Monoamine Oxidase Inhibitors (MAOI): Role of MAOIs in Pharmacotherapy

Depression

Phenelzine, isocarboxazid, tranylcypromine, and transdermal selegiline are all FDA-approved only for the treatment of major depressive disorder. FDA guidance varies among these agents (16-19):

• Labeling for tranylcypromine states that it is indicated in adults with major depressive disorder who have not responded adequately to other antidepressants; it further states that tranylcypromine is not indicated for initial treatment of major depressive disorder because of the potential for serious adverse reactions and drug interactions and the need for dietary restrictions.
• Isocarboxazid labeling states that, because of potentially serious side effects, it is not the antidepressant of first choice in the treatment of newly diagnosed patients.
• Phenelzine’s package insert states that it was found effective in patients with depression characterized as “atypical”, “non-endogenous”, or “neurotic”. It further describes these patients as having mixed anxiety and depression, phobic, or hypochondriacal features and states that there is less conclusive evidence of phenelzine’s usefulness in severely depressed patients with endogenous features such as neurovegetative symptoms (e.g., loss of appetite, weight loss, insomnia).
• The package insert for transdermal selegiline states that it is indicated for adults with major depressive disorder; it does not indicate that transdermal selegiline is a second- or third-line agent.

Moclobemide is labeled only for the treatment of major depression in Canada and Australia (20,21). In Europe, moclobemide is also labeled for the treatment of social phobia (22).

The literature regarding the effectiveness of MAOIs in depressive illnesses is fairly consistent. Shulman et al (3) reviewed studies of MAOIs in the treatment of mood disorders. In outpatients with depression, MAOIs produced a 50 – 70% response rate – similar to that seen with TCAs and SSRIs. Major depressive disorder with atypical features is depression characterized by mood reactivity plus at least 2 of the following symptoms: significant weight gain / increased appetite, increased sleep, leaden paralysis, and long-standing pattern of sensitivity to interpersonal rejection. There is evidence that MAO-A activity is increased in this type of depression (6). MAOIs (especially phenelzine) have been shown to be more effective than TCAs for this type of depression (3,23). Depression not adequately responding to TCAs shows an approximately 50% response rate to MAOIs (24). Bipolar depression may also respond well to MAOIs with a possibly lower risk of switches to mania compared to tricyclic antidepressants or lamotrigine in combination with lithium, valproate, or carbamazepine (3,23,25).

In phase 4 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies, the remission rate for tranylcypromine was similar to that for mirtazapine combined with venlafaxine – 6.9% and 13.7% respectively (p = NS) (26). This has been cited as evidence for a lack of efficacy of tranylcypromine as a third- or fourth-line agent for depression. However, it was used in patients who had already failed to remit with several other treatments and were therefore quite treatment resistant. Doses of tranylcypromine also may not have been optimized; the mean dose was 39.6 mg/day. There are reports that patients with treatment-resistant depression may respond to tranylcypromine at doses of 100 mg/day (27). Additionally, some experts (4) point out that MAOIs may be more effective than other antidepressants and electroconvulsive therapy (ECT).

Anxiety Disorders

MAOIs are also known to be effective for treatment of anxiety disorders such as panic disorder and social anxiety disorder (1,2,28,29). Their antianxiety efficