ELSEVIER REVIEW MAOis in the Contemporary Treatment of Depression Michael E. Thase, M.D., Madhukar H. Trivedi, M.D., and A. John Rush, M.D. We review the literature on the effectiveness of the comparator tricyclics for inpatients, whereas monoamine oxidase inhibitors (MAOis) and present tranylcypromine has not been adequately studied. Both metaanalyses of controlled trials comparing the FDA­ phenelzine and tranylcypromine appear to be more approved MAOis with both placebo and comparator effective than tricyclics in depressed outpatients with tricyclic antidepressants. For outpatients, metaanalyses atypical features. Monoamine oxidase inhibitors are also with intent-to-treat samples revealed generally comparable effective treatments for outpatients who have failed to overall efficacy for phenelzine, isocarboxazid, and respond to tricyclic antidepressants. Our review also tranylcypromine. Drug-placebo differences were 29. 5% suggests (1) the FDA-approved MAO!s treat a somewhat (± 11.1%) (phenelzine; nine studies), 41.3% (±18.0%) different group of patients than tricyclics; (2) more (isocarboxazid; three studies), and 22.1 % ( ± 25.4%) severely depressed inpatients may not respond as well to (tranylcypromine; three studies). For inpatients, MAO Is as to tricyclics; and (3) because of preferential phenelzine was 22.3% ( ± 30. 7%) (five studies) more MAO! responsivity, atypical or anergic depressions may effective than placebo, whereas the isocarboxazid-placebo be biologically different than classical depressions. difference was lower (15.3%) ( ± 12.6%). Both phenelzine [Neuropsychopharmacology 12:185-219, 1995] and isocarboxazid were significantly less effective than KEY WORDS: Phenelzine; Tranylcypromine; 1991) for reasons of both efficacy and safety. In this re­ Isocarboxazid; MAOis; Depression; Antidepressant port, we review the literature on the MAOls currently efficacy; Metaanalysis approved for the treatment of depression in the United Monoamine oxidase inhibitor (MAOI) antidepressants States by the Food and Drug Administration (FDA). Fol­ have been in use for nearly 40 years (Ayd 1957; Crane lowing a brief overview of the clinical pharmacology 1957; Kline 1958; West and Dally 1959; Sargent 1961), of the MAOis, we examine their efficacy as acute and during which time their popularity has waxed and maintenance phase treatments using metaanalysis. waned (e.g., Quitkin et al. 1979; Paykel and White Efficacy is determined with respect to placebo-control 1989). Recently, they have been largely viewed as (PBO) and relative to standard tricyclic antidepressant second- or third-line antidepressant medications (TCA) comparators. The relationship of response to de­ (Paykel and White 1989; Clary et al. 1990; Nierenberg gree of platelet MAO inhibition is considered, as are the side effects, tolerability, and safety of these agents. Finally, the literature on proposed MAOI-responsive From the University of Pittsburgh Medical Center and Western Psychiatry Institute and Clinic (MET), Pittsburgh, Pennsylvania and subforms of depression is summarized. Department of Psychiatry, University of Texas Southwestern Medical Center (MHT, AJR), Dallas, Texas. Address correspondence to: Michael E. Thase, M.D., University of Pittsburgh Medical Center and Western Psychiatric Institute and CLINICAL PHARMACOLOGY OF MAOis Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213. Received November 24, 1993; revised July 12, 1994; accepted July There are currently four FDA-approved MAOis avail­ 15, 1994. able in the United States. They are phenelzine sulfate NEUROPSYCHOPHARMACOLOGY 1995-VOL. 12, NO. 3 © 1995 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/95/$9 .SO 655 Avenue of the Americas, New York, NY 10010 SSDI 0893-133X(94)00058-8 186 M.E. Thase et al. NEUROPSYCHOPHARMACOLOGY 1995-VOL. 12, NO. 3 (PHZ) (Nardil), isocarboxazid (ISO) (Marplan), tranyl­ brofaromine are selective for Type A MAOI. The re­ cypromine sulfate (TRP) (Parnate), and selegiline hy­ maining three FDA-approved MAOis are "mixed" in­ drochloride (SEL) (Eldepryl). However, SEL's approval hibitors, because they inhibit both Type A and Type is limited to the treatment of Parkinson's disease, and B enzymes even at lower dosages. a recent decision by the manufacturer of ISO may re­ Clorgyline, pargyline, and the four FDA-approved move it from the market. A fifth MAOI, pargyline (Eu­ MAOis are relatively irreversible, meaning that the tonyl), was approved for use in severe hypertension drugs bind tightly to the enzyme for the life of the en­ but is no longer being manufactured because of an un­ zyme. A minimum period of 7 to 14 days is needed to favorable risk-bene&t ratio in comparison with newer adequately "wash out" MAO inhibition caused by the antihypertensive