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Home , Antidepressant

Increased knowledge of MAOIs has made these agents worthy of reconsideration

Eric C. Kosinski, MD or patients with major depressive disorder (MDD), monoamine Staff Psychiatrist oxidase inhibitors (MAOIs) have efficacy comparable to that of Health Alliance Hospital Leominster, MA Fother . However, concerns about — UMass Memorial Medical Center particularly hypertensive crisis—and -drug interactions have led Worcester, MA clinicians to prescribe MAOIs less often than newer antidepressants. Anthony J. Rothschild, MD A 1999 survey of 573 Michigan psychiatrists found that 30% had not Irving S. and Betty Brudnick Endowed Chair and Professor of Psychiatry prescribed an MAOI within the past 3 years, and 12% had never pre- Director, Center for Psychopharmacologic scribed an MAOI.1 Although there are challenges to using these agents, Research and Treatment we prefer prescribing MAOIs to depressed patients who have not re- Director, UMass Center Department of Psychiatry sponded to previous trials over trying untested antide- University of Massachusetts Medical School pressant combinations. Worcester, MA Currently, MAOIs are used primarily for patients who have not re- sponded to other antidepressant trials and are considered treatment resistant. Treatment-resistant depression (TRD) typically is defined as nonresponse to ≥3 adequate antidepressant trials. TRD is a major cause of disability and loss of productivity. These patients tend to do poorly over the long term, with high rates of hospitalization and at- tempts. Several controlled trials have shown that patients who fail other antidepressants may respond to MAOIs.2-4 Our knowledge regarding MAOIs has grown considerably. We have learned more about depression subtypes that MAOIs may help. As we learned more about dietary restrictions for patients taking MAOIs, the list of “forbidden foods” has decreased. Advances in treating a hyper- tensive crisis have decreased the need for hospitalization. By educat- ing ourselves and our patients about MAOIs, we can provide another option for treating MDD. continued © C.J. BURTON/CORBIS

Current Psychiatry Vol. 11, No. 12 21 Table 1 Recommended dosages of inhibitors Starting dosages Usual therapeutic dosage 10 mg twice a day 30 to 60 mg/d 15 mg twice a day 45 to 90 mg/d transdermal 6 mg patch/d 6 to 12 mg patch/d Monoamine 10 mg, 2 or 3 times a day 30 to 60 mg/d oxidase inhibitors Source: Adapted from reference 8

An older antidepressant class body must renew its MAO levels before a MAOIs were introduced approximately 60 patient is no longer at risk for a hyperten- years ago. Their potential for treating de- sive crisis, a process that may take up to 2 pression was discovered when a tubercu- weeks. Clinicians must take care to ensure Clinical Point losis treatment——was found to their patients avoid foods that contain tyra- Several trials have reduce depressive symptoms. Researchers mine and contraindicated with determined iproniazid’s antidepressant ef- MAOIs during this period. found MAOIs fects were the result of blocking removal MAOIs also differ from each other in may benefit of the amine group by monoamine oxidase enzyme selectivity. There are 2 subtypes outpatients with (MAO) from , , of MAO enzymes—MAOA and MAOB. MDD who have not and .5 A second MAOI, tranylcy- Generally, the antidepressant activity of promine, was discovered when it was found MAOIs appears to be directed toward MAOA responded to other 6 to be ineffective for treating decongestion. inhibition. MAOA has been found to be more antidepressants MAOI use in psychiatric practice has specific for binding to serotonin and norepi-

undergone significant changes since these nephrine and MAOB to be more specific for medications were introduced. The discov- phenylethylamine. Dopamine is equally de-

ery of hypertensive crises related to tyra- aminated by both MAOA and MAOB.

mine consumption led to decreased MAOI Reversible MAOA inhibitors require few- use, as did the rise of antidepres- er restrictions on diet or concurrent medica-

sants (TCAs) shortly thereafter. In the 1960s, tions, but efficacy data of reversible MAOA research compared the relative efficacy of inhibitors is mixed. MAOIs to TCAs, and they became second- line antidepressants after the TCAs. In the late 1980s, the introduction of Clinical use of MAOIs and other selective serotonin in- Four MAOIs are available in the United hibitors (SSRIs) resulted in a significant States: tranylcypromine, phenelzine, iso- drop-off in MAOI use. carboxazid, and selegiline. Selegiline is the only MAOI available as a . Transdermal administration results in fewer Pharmacologic effects effects on MAO in the , MAO is a class of enzymes that initiate which means no dietary restrictions at the Discuss this article at oxidation of extracellular neurotransmit- 6 mg/d starting dose, although the manu- www.facebook.com/ ters such as serotonin, norepinephrine, and facturer recommends patients follow the CurrentPsychiatry dopamine. MAOIs can be classified based MAO diet at 9 mg/d and 12 mg/d doses.7

on their relative affinity to MAO as well Although selegiline is selective for MAOB at as their enzyme selectivity. The first dis- low doses, it becomes nonselective at thera- tinguishing characteristic is whether the peutic doses for depression. Recommended drug binds to MAO in a reversible or irre- dosages for MAOIs can be found in Table 1.8 versible manner. Currently, all MAOIs that are FDA-approved for treating depression Researchers have Current Psychiatry Depression subtypes. 22 December 2012 bind irreversibly to MAO. As a result, the observed that MAOIs are effective for treating .9 Atypical de- Table 2 pression is characterized by significant in- creases in , appetite, or weight; leaden Food restrictions with MAOIs paralysis; and a pattern of extreme sensitiv- Severe ity to interpersonal loss often referred to as Aged cheeses “rejection sensitivity.” Other subtypes of Aged meats (pepperoni, sausage, salami) depression—such as depression with mel- Sauerkraut ancholic features and —respond Soy sauce to MAOIs.10,11 Fava or broad bean pods Several controlled trials have found a bet- Banana peels ter response rate to MAOI therapy in outpa- All beers on tap tients with MDD who have not responded Use in moderation (≤2 servings/d) to other antidepressants.2,12 In a 6-week, Red wine (4 oz) double-blind trial, Vallejo et al10 reported White wine (4 oz) that the TCA and high-dose Bottled or canned beers (12 oz) phenelzine were equally efficacious in 32 Mild to none patients with major depression with melan- Avocados Clinical Point cholia. In 32 dysthymic patients, high-dose Banana pulp Hypertensive crisis phenelzine was superior to imipramine. Bouillon is the most serious Himmelhoch et al13 compared efficacy of Chocolate tranylcypromine with that of imipramine in Fresh cheeses (cottage cheese, cream cheese, of MAOIs, treating anergic bipolar depressive illness. processed cheese slices) but often it can be Fresh or processed meat Patients receiving tranylcypromine expe- treated without rienced significantly greater symptomatic MAOIs: monoamine oxidase inhibitors Source: Adapted from references 4,17,18 hospitalization improvement and higher global response without increased risk of treatment-emer- gent or . Serum monitoring of MAOIs is not clini- pertensive crises is unknown, it is thought cally indicated and there are no correlations that if a patient with depleted MAO levels between drug levels and effectiveness.14 In ingests , it may displace intracellu- a study that examined the correlation of lar norepinephrine, leading to a rapid rise inhibiting MAO and MAOIs’ anti- in pressure. Hypertensive crises are effects, researchers found that a rare among patients who adhere to a tyra- higher dose of phenelzine (60 mg/d) was mine-free diet. significantly better in treating depression In a hypertensive crisis, patients expe- and than a lower dose (30 mg/d), rience significant hypertension, head- and only the higher dose achieved 80% of aches, tachycardia, diaphoresis, and platelet MAO inhibition.15 Further studies vomiting. Intravenous —an with other MAOIs did not reproduce this ef- α- receptor blocker—can be used fect and platelet MAO inhibition is not regu- as an ; often a single dose is effec- larly used to assess adequate dosing. tive.16 Alternatively, calcium channel block- ers such as nifedipine can be prescribed. A patient can take 10 mg/hour and be ob- A refined view of side effects served in the emergency room until symp- Clinicians often consider hypertensive crisis toms are relieved (usually only 1 or 2 doses to be the most serious side effect of MAOIs. are needed) without being admitted to Many clinicians recommend that their pa- the hospital. tients wear bracelets stating they are taking MAOIs in case they become unconscious in Dietary restrictions. In the 1970s and an emergency. Consumption of tyramine, a 1980s, the “MAOI diet” list of prohibited substrate for the MAO enzyme, may trigger foods contained >70 items. As patients on a hypertensive crisis. Although the exact an overly inclusive diet began to “cheat,” Current Psychiatry mechanism by which tyramine causes hy- they struggled to differentiate foods that Vol. 11, No. 12 23 Table 3 MAOIs: Stay vigilant for side effects Medication Common side effects Isocarboxazid Anxiety, blurred vision, , , , , mania, , , Phenelzine Constipation, disorder of ejaculation and/or orgasm, dizziness, edema, fatigue, headache, hyperreflexia, impotence, elevated values on liver function tests, Monoamine orthostatic , sleep disorders, somnolence, tremor, weight gain, oxidase inhibitors xerostomia Selegiline Application site reaction, decreased systolic blood pressure, diarrhea, headache, transdermal indigestion, insomnia, , weight loss, xerostomia Tranylcypromine Agitation, anxiety, constipation, diarrhea, dizziness, headache, impotence, insomnia, loss of appetite, mania, nausea, orthostatic hypotension, somnolence, weight gain, xerostomia MAOIs: monoamine oxidase inhibitors Source: Adapted from reference 20 Clinical Point Based on rigorous were moderately safe from those that were ive care such as administering IV fluids. reviews of tyramine highly dangerous. Over time, in addition to Orthostatic hypotension is a common content, the number foods that contained tyramine, foods that cardiovascular side effect of MAOIs that of ‘forbidden foods’ contained compounds that caused symp- may lead to dizziness or syncope. Typically for patients taking an toms similar to those of a hypertensive cri- this is seen 2 to 3 weeks after initiating sis were added to many MAOI diets. For MAOI treatment. If hypotension remains MAOI has decreased example, chocolate, which contains phenyl- a problem, can be pre- ethylamine, is associated with scribed with monitoring of serum potas- , which can be confused with sium for hypokalemia. Increasing doses of MAOI-related emergencies. Likewise, tan- tranylcypromine can increase supine—but nic acids found in red wines caused simi- not standing—diastolic blood pressure.19 lar symptoms. In recent years, the number Distinguish this type of blood pressure of “forbidden foods” on the MAO diet has elevation from a hypertensive crisis by decreased. Table 2 (page 23)4,17,18 contains an monitoring blood pressure with the patient up-to-date list of foods with elevated tyra- sitting and standing and before and after he mine content, based on systematic reviews or she walks for 60 seconds. and more rigorous evaluations of tyramine Insomnia and day-night shifting—sleep- content of foods. ing during the day and staying awake at night—are common and patients often cite Potential drug-drug interactions. these as reasons for discontinuing MAOIs. Concomitant use of SSRIs, serotonin- Many patients who respond to MAOIs re- norepinephrine reuptake inhibitors (SNRIs), port periods of substantial sleepiness in the , , epinephrine, local mid to late afternoon. Table 320 provides a containing sympathomimetic more complete list of reported side effects agents, and with MAOIs and their frequencies. could cause . Serotonin syndrome is characterized by hypertonicity, autonomic signs, hallucinations, rhabdomy- Practice guidelines olysis, and hyperthermia, and can be fatal if The American Psychiatric Association’s not promptly treated. Treatment is guided practice guidelines for treating major de- by presentation severity and discontinuing pression state that MAOIs are effective in the causative medications is of utmost im- treating subgroups of patients with MDD portance. Interventions include aggressive with atypical features who have failed treatment for hyperthermia, including ex- TCA trials.21 These guidelines also state Current Psychiatry 24 December 2012 ternal cooling and hydration, and support- that MAOIs have been shown to be effec- tive treatment for some patients who have tations, concerns about an increased risk failed other antidepressants. However, for of suicide in patients with TRD26 and the TRD patients who have not responded to high likelihood of a poor outcome associ- SSRIs or SNRIs, the effectiveness of MAOIs ated with persistent nonresponse to prior compared with other strategies is unclear.22 treatments must be weighed against the One study found adding to an relatively low risk of a hypertensive event MAOI may provide more rapid or more with MAOIs.6 efficacious response than MAOI mono- therapy.23 Guze et al24 evaluated the effects References 1. Balon R, Mufti R, Arfken CL. A survey of prescribing of high-dose MAOI treatment for 2 TRD pa- practices for monoamine oxidase inhibitors. Psychiatr Serv. tients; both patients improved without any 1999;50(7):945-947. 2. Nolen WA, van de Putte JJ, Dijken WA, et al. Treatment side effects. strategy in depression. II. MAO inhibitors in depression MAOIs have been used for >6 decades, resistant to cyclic antidepressants: two controlled crossover studies with tranylcypromine versus L-5- and published studies continue to docu- hydroxytryptophan and . Acta Psychiatr Scand. ment their efficacy and safety when pa- 1988;78(6):676-683. 3. McGrath PJ, Stewart JW, Harrison W, et al. Treatment 11,12,14,15,25 tients are monitored appropriately. of tricyclic refractory depression with a monoamine However, based on our observations we oxidase inhibitor antidepressant. Psychopharmacol Bull. Clinical Point 1987;23(1):169-172. suspect MAOIs are underutilized in clinical 4. Amsterdam JD. Monoamine oxidase inhibitor therapy Practice guidelines practice today. We are concerned that such in severe and resistant depression. Psychiatr Ann. 2006; 36(9):607-613. state MAOIs are practices can trickle down into residency 5. Schildkraut JJ. The catecholamine hypothesis of affective training programs. Psychiatric residents disorders: a review of supporting evidence. Am J Psychiatry. effective for patients 1965;122(5):509-522. typically do not receive adequate train- 6. Kennedy SH, Holt A, Baker GB. Monoamine oxidase with depression with ing in prescribing MAOIs, largely because inhibitors. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s comprehensive textbook of psychiatry. 8th ed. atypical features who many training faculty are not prescribing Philadelphia, PA: Lippincott Williams & Wilkins; 2005: have failed tricyclic MAOIs themselves. Despite MAOIs’ limi- 1076-1080. continued antidepressants 12. Thase ME, Frank E, Mallinger AG, et al. Treatment of imipramine-resistant recurrent depression, III: efficacy of Related Resources monoamine oxidase inhibitors. J Clin Psychiatry. 1992; • McCabe-Sellers BJ, Staggs CG, Bogle ML. Tyramine in foods 53(1):5-11. and monoamine oxidase inhibitor : a crossroad 13. Himmelhoch JM, Thase ME, Mallinger AG, et al. where , nutrition, pharmacy, and food indus- Tranylcypromine versus imipramine in anergic bipolar try converge. Journal of Food Composition and Analysis. depression. Am J Psychiatry. 1991;148(7):910-916. 2006;19(suppl):S58-S65. 14. Rothschild AJ, ed. The evidence-based guide to antidepressant medications. Arlington, VA: American • Fiedorowicz JG, Swartz KL. The role of monoamine oxidase Psychiatric Publishing, Inc.; 2012:15-20. inhibitors in current psychiatric practice. J Psychiatr Pract. 15. Ravaris CL, Nies A, Robinson DS, et al. A multiple-dose, Monoamine 2004;10(4):239-248. controlled study of phenelzine in depression-anxiety states. Arch Gen Psychiatry. 1976;33(3):347-350. oxidase inhibitors Drug Brand Names 16. Cockhill LA, Remick RA. Blood pressure effects of Clomipramine • Anafranil Nifedipine • Adalat, monoamine oxidase inhibitors—the highs and lows. Can J Epinephrine • Adrenalin, Afeditab Psychiatry. 1987;32(9):803-808. EpiPen Phenelzine • Nardil 17. Shulman KI, Walker SE. A reevaluation of dietary restrictions Fluoxetine • Prozac Phentolamine • OraVerse, for irreversible monoamine oxidase inhibitors. Psychiatr Imipramine • Tofranil Regitine Ann. 2001;31(6):378-384. Isocarboxazid • Marplan Selegiline • EMSAM 18. Gardner DM, Shulman KI, Walker SE, et al. The making Lithium • Eskalith, Lithobid Tranylcypromine • Parnate of a user friendly MAOI diet. J Clin Psychiatry. 1996;57(3): 99-104. Disclosures 19. Keck PE Jr, Carter WP, Nierenberg AA, et al. Acute Dr. Kosinski reports no financial relationship with any com- cardiovascular effects of tranylcypromine: correlation with Clinical Point plasma drug, metabolite, norepinephrine, and MHPG pany whose products are mentioned in this article or with levels. J Clin Psychiatry. 1991;52(6):250-254. manufacturers of competing products. 20. Micromedex Healthcare Series [UMass Memorial Studies continue to Dr. Rothschild receives grant or research support from Healthcare Intranet System]. Version 5.1. Greenwood document MAOIs’ Cyberonics, the National Institute of Mental Health, St. Jude Village, CO: Thomson Reuters (Healthcare) Inc. Medical, and Takeda, and is a consultant to Allergan, Eli Lilly and 21. American Psychiatric Association. Practice guideline for the safety and efficacy Company, GlaxoSmithKline, Noven Pharmaceuticals, Inc., treatment of patients with major depressive disorder, third Shire Pharmaceuticals, and Sunovion. edition. http://psychiatryonline.org/content.aspx?bookid when patients =28§ionid=1667485. Published October 2010. Accessed October 26, 2012. are monitored 22. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus plus following three failed appropriately antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541; quiz 1666. 7. EMSAM [package insert]. Napa, CA: Dey Pharm LP; 2011. 23. Nelson JC, Byck R. Rapid response to lithium in phenelzine 8. Amsterdam JD, Chopra M. Monoamine oxidase inhibitors non-responders. Br J Psychiatry. 1982;141:85-86. revisited. Psychiatric Ann. 2001;31(6):361-370. 24. Guze BH, Baxter LR Jr, Rego J. Refractory depression treated 9. Quitkin FM, Stewart JW, McGrath PJ, et al. Phenelzine with high doses of monoamine oxidase inhibitor. J Clin versus imipramine in the treatment of probable atypical Psychiatry. 1987;48(1):31-32. depression: defining syndrome boundaries of selective 25. Robinson DS, Gilmor ML, Yang Y, et al. Treatment effects MAOI responders. Am J Psychiatry. 1988;145(3):306-311. of selegiline transdermal system on symptoms of major 10. Vallejo J, Gasto C, Catalan R, et al. Double-blind study depressive disorder: a meta analysis of short term, of imipramine versus phenelzine in melancholias and controlled, efficacy trials. Psychopharmacol Bull. 2007;40(3): dysthymic disorders. Br J Psychiatry. 1987;151:639-642. 15-28. 11. White K, Razani J, Cadow B, et al. Trancylpromine vs. 26. Keller MB, Lavori PW, Rice J, et al. The persistent risk vs. placebo in depressed outpatients: a of chronicity in recurrent episodes of nonbipolar major controlled trial. (Berl). 1984;82(3): depressive disorder: a prospective follow-up. Am J 258-262. 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Bottom Line The efficacy of monoamine oxidase inhibitors (MAOIs) for depression is comparable to that of other antidepressants. Concerns about side effects—primarily hypertensive crisis—and dietary restrictions have lead many clinicians to curtail their use of MAOIs, but increased knowledge of these drugs can help psychiatrists Current Psychiatry 26 December 2012 reconsider this treatment option, particularly for patients with atypical depression.