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Forgotten treatment for depression: increased knowledge of MAOIs has made these agents worthy of reconsideration.

For patients with major depressive disorder (MDD), monoamine oxidase inhibitors (MAOIs) have efficacy comparable to that of other antidepressants. However, concerns about side effects--particularly hypertensive crisis--and drug-drug interactions have led clinicians to prescribe MAOIs less often than newer antidepressants. A 1999 survey of 573 Michigan psychiatrists found that 30% had not prescribed an MAOI within the past 3 years, and 12% had never prescribed an MAOI. (1) Although there are challenges to using these agents, we prefer prescribing MAOIs to depressed patients who have not responded to previous antidepressant trials over trying untested antidepressant combinations.

Currently, MAOIs are used primarily for patients who have not responded to other antidepressant trials and are considered treatment resistant. Treatment-resistant depression (TRD) typically is defined as nonresponse to [greater than or equal 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 suicide attempts. 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 hypertensive crisis have decreased the need for hospitalization. By educating ourselves and our patients about MAOIs, we can provide another option for treating MDD.

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An older antidepressant class

MAOIs were introduced approximately 60 years ago. Their potential for treating depression was discovered when a tuberculosis treatment--iproniazid--was found to reduce depressive symptoms. Researchers determined iproniazid's antidepressant effects were the result of blocking removal of the amine group by monoamine oxidase (MAO) from dopamine, norepinephrine, and serotonin. (5) A second MAOI, tranylcypromine, was discovered when it was found to be ineffective for treating decongestion. (6)

MAOI use in psychiatric practice has undergone significant changes since these medications were introduced. The discovery of hypertensive crises related to tyramine consumption led to decreased MAOI use, as did the rise of tricyclic antidepressants (TCAs) shortly thereafter. In the 1960s, research compared the relative efficacy of MAOIs to TCAs, and they became second-line antidepressants after the TCAs. In the late 1980s, the introduction of fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) resulted in a significant drop-off in MAOI use.

Pharmacologic effects

MAO is a class of enzymes that initiate oxidation of extracellular neurotransmitters such as serotonin, norepinephrine, and dopamine. MAOIs can be classified based on their relative affinity to MAO as well as their enzyme selectivity. The first distinguishing characteristic is whether the drug binds to MAO in a reversible or irreversible manner. Currently, all MAOIs that are FDA-approved for treating depression bind irreversibly to MAO. As a result, the body must renew its MAO levels before a patient is no longer at risk for a hypertensive crisis, a process that may take up to 2 weeks. Clinicians must take care to ensure their patients avoid foods that contain tyramine and medications contraindicated with MAOIs during this period.

MAOIs also differ from each other in enzyme selectivity. There are 2 subtypes of MAO enzymes--MA[O.sub.A] and MA[O.sub.B]. Generally, the antidepressant activity of MAOIs appears to be directed toward MA[O.sub.A] inhibition. MAOA has been found to be more specific for binding to serotonin and norepinephrine and MA0B to be more specific for phenylethylamine. Dopamine is equally deaminated by both MA[O.sub.A] and MA[Osub.B].

Reversible MA[O.sub.A] inhibitors require fewer restrictions on diet or concurrent medications, but efficacy data of reversible MA[O.sub.A] inhibitors is mixed.

Clinical use of MAOIs

Four MAOIs are available in the United States: tranylcypromine, phenelzine, isocarboxazid, and selegiline. Selegiline is the only MAOI available as a transdermal patch. Transdermal administration results in fewer effects on MAO in the gastrointestinal tract, which means no dietary restrictions at the 6 mg/d starting dose, although the manufacturer recommends patients follow the MAO diet at 9 mg/d and 12 mg/d doses. (7) Although selegiline is selective for MA[O.sub.B] at low doses, it becomes nonselective at therapeutic doses for depression. Recommended dosages for MAOIs can be found in Table 1. (8)
Table 1

Recommended dosages of monoamine oxidase inhibitors

Medication                Starting dosages    Usual therapeutic_dosage

Selegiline transdermal    10 mg twice a day     30 to 60 mg/d

Tranykyprornine           15 mg twice a day     45 to 90mg/d

Isocarboxazid             6 mg patch/d          6 to 12 mg patch/d

Pheneizine                10 mg, 2 or 3       30 to 60 mg/d
                          times a day

Source: Adapted from reference 8


Depression subtypes. Researchers have observed that MAOIs are effective for treating atypical depression. (9) Atypical depression is characterized by significant increases in sleep, appetite, or weight; leaden paralysis; and a pattern of extreme sensitivity to interpersonal loss often referred to as "rejection sensitivity." Other subtypes of depression--such as depression with melancholic features and dysthymia--respond to MAOIs. (10), (11)

Several controlled trials have found abetter response rate to MAOI therapy in outpatients with MDD who have not responded to other antidepressants. (2), (12) In a 6-week, double-blind trial, Vallejo et al (10) reported that the TCA imipramine and high-dose phenelzine were equally efficacious in 32 patients with major depression with melancholia. In 32 dysthymic patients, high-dose phenelzine was superior to imipramine. Himmelhoch et al (13) compared efficacy of tranylcypromine with that of imipramine in treating anergic bipolar depressive illness. Patients receiving tranylcypromine experienced significantly greater symptomatic improvement and higher global response without increased risk of treatment-emergent hypomania or mania.

Serum monitoring of MAOIs is not clinically indicated and there are no correlations between drug levels and effectiveness.14 In a study that examined the correlation of inhibiting platelet MAO and MAOIs' antidepressant effects, researchers found that a higher dose of phenelzine (60 mg /d) was significantly better in treating depression and anxiety than a lower dose (30 mg/d), and only the higher dose achieved 80% of platelet MAO inhibition. (15) Further studies with other MAOIs did not reproduce this effect and platelet MAO inhibition is not regularly used to assess adequate dosing.

A refined view of side effects

Clinicians often consider hypertensive crisis to be the most serious side effect of MAOIs. Many clinicians recommend that their patients wear bracelets stating they are taking MAOIs in case they become unconscious in an emergency. Consumption of tyramine, a substrate for the MAO enzyme, may trigger a hypertensive crisis. Although the exact mechanism by which tyramine causes pertensive crises is unknown, it is thought that if a patient with depleted MAO levels ingests tyramine, it may displace intracellular norepinephrine, leading to a rapid rise in blood pressure. Hypertensive crises are rare among patients who adhere to a tyramine-free diet.

In a hypertensive crisis, patients experience significant hypertension, headaches, tachycardia, diaphoresis, and vomiting. Intravenous phentolamine--an a-adrenergic receptor blocker--can be used as an antidote; often a single dose is effec-tive.16 Alternatively, calcium channel blockers such as nifedipine can be prescribed. A patient can take 10 mg/hour and be observed in the emergency room until symptoms are relieved (usually only 1 or 2 doses are needed) without being admitted to the hospital.

Dietary restrictions. In the 1970s and 1980s, the "MAOI diet" list of prohibited foods contained >70 items. As patients on an overly inclusive diet began to "cheat," they struggled to differentiate foods that were moderately safe from those that were highly dangerous. Over time, in addition to foods that contained tyramine, foods that contained compounds that caused symptoms similar to those of a hypertensive crisis were added to many MAOI diets. For example, chocolate, which contains phenyl-ethylamine, is associated with migraine headaches, which can be confused with MAOI-related emergencies. Likewise, tannic acids found in red wines caused similar symptoms. In recent years, the number of "forbidden foods" on the MAO diet has decreased. Table 2 (page 23) (4) (17) (18) contains an up-to-date list of foods with elevated tyramine content, based on systematic reviews and more rigorous evaluations of tyramine content of foods.

Table 2

Food restrictions with MAOI

Severe

Aged cheeses

Aged meats (pepperoni, sausage, salami)

Sauerkraut

Soy sauce

Fava or broad bean pods

Banana peels

All beers on tap

Use in moderation ([greater than or equal to]2 servings/d)

Red wine (4 oz)

White wine (4 oz)

Bottled or canned beers (12 oz)

Mild to none

Avocados

Banana pulp

Bouillon

Chocolate

Fresh cheeses (cottage cheese, cream cheese, processed cheese slices)

Fresh or processed meat

MAOIs: monoamine oxidase inhibitors

Source: Adapted from references 4,17,18

Potential drug-drug interactions. Concomitant use of SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), opioids, clomipramine, epinephrine, local anesthetics containing sympathomimetic agents, and decongestants with MAOIs could cause serotonin syndrome. Serotonin syndrome is characterized by hypertonicity, autonomic signs, hallucinations, rhabdomyolysis, and hyperthermia, and can be fatal if not promptly treated. Treatment is guided by presentation severity and discontinuing the causative medications is of utmost importance. Interventions include aggressive treatment for hyperthermia, including external cooling and hydration, and supportive care such as administering IV fluids.