agents. Two additional MAOI an­ irreversible MAOis. Not surprisingly, the clinical effects tidepressants, moclobemide and brofaromine, are ap­ of the irreversible MAOis may persist for days or even proved for use in Europe and/or Canada, but are not several weeks after discontinuation (Murphy et al. being studied for approval in the United States (Thase 1987). By contrast, clinical effects that are plasma-level in press). Nevertheless, these drugs appear to be effec­ dependent (e.g., orthostasis) may reverse within hours tive antidepressants when compared to either PBO or to a few days of drug discontinuation (Murphy et al. standard comparators (e.g., Norman et al. 1985; Lecru­ 1987; Robinson and Kurtz 1987; Mallinger and Smith bier and Guel& 1990; Larsen et al. 1991; Nolen et al. 1991). The newer Type-A selective MAOis, moclobe­ 1993; Volz et al. 1994). Another MAOI, clorgyline, also mide and brofaromine, are reversible and thus have a appears to have significant antidepressant activity (e.g., shorter duration of effects on enzyme inhibition (Moller Potter et al. 1982). However, because of both proprie­ et al. 1991; Roth and Guelfi 1992). Whereas drug plasma tary and side-effect issues, clorgyline is not under ac­ levels of both the reversible and irreversible MAOIs can tive investigation at this time. be measured using methodology analogous to that for Monoamine oxidase inhibitors may be classified by trace monoamines or amphetamines (e.g., Cooper et their chemical structure (hydrazine versus nonhydra­ al. 1978; Karoum et al. 1982; Mallinger et al. 1990; Din­ zine), by their relative selectivity for subforms of MAO gemanse et al. 1992), available evidence concerning (Type A, Type B, or mixed), or by the degree of affinity plasma level-response relationships is scant. Plasma to enzyme inhibition sites (i.e., reversible versus func­ level monitoring of the irreversible MAOIs does not ap­ tionally irreversible) {Klein and Davis 1969; Mann et al. pear to be of clinical value, perhaps because of the short 1984; Murphy et al. 1984). The type B MAO, found in half-lives of these medications in relation to their phar­ brain, platelets, and elsewhere, has substrate specificity macodynamic effects (e.g., Mallinger et al. 1990). Avail­ for phenethylamine and dopamine. Type A MAO, able evidence suggests that plasma levels are also not found in the brain, gut, and liver (but not platelets) is useful for the prediction of response to either the irre­ relatively substrate-specific for norepinephrine, sero­ versible (Mallinger et al. 1990) or reversible (Fritze et tonin, and tyramine (Mann et al. 1984; Murphy et al. al. 1990; Danish University Antidepressant Group 1993) 1984, 1987). MAOis. Pargyline was the first FDA-approved MAOI to be All four FDA-approved MAOis have some struc­ considered relatively selective for Type B MAO (Mur­ tural resemblance to amphetamine. However, they are phy et al. 1984). Type B enzymatic selectivity was orig­ neither habit forming or euphoriogenic for the vast inally considered desirable as a solution to the dietary majority of patients (Mallinger and Smith 1991; Thase restrictions necessitated by inhibition of tyramine me­ in press). Nevertheless, metabolic pathways for two of tabolism. However, appropriately designed dose­ the nonhydrazine MAOis (SEL and TRP) may yield response studies regarding pargyline's enzymatic selec­ small amounts of amphetamine (Youdim et al. 1979; tivity were not performed in humans, and pargyline Karoum et al. 1982). The structure of TRP, which may did not show much promise as an antidepressant (Mur­ be viewed as a cyclized form of amphetamine, proba­ phy et al. 1987). Selegiline hydrochloride is also a selec­ bly precludes its metabolism to amphetamine except tive inhibitor of Type B MAO at low doses (i.e., 5 to under unusual circumstances, such as following a mas­ 10 mg/day) (Mann et al. 1984). However, there is little sive overdose (Youdim et al. 1979). Moclobemide and evidence to suggest that SEL is an effective antidepres­ brofaromine are also nonhydrazine MAOis. Phenelzine sant at these doses (e.g., Quitkin et al. 1984; Mann et sulfate and isocarboxazid differ from the other MAOis al. 1989). In fact, SEL appears to lose its specificity for in that they are hydrazine compounds; both drugs have MAO-B inhibition at the very dosages at which it sur­ a nitrogen-to-nitrogen bond in their side chain (Klein passes PBO as an effective antidepressant (Quitkin et and Davis 1969; Murphy et al. 1984). Considerable clin­ al. 1984; Mann et al. 1989). This suggests that Type A ical evidence indicates that the hydrazine MAOis have MAO may be more critical in the pathophysiology of greater hepatotoxicity than the nonhydrazines (Klein depression and/or more central