This article addresses the use of monoamine oxidase inhibitors (MAOIs) for a variety of psychiatric disorders—excluding neurodegenerative diseases. We mainly explore the effective value of MAOIs through nosology and refractory depression.
Treatment Refractory Depression
Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are perceived as user-friendly depression treatments. MAOIs, however, are often never used or used as a last option to treat depression. When a depressed patient has not improved after several antidepressant trials, the patient is considered to have “treatment refractory depression” (TRD). Different authors have provided definitions of TRD; as remission is the goal of treating depression and treatment should only be deemed ineffective after adequate use, our TRD definition is failure to remit following adequate trials with at least two adequately dosed antidepressants having different putative mechanisms of action. “Adequate trial” means at least 2 weeks on at least two-thirds percent of the Physicians’ Desk Reference maximal dose guidelines.
One chart review1 and four open-label consecutive case series2–5 treated 87 patients having variously defined TRD—the majority having failed to benefit from at least two prior adequate treatments. Forty-seven (54%) either responded or remitted following treatment with MAOI, either alone or in combination with lithium, stimulant, and/or tricyclic antidepressant. We found no chart review or case series suggesting poor response to MAOI therapy in TRD patients. This suggests the possible efficacy of MAOIs for TRD, but dual criticisms include no control group to assess the likelihood of spontaneous remission, and open-label assessments that raise questions of possible bias.
We found five random assignment studies, two with open-label treatment and unblinded ratings, one with open-label treatment but blind ratings, and two with both treatment and ratings having been double blind. Two random assignment studies are uninformative as inadequately dosed MAOI was inferior to the comparator (electroconvulsive therapy) in one,6 and two MAOIs did not differ in the other study.7 A random assignment but unblinded comparison of imipramine and phenelzine did not differentiate the two drugs.8 However, two Nolen studies3 demonstrated tranylcypromine’s efficacy, although only one was both randomized and double blind. The open-label study showed superior efficacy to tranylcypromine relative to L-5-HTP, while the double-blind study showed trend significance in the primary analysis (45% responded to tranylcypromine and 10% to nomifensine; in subsequent crossover, P < .1) and statistical superiority of tranylcypromine relative to nomifensine in a secondary analysis of the Hamilton Rating Scale for Depression scores. A final unblinded study found low response to randomized open-label treatment comparing tranylcypromine to the combination of mirtazapine and venlafaxine.9 The study can be faulted for using a low dose of tranylcypromine (mean dose 36 mg per day ± 19).
The best study of TRD (second study described in reference 8) only showed definitive (ie, statistically significant drug-placebo difference) efficacy on a secondary measure. The other studies may be supportive, but not definitive due to design flaws. The two uncontrolled studies suggesting poor efficacy may have used too low a dose of MAOI, while the other studies are consistent with MAOI efficacy for TRD. Nevertheless, we consider the evidence suggestive without being definitive that MAOI therapy is effective for TRD.
Use of MAOIs for Endogenous Depression and Melancholia
Because melancholia was not introduced into the Diagnostic and Statistical Manual of Mental Disorders (DSM) until 1980, studies prior to that date used terms such as: “endogenously depressed,” “endogenous depression,” or “typical depression.” In our literature search, we included such studies while recognizing the looseness of equating these terms. We also included studies of severely depressed inpatients as these frequently have what would today be labeled depression with melancholic features.
We found six double-blind, randomized trials of MAOIs in endogenous depression, melancholia, or inpatients, one randomized but not double-blind inpatient study, three open-label consecutive series of endogenously or melancholically depressed outpatients, plus two studies of mixed outpatients in which endogenous depression or “typical” depression was assessed as a predictor of MAOI response.
One double-blind study randomized inpatients to either of two different doses of isocarboxazid, finding no difference in response, so it is relatively uninformative beyond the likelihood of global improvement from all sources.10 Two studies used an intensive design (ie, patients randomly received drug or placebo sequentially). One intensive design study reported that 12 of 50 patients had a drug effect (ie, improved on iproniazid, relapsed on placebo, and improved again when iproniazid was reintroduced).11 The other intensive design study reported that 53% of the 13 endogenously depressed patients either remitted or experienced “marked improvement”; while 14% of 21 placebo-treated patients also achieved this level of benefit, the rate of placebo response is not stated for the endogenous subset.12 Even if all three of the patients responding to placebo were in the endogenous subset, the findings would significantly demonstrate phenelzine’s efficacy for endogenous depression.
Middlefell et al.13 compared phenelzine to placebo in 132 inpatients—the “majority endogenous.” The statistics they present are confusing, but they conclude, “our findings support . . . [phenelzine’s efficacy] for endogenous depression.”13 Vallejo et al.14 randomly assigned 34 depressed patients with DSM-III melancholia to double-blind treatment with phenelzine or imipramine, reporting equivalent improvement. Similarly, Davidson et al.15 randomly assigned inpatients to imipramine or phenelzine, reporting equivalent results. Because tricyclic antidepressants are accepted as effective for treating melancholia, these latter two studies support phenelzine’s efficacy for endogenous depression, although the possibility of a type II error (a true difference missed due to either random events or small sample) must be considered.
Five open-label consecutive series reported use of MAOIs for melancholia, endogenous depression, or inpatient depression.13,16–19 Two of the series reported that individual symptoms improved, without mention of whether there was substantial mood or overall syndrome improvement; thus, these studies are relatively uninformative.18,19 Three of the open-label series reported substantial efficacy,13,16,17 although open to the potential for biased ratings. Also, all were outpatient studies, possibly implying less severely depressed patients.
Three positive double-blind, placebo-controlled studies should be sufficient to declare the efficacy of MAOIs for endogenous depression/depression with melancholic features. Nevertheless, we consider the failure of these studies to clearly present their results sufficiently problematic to consider the evidence more suggestive than adequately demonstrated.
MAOIs for Bipolar Depression
We found two small case reports,20,21 one case series,22 two randomized, double-blind studies,23,24 and a crossover study25 assessing possible efficacy of MAOIs for depressed patients with bipolar disorder. Because case reports usually describe only successes, a denominator cannot be deduced to estimate the likelihood of benefit.
Case series, such as Himmelhoch et al.,22 give a denominator that provides how often benefit might be anticipated but do not allow an estimate of how much observed improvement can be attributed to the treatment (ie, the extent to which some of the observed improvements might better be attributed to spontaneous remission or other nonpharmacologic reasons). That Himmelhoch et al.24 demonstrated superiority of tranylcypromine over another established antidepressant medication represents an impressive single good study. The earlier Himmelhoch et al.23 study included patients without a diagnosis of bipolar disorder and did not show results limited to those having a history of mania or hypomania, so their conclusion that tranylcypromine is effective for patients having anergic bipolar depression must be accepted as a suggestion rather than proven. The Thase et al.25 crossover study provides support for the primary finding but cannot be considered definitive because the crossover treatment did not begin with equivalent groups (that is, one consisted of imipramine nonresponders, the other of tranylcypromine nonresponders, a systematic difference rather than a random one).
Despite suggestive evidence, because there is only a single definitive trial, it remains to be convincingly demonstrated whether MAOIs are effective treatment for bipolar depression.
Use of MAOIs for Eating Disorders
Open clinical trials suggested the efficacy of phenelzine,26,27 tranylcypromine,28 and a consecutive case series for isocarboxazid29 as treatment for bulimia. Four RCTs30–33 and a reanalysis of an RCT having a different purpose34 confirmed the advantage of phenelzine and isocarboxazid relative to placebo. As several MAOI studies showed similar benefit in depressed versus nondepressed patients, the efficacy of MAOIs for this disorder appears separate from its mood effects. Five positive double-blind, placebo-controlled studies, without contradictory studies, appear sufficient to deem MAOIs effective in treating bulimia.
We found two consecutive series of MAOI for anorexia nervosa, neither suggesting frequent efficacy, and no studies of MAOI for binge eating disorder.29,35 The place of MAOIs in treating these problems seems insufficiently investigated to warrant further comment.
MAOIs for Obsessive Compulsive Disorder
Six case reports36–42 encompassing 14 patients found nine patients whose obsessive compulsive disorder (OCD) only remitted when treated with an MAOI. These cases suggest the efficacy of MAOI therapy for this disorder. A controlled study was unable to distinguish phenelzine from clomipramine in 26 patients having OCD, suggesting phenelzine’s equivalence to an established OCD treatment.43 A 10-week randomized, double-blind RCT compared phenelzine, fluoxetine, and placebo in 54 OCD patients; fluoxetine was superior to the MAOI and placebo, which did not differ.44 Despite the suggestion of the case reports and the controlled study, we conclude that efficacy of MAOIs for OCD has not been clearly demonstrated.
MAOIs in Borderline Personality Disorder
The study of pharmacologic treatment of borderline personality disorder (BPD) has been challenging. BPD criteria overlap elements seen in mood disorder and in impulse control disorder. Its features, including rejection sensitivity, affective instability, emptiness, irritability, and fears of being alone are seen in many different disorders. Additionally, the impulsivity and behavioral dyscontrol make its systematic study difficult. Nevertheless, several researchers have taken on this challenge, rendering suggestive results, which may encourage further research and treatment considerations.
A double-blind, patient crossover study45 and a parallel design RCT46 both concluded that tranylcypromine and phenelzine, respectively, were superior to both haloperidol and placebo in treating borderline personality disorder. Parsons et al.47 reanalyzed a series of studies48–50 that investigated the relative effectiveness of double-blind and randomized treatment with phenelzine, imipramine, or placebo for atypical depression. Parsons et al.47 inferred the presence or absence of borderline personality disorder from a present/absent checklist of borderline symptoms. Among the patients presenting borderline symptoms, phenelzine was rated as significantly more often effective in ameliorating symptoms than imipramine or placebo, which did not differ.
Although three RCTs appear to support the efficacy of MAOIs for borderline personality disorder, each can be faulted. The tranylcypromine study did not compare patients randomized to tranylcypromine versus those initially given placebo. Instead, all patients received five different treatments in random order; after a year, patients and doctors rank-ordered the treatments by how helpful they had been, making it difficult to judge how clinically significant the rankings were. The first phenelzine study46 differentiated MAOI from haloperidol and placebo; however, this differentiation was limited to a subset of the borderline criteria, albeit an important one. The Parsons et al.47 study was compromised by two major flaws: employing a checklist rather than a clinical assessment of diagnostic criteria; and all subjects had depression with atypical features, complicating diagnostic accuracy with overlapping signs and symptoms (mood reactivity, labile affect, rejection sensitivity) and limiting its generalizability. The other two studies45,46 also limit generalization as both were conducted on inpatients. While two positive RCTs seem adequate to demonstrate efficacy, their methodological problems raise questions about whether the findings should be generalized to all patients with borderline personality disorder, or limited to inpatients or those with atypical depression.
MAOIs in Attention-Deficit/Hyperactivity Disorder
We found two open-label studies of moclobemide48–49 suggesting possible benefit plus three drug-drug comparisons studies50–52 that did not differentiate MAOI (selegiline, clorgiline, tranylcypromine) from a stimulant. Drug-drug comparisons studies are subject to type II errors (ie, not detecting a true difference), a problem particularly likely with the small sample sizes these studies reported. Three randomized, double-blind, placebo-controlled studies all reported significantly superior response to selegiline relative to placebo.53–55 Therefore, we consider selegiline to have ample evidence as an effective treatment of ADHD. Open-label studies of other MAOIs suggest these results may be generalizable to other MAOIs, but further studies are required.
MAOIs in Social Phobia
We found four consecutive case series suggesting that tranylcypromine,56 phenelzine,57 and moclobemide58 may be effective treatment for social phobia. The fourth study evaluating monoamine oxidase (MAO)-B specific inhibition59 reported only 19% of patients (3 of 16) with social phobia having good outcomes, perhaps suggesting MAO-A inhibition is required to achieve benefit for social anxiety.
We found 11 placebo-controlled RCTs of MAOIs for social phobia. Nine were positive, including four of five using phenelzine,60–64 three investigating brofaromine,65–67 and two of four utilizing moclobemide62,68–70 (one study62 compared both moclobemide and phenelzine to placebo). Together, these studies present strong evidence of phenelzine and the reversible MAOI brofaromine as effective treatment for social anxiety. Also, despite two negative studies,69,70 two positive RCTs of moclobemide seem to adequately demonstrate the efficacy of this reversible inhibitor of monoamine oxidase type A (RIMA) as well.
MAOIs in Panic Disorder
A consecutive case series71 reported 34 of 35 (97%) patients with panic disorder and agoraphobia completely remitted from panic attacks after 6 months on phenelzine. Six RCTs had a placebo control group of which four showed phenelzine,72,73 brofaromine,74 and iproniazid75 statistically superior to placebo, although in most cases not for agoraphobia. Two RCTs did not find phenelzine helpful for panic disorder relative to placebo.76,77 Ballenger78 asserts without data that unpublished RCTs have shown that tranylcypromine and phenelzine are superior to both benzodiazepines and imipramine as treatment of panic disorder and agoraphobia. Without adequate details of the two studies, it is difficult to accept this assertion. Finally, three equivalency RCTs (ie, drug-drug comparisons without placebo control) suggested that brofaramine79,80 and moclobemide81 are equivalently effective as clomipramine, fluvoxamine, and fluoxetine, respectively.
Thus, four RCTs demonstrate the efficacy of a variety of MAOIs as treatment for panic disorder. This is supported by three equivalency studies with RIMAs and one consecutive case series with phenelzine plus the assertions of Ballenger et al.78 that two unpublished studies also confirm the efficacy of MAOIs for panic disorder. However, except for the case series, most studies suggested MAOIs may not be good treatment for agoraphobia, which commonly accompanies panic disorder and can significantly impair work or community life.
There is good evidence (two or more positive RCTs) of the efficacy of MAOIs as treatment for ADHD, bulimia, social phobia, and panic disorder. While there are three positive RCTs each in borderline personality disorder and endogenous depression/melancholia, each has flaws limiting our endorsement of MAOIs for this condition. A single positive RCT suggests MAOIs may be effective therapy for bipolar depression and TRD, respectively, but a second positive placebo-controlled RCT is required before efficacy of MAOIs for these conditions can be asserted. The lack of positive RCTs of MAOIs as treatment for OCD prevents us from endorsing their use for this disorder. Suggestive evidence suggests additional treatment studies of MAOIs for bipolar depression and TRD, especially because these are problems clinicians commonly face without solid literature to guide their treatment choices.
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