Orthostatic hypotension is a common cardiovascular side effect of MAOIs that may lead to dizziness or syncope. Typically this is seen 2 to 3 weeks after initiating MAOI treatment. If hypotension remains a problem, mirteralocorticoids can be prescribed with monitoring of serum potassium for hypokalemia. Increasing doses of tranylcypromine can increase supine--but not standing--diastolic blood pressure. (19) Distinguish this type of blood pressure elevation from a hypertensive crisis by monitoring blood pressure with the patient sitting and standing and before and after he or she walks for 60 seconds.

Insomnia and day-night shifting--sleep-ing during the day and staying awake at night--are common and patients often cite these as reasons for discontinuing MAOIs. Many patients who respond to MAOIs report periods of substantial sleepiness in the mid to late afternoon. Table 3 (20) provides a more complete list of reported side effects and their frequencies.
Table 3

MAOIs: Stay vigilant for side effects

  Medication                Common side effects

Isocarboxazid    Anxiety, blurred vision, constipation,
                 dizziness, headache, insomnia, mania,
                 somnolence, weight gain, xerostomia

Phenelzine       Constipation, disorder of ejaculation
                 and/or orgasm, dizziness, edema, fatigue,
                 headache, hyperreflexia, impotence,
                 elevated values on liver function tests,
                 orthostatic hypotension, sleep disorders,
                 somnolence, tremor, weight gain,
                 xerostomia

Selegiline       Application site reaction, decreased
transdermal      systolic blood pressure, diarrhea,
                 headache, indigestion, insomnia,
                 orthostatic hypotension, 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


Practice guidelines

The American Psychiatric Association's practice guidelines for treating major depression state that MAOIs are effective in treating subgroups of patients with MDD with atypical features who have failed TCA trials.21 These guidelines also state that MAOIs have been shown to be effective treatment for some patients who have failed other antidepressants. However, for TRD patients who have not responded to SSRIs or SNRIs, the effectiveness of MAOls compared with other strategies is unclear."

One study found adding lithium to an MAOI may provide more rapid or more efficacious response than MAOI monotherapy. (23) Guze et al (24) evaluated the effects of high-dose MAOI treatment for 2 TRD patients; both patients improved without any side effects.

MAOIs have been used for >6 decades, and published studies continue to document their efficacy and safety when patients are monitored appropriately. (11), (12), (14), (15), (25) However, based on our observations we suspect MAOIs are underutilized in clinical practice today. We are concerned that such practices can trickle down into residency training programs. Psychiatric residents typically do not receive adequate training in prescribing MAOIs, largely because many training faculty are not prescribing MAOIs themselves. Despite MAOIs' limitations, concerns about an increased risk of suicide in patients with TRD (26) and the high likelihood of a poor outcome associated with persistent nonresponse to prior treatments must be weighed against the relatively low risk of a hypertensive event with MAOIs. (6)

Bottom Line

The efficacy of monoamine oxidase inhibitors (MA01s) 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 MAOls, but increased knowledge of these drugs can help psychiatrists reconsider this treatment option, particularly for patients with atypical depression.

Clinical Point

Several trials have found MAOIs may benefit outpatients with MDD who have not responded to other antidepressants

Discuss this article at www.facebook.com/CurrentPsychiatry

Clinical Point

Hypertensive crisis is the most serious side effect of MAOIs, but often it can be treated without hospitalization

Clinical Point

Based on rigorous reviews of tyramine content, the number of 'forbidden foods' for patients taking an MAOI has decreased

Clinical Point

Practice guidelines state MAOls are effective for patients with depression with atypical features who have failed tricyclic antidepressants

Clinical Point

Studies continue to document MAOls' safety and efficacy when patients are monitored appropriately

RELATED ARTICLE: Related Resources

* McCabe-Sellers BJ, Staggs CG, Bogle ML. Tyramine in foods and monoamine oxidase inhibitor drugs: a crossroad where medicine, nutrition, pharmacy, and food industry converge. Journal of Food Composition and Analysis. 2006;19(suppl):S58-S65.

* Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 2004;10(4):239-248.

Drug Brand Names

Clomipramine * Anafranil

Epinephrine * Adrenalin, EpiPen

Fluoxetine * Prozac

Imipramine * Tofranil

Isocarboxazid * Marplan

Lithium * Eskalith, Lithobid

Nifedipine * Adalat, Afeditab

Phenelzine * Nardil

Phentolamine * OraVerse, Regitine

Selegiline * EMSAM

Tranylcypromine Parnate

Disclosures

Dr. Kosinski reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rothschild receives grant or research support from Cyberonics, the National Institute of Mental Health, St. Jude Medical, and Takeda, and is a consultant to Allergan, Eli Lilly and Company, GlaxoSmithKline, Noven Pharmaceuticals, Pfizer Inc., Shire Pharmaceuticals, and Sunovion.

