Evidence-Based Reviews

Monoamine oxidase inhibitors: Forgotten treatment for depression

Current Psychiatry. 2012 December;11(12):20-26

References

1. Balon R, Mufti R, Arfken CL. A survey of prescribing practices for monoamine oxidase inhibitors. Psychiatr Serv. 1999;50(7):945-947.

2. Nolen WA, van de Putte JJ, Dijken WA, et al. Treatment strategy in depression. II. 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, III: efficacy of monoamine oxidase inhibitors. J Clin Psychiatry. 1992;53(1):5-11.

13. Himmelhoch JM, Thase ME, Mallinger 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. 1976;33(3):347-350.

16. Cockhill LA, Remick RA. Blood pressure effects of monoamine oxidase inhibitors—the highs and lows. Can J Psychiatry. 1987;32(9):803-808.

17. Shulman KI, 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, Nierenberg 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.

^10,11

Clinical Point

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

Several controlled trials have found a better 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 al¹⁰ 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 al¹³ 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

Clinical Point

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

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 hypertensive 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 α-adrenergic receptor blocker—can be used as an antidote; often a single dose is effective.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.

Clinical Point

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

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 phenylethylamine, 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 2^4,17,18 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 MAOIs

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 (≤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, mineralocorticoids 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.