ally irreversible, nonselective MAOIs such tonin, norepinephrine, and dopamine is as phenelzine, tranylcypromine, or isocar- fundamental to managing major depres- boxazid.3,4 Nonselective MAOIs thus offer Discuss this article at sive disorder (MDD), yet only nonselective a therapeutic opportunity for patients who www.facebook.com/ MAOIs directly promote neurotransmission do not respond to single or dual-mechanism CurrentPsychiatry of all 3 by inhibiting MAO-A and MAO-B.2 strategies; moreover, nonselective MAOIs The Sequenced Treatment Alternatives to have compelling effectiveness data for Relieve Depression (STAR*D) study demon- other conditions, including panic disorder strated that <50% of MDD patients achieve and social phobia.5 Although MAOIs are remission in monotherapy trials of selec- among the most effective pharmacologic Current Psychiatry 16 December 2017 tive serotonin reuptake inhibitors, sero- agents for MDD,6 they are underutilized continued on page 18 continued from page 16 Table 2 Substrates for monoamine oxidase enzymes MAO-A MAO-B Substrates Serotonin Dopamine Norepinephrine Phenylethylamine Dopamine Monoamine Tyramine oxidase inhibitors Tissue localization Brain, gut, liver, placenta, skin Brain, platelets, lymphocytes MAO: monoamine oxidase Source: References 9,10 Figure 1 Comparative gut monoamine oxidase inhibition of transdermal and oral selegiline in an animal model Clinical Point Transdermal Oral 100 Cortex 100 Cortex CNS MAO-A 90 Duodenum 90 Duodenum inhibition is 80 Liver 80 Liver 70 70 n necessary for 60 60 antidepressant 50 50 40 40 effects % Inhibitio 30 30 20 20 10 10 Patch area 0 0 (cm2)/24 hr 0.4 0.71 1.0 1.5 2.0 2.5 3.75 5 10 0.10.3 13510152030545 0 100 mg kg1/24 hr 0.68 1.24 1.76 2.68 3.6 4.55 7.37 9.9 21.29 Daily dose (mg/kg) Source: Reference 12 because of an inadequate understanding of discerned that norepinephrine was only a risk mechanisms and resultant fear of cata- substrate for MAO-A, and that this form of strophic outcomes. Because of the difficulties MAO was sensitive to clorgyline inhibition. encountered in achieving clinical remission Thus, the forms of MAO were characterized for MDD, the nonselective MAOIs deserve by their preferred substrates (Table 29,10), a second look. and then later by their tissue distribution. Phenylethylamine is a naturally occurring Differentiation of MAO-A from MAO-B. It compound found in foods, such as choco- is essential to understand the mechanism of late, and has an in vitro pharmacology simi- action of MAOIs, specifically the impact of lar to amphetamine but with 1 important MAO-A inhibition. Although the enzyme difference: it has a short half-life of 5 to 10 MAO was known in the 1950s, it wasn’t until minutes after oral ingestion, and therefore 1968 that Johnston7 postulated the existence no appreciable CNS impact. of >1 form. In 1971, Goridis and Neff8 used Within the CNS, norepinephrine and clorgyline to examine the deamination rate dopamine neurons possess both MAO by MAO of tyramine and norepinephrine. forms, with the MAO-A content greater They found that tyramine appeared to be a than MAO-B. Serotonergic neurons only substrate of both MAO isoforms, but only contain MAO-B.11 Outside of the CNS, 1 of the MAO types was sensitive to the MAO-A predominates, with only plate- Current Psychiatry 18 December 2017 inhibitory effects of clorgyline. They also lets and lymphocytes possessing MAO-B Figure 2 Chemical classification of nonselective monoamine oxidase inhibitors CH3 O H N N H CH3 N IPRONIAZID O N NH2 H N NH N 2 H H CH3 N O Clinical Point Patients taking ISOCARBOXAZID PHENELZINE selegiline should (Hydrazine) (Hydrazine) TRANYLCYPROMINE disclose their use of (Nonhydrazine) this medication prior to undergoing drug testing procedures activity.11 The overall relative tissue pro- Differentiation of MAOIs by chemi- portions of MAO-A to MAO-B activity cal class. The earliest MAOI, iproniazid, are: brain, 25% MAO-A, 75% MAO-B; liver, was a hydrazine derivative and exhib- 50% MAO-A, 50% MAO-B; intestine, 80% ited hepatotoxicity,13 as did certain other MAO-A, 20% MAO-B; and peripheral adren- hydrazine MAOIs. This lead to a search for ergic neurons, 90% MAO-A, 10% MAO-B. safer hydrazine and nonhydrazine alter- Because of its specificity for serotonin natives. Isocarboxazid and phenelzine are and norepinephrine, CNS MAO-A inhibi- the 2 hydrazine MAOIs available in the tion is necessary for antidepressant effects. United States, while tranylcypromine and MAO-B inhibition by itself does not appear selegiline transdermal are nonhydrazines to raise CNS dopamine levels unless exog- (Figure 2). enous dopamine is supplied.11 All MAOIs What distinguishes the nonhydra- used in the United States to treat depres- zine medication selegiline is that its sion are irreversible, nonselective inhibitors of metabolism generates L-amphetamine MAO-A and MAO-B. metabolites (Figure 3,14 page 20). This Selegiline in oral form generates low property was thought to be shared by plasma levels and primarily inhibits MAO-B. other non hydrazines, but recent studies The transdermal form of selegiline achieves indicate than neither tranylcypromine15 significantly greater systemic exposure, and nor the MAO-B–selective rasagiline pos- at these higher plasma levels selegiline is a sess amphetamine metabolites.16 Unlike nonselective, irreversible MAOI effective for the dextro isomers, L-amphetamine struc- MDD (Figure 1,12 page 18).