Evidence-Based Reviews

MAO inhibitors: An option worth trying in treatment-resistant cases

Current Psychiatry. 2002 June;1(6):40-47

Fears of hypertensive complications, drug-food interactions, and other side effects discourage many psychiatrists from prescribing MAOIs. The authors urge readers to rediscover these drugs, especially for treatment-resistant depressions and related disorders.

References

1. Thase ME, Mallinger AG, McKnight D, et al. Treatment of imipramine-resistant recurrent depression; IV; a double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry 1992;149:195-8.

2. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacol 1995;12(3):185-219.

3. Angst J, Amrein R, Stahl M. Moclobemide and tricyclic antidepressants in severe depression: meta-analysis and prospective studies. J Clin Psychopharmacology 1995;4(52):165-235.

4. Bodkin JA, Cohen BM, Cannon S, Salomon MS, Zornberg GL, Cole JO. Selegiline treatment of negative symptoms of schizophrenia and schizoaffective disorder: an open trial investigating the role of dopamine. J Nerv Ment Dis 1996;184:295-301.

5. Hudson JL, Pope HG. Affective spectrum disorder: does antidepressant response identify a family of disorders with a common pathophysiology? Am J Psychiatry 1990;147(15):552-64.

6. McGrath PJ, Stewart JW, Quitkin FM. The use of MAOIs for treating atypical depression. Psychiatric Ann 2001;31(6):371-5.

7. Davidson J, Giller EL, Zisook S, et al. An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Arch Gen Psychiatry 1988;45:120-7.

8. Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991;148(7):910-6.

9. Leibowitz MR, Heimberg RG, Schneier FR, et al. Cognitive-behavioral group therapy versus phenelzine in social phobia: long-term outcome. Depress Anxiety 1999;10(3):89-98.

10. Kosten TR, Frank JB, Dan E, McDougle CJ, Giller EL, Jr. Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine. J Nerv Ment Dis 1991;179(6):366-70.

11. Pare CM. The present status of monoamine oxidase inhibitors. Br J Psychiatry 1985;146:576-84.

12. Goodwin FK, Jamison KR. Manic Depressive Illness. New York, Oxford University Press, 1990.

13. Glue P, Coupland N, Nutt DJ. Pharmacological basis for the therapeutic activity of MAOIs. In: Kennedy SH, ed. Clinical advances in monoamine oxidase inhibitor therapies. Progress in psychiatry, No. 43 Washington, DC: American Psychiatric Press, 1994;1-31.

14. Shopsin B, Friedman E, Gershon S. Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry 1976;33:881-91.

15. Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of action of antidepressant treatment: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990;47:411-18.

16. Shader R, Greenblatt D. The reappearance of a monoamine oxidase inhibitor (isocarboxazid). J Clin Psychopharmacol 1999;19(2):105-6.

17. McGrath PJ, Quitkin FM, Harrison W, et al. Treatment of melancholia with tranyl cypromine. Am J Psychiatry 1984;141:288-9.

18. White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Psychopharmacol 1981;1:264-82.

19. Nierenberg AA, Keck PE, Jr. Management of MAOI-associated insomnia with trazadone. J Clin Psychopharmacol 1989;9(1):42-5.

20. Hoes MJ, Zeijpveld JH. Mirtazapine as a treatment for serotonin syndrome. Pharmacopsychiatry 1996;29(2):81.-

21. Shulman KI, Walker SE. A reevaluation of dietary restrictions for irreversible MAOIs. Psychiatric Ann 2001;31(6):378-84.

22. Healy D. The Antidepressant Era. Cambridge, MA: Harvard University Press, 1997.

23. Bieck PR, Antonin K-H. Tyramine potentiation during treatment with MAOIs. In: Kennedy SH, ed. Clinical advances in monoamine oxidase inhibitor therapies. Progress in psychiatry, No. 43. Washington, DC: American Psychiatric Press, 1994;83-110.

24. Keck PE, Carter WP, et al. Acute cardiovascular effects of tranylcypromine: correlation with plasma drug, metabolite, norepinephrine and MHPG levels. J Clin Psychiatry 1991;92(6):250-4.

25. Keck PE, Pope HG, Jr, Nierenberg AA. Autoinduction of hypertensive reactions by tranylcypromine? J Clin Psychopharmacol 1989;9(1):148-51.

26. Teicher MH, Cohen BM, Baldessarini RJ, Cole JO. Severe daytime somnolence in patients treated with an MAOI. AmJ. Psychiatry 1988;145(12):1552-6.

27. Lotufo-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine oxidase Type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology 1999;20:226-47.