References

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(2.) Nolen WA, van de Putte JJ, Dijken WA, et al. Treatment strategy in depression. H. MAO inhibitors in depression resistant to cyclic antidepressants: two controlled crossover studies with tranylcypromine versus L-5-hydroxytryptophan and nomifensine. Acta Psychiatr Scand. 1988;78(6):676-683,

(3.) McGrath PJ, Stewart JW, Harrison W, et al. Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull. 1987;23(1):169-172.

(4.) Amsterdam JD. Monoamine oxidase inhibitor therapy in severe and resistant depression. Psychiatr Ann. 2006; 36(9):607-613.

(5.) Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122(5):509-522.

(6.) Kennedy SH, Holt A, Baker GB. Monoamine oxidase inhibitors. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock's comprehensive textbook of psychiatry 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 1076-1080.

(7.) EMSAM [package insert]. Napa, CA: Dey Pharm LP; 2011.

(8.) Amsterdam JD, Chopra M. Monoamine oxidase inhibitors revisited. Psychiatric Ann. 2001;31(6):361-370.

(9.) Quitkin FM, Stewart JW, McGrath PJ, et al. Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders. Am J Psychiatry. 1988;145(3):306-311.

(10.) Vallejo J, Gasto C, Catalan R, et al. Double-blind study of imipramine versus phenelzine in melancholias and dysthymic disorders. Br J Psychiatry. 1987;151:639-642.

(11.) White K, Razani J, Cadow B, et al. Trancylpromine vs. nortriptyline vs. placebo in depressed outpatients: a controlled trial. Psychopharmacology (Berl). 1984;82(3): 258-262.

(12.) Thase ME, Frank E, Mallinger AG, et al. Treatment of imipramine-resistant recurrent depression, M: efficacy of monoamine oxidase inhibitors. J Clin Psychiatry 1992; 53(1):5-11.

(13.) Himmelhoch JM, Thase ME, Ma flinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991;148(7):910-916.

(14.) Rothschild AJ, ed. The evidence-based guide to antidepressant medications. Arlington, VA: American Psychiatric Publishing, Inc.; 2012:15-20.

(15.) Ravaris CL, Nies A, Robinson DS, et al. A multiple-dose, controlled study of phenelzine in depression-anxiety states. Arch Gen Psychiatry 197633(3):347-350.

(16.) Cockhill LA, Remick RA. Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 198732(9):803-808.

(17.) Shulman Kr, Walker SE. A reevaluation of dietary restrictions for irreversible monoamine oxidase inhibitors. Psychiatr Ann. 2001;31(6):378-384.

(18.) Gardner DM, Shulman KI, Walker SE, et al. The making of a user friendly MAOI diet. J Clin Psychiatry. 1996;57(3): 99-104.

(19.) Keck PE Jr, Carter WP, Niere.nberg AA, et al. Acute cardiovascular effects of tranylcypromine: correlation with plasma drug, metabolite, norepinephrine, and MHPG levels. J Clin Psychiatry 1991;52(6):250-254.

(20.) Micromedex Healthcare Series [UMass Memorial Healthcare Intranet System]. Version 5.1. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc.

(21.) American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1667485. Published October 2010. Accessed October 26,2012.

(22.) McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541; quiz 1666.

(23.) Nelson JC, Byck R. Rapid response to lithium in phenelzine non-responders. Br J Psychiatry. 1982;141:85-86,

(24.) Guze BH, Baxter LR Jr, Rego J. Refractory depression treated with high doses of monoamine oxidase inhibitor. J Clin Psychiatry 1987;48(1):31-32.

(25.) Robinson DS, Gilmor ML, Yang Y, et al. Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta analysis of short term, placebo controlled, efficacy trials. Psychopharmacol Bull. 2007;40(3): 15-28.

(26.) Keller MB, Lavori PW, Rice J, et al. The persistent risk of chronicity in recurrent episodes of nonbipolar major depressive disorder: a prospective follow-up. Am J Psychiatry. 1986;143(1).24-28.

Eric C. Kosinski, MD

Staff Psychiatrist Health Alliance Hospital Leominster, MA UMass Memorial Medical Center Worcester, MA

Anthony J. Rothschild, MD

Irving S. and Betty Brudnick Endowed Chair and Professor of Psychiatry

Director, Center for Psychopharmacologic Research and Treatment

Director, UMass

Depression Center Department of Psychiatry

University of Massachusetts Medical School Worcester, MA
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Title Annotation:monoamine oxidase inhibitors
Author:Kosinski, Eric C.; Rothschild, Anthony J.
Publication:Current Psychiatry
Article Type:Drug overview
Date:Dec 1, 2012
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