28. Bodkin JA, Kwon AE. Selegiline and other atypical monoamine oxidase inhibitors in depression. Psychiatric Ann 2001;31(6):385-91.

Many fully trained psychiatrists, even psychopharmacologists, have rarely prescribed a monoamine oxidase inhibitor (MAOI), afraid of the possible consequences. One Boston-area psychiatrist who plans to retire soon has 12 patients who have been doing well for years on MAOIs. Before he called us, no psychiatrist in the area was willing to accept these patients who intended to stay on MAOIs.

Despite their potential side effects, the older MAOIs (phenelzine, tranylcypromine, isocarboxazid, and selegiline) have all been proven effective in depression; some studies have found them more effective than tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs).^1,2 In our experience, MAOIs succeed in at least one-half the depressed patients who have failed on other antidepressants, and they are highly useful in treatment-resistant depressions and related disorders. Further, hypertensive crises are rare, and dietary restrictions are often exaggerated.

Drawing from the evidence and from our nearly 50 years’ experience in the use of MAOIs, we hope to acquaint or re-acquaint you with how to use these agents safely and to maximum effect.

When to use an MAOI

Reviews, meta-analyses, and more than 250 controlled studies have addressed MAOIs in psychiatric conditions.

The bulk of the literature reports a response rate of about 70% in various types of depression and anxiety.³ Unfortunately, because of the absence of major federal or industry funding, the findings are difficult to integrate, with most investigators testing different MAOIs on different subpopulations. This type of fragmented research, however, is not unique to MAOIs.

We at McLean have found MAOIs useful as second-line agents—and occasionally as first-line agents—in treating depression. We also use them as third-, fourth-, or fifth-line agents because we see many patients who have failed to respond to or tolerate several other antidepressants or whose response to other antidepressants has faded.

MAOIs are effective for a range of clinical presentations in inpatients and outpatients—depressive disorders (endogenous and atypical, unipolar and bipolar, neurasthenic and phobic), anxiety disorders (panic disorder and social phobia), and conditions as far afield as borderline personality disorder and the negative symptoms of schizophrenia.⁴

In controlled trials, many investigators have shown an MAOI to be more effective in some clinical conditions than a tricyclic and than a placebo.⁵ For example:

A group at Columbia University studied phenelzine in various permutations of atypical depression (rejection sensitivity, overeating, oversleeping, mood reactivity, severe lack of physical energy).⁶
Davidson et al studied isocarboxazid in anxious depression.⁷
Thase and Himmelhoch studied tranylcypromine in anergic and bipolar depressions.⁸
Liebowitz followed up with studies of phenelzine and tranylcypromine in social phobia.⁹
At Yale, early studies were done with phenelzine in posttraumatic stress disorder (PTSD).¹⁰
The British have generally argued for use of MAOIs in mixed anxiety and depression.¹¹
The magisterial text Manic Depressive Illness recommends MAOIs as first-line treatment for bipolar depression.¹²

All of these studies yielded clinically and statistically substantial results with modest adverse effects.

Box 1

HOW MAOIs WORK

The enzymes MAO-A and MAO-B were identified in the 1950s. MAO-A occurs mainly in the intestine and brain, and the enzyme preferentially oxidizes (inactivates) serotonin and norepinephrine. MAO-B occurs in the brain and in platelets as well as in other tissues, and it inactivates phenylethylamine and benzylamine. Both enzymes metabolize tyramine and dopamine. The older MAOIs (phenelzine, tranylcypromine, isocarboxazid and high-dose selegiline) are irreversible MAO A and B inhibitors and block the actions of both enzymes from 14 to 28 days while new MAO enzymes are being resynthesized.

The actions of all MAOIs are presumed to be mediated by the blocking of the metabolism of intra- and extraneuronal biogenic amines, leading to increased brain levels of serotonin, norepinephrine, and dopamine.¹³ Even in the 1950s, when work with MAOIs was just beginning, these biogenic amines were suspected of being low or underactive in depression.

Research offers no real clues as to which enzyme is more important to inhibit or which of the various brain chemicals increased during MAOI therapy are crucial to clinical improvement. Two small studies suggest that decreasing the synthesis of brain serotonin will produce a temporary return of symptoms in patients clinically improved on MAOIs.^14,15

The hypertensive crisis caused by tyramine has been shown to result from the inhibition of MAO-A, not MAO-B. More recent studies show effects of most MAOIs on receptors as well as enzymes. The basis or bases for MAO inhibitor actions may be more complex or different than anticipated.¹⁶

Characteristics of each agent

In the United States, a psychiatrist interested in using an MAOI for depressed patients can choose from among four agents. These older MAOIs are irreversible blockers of the enzymes MAO-A and MAO-B (Box 1).^13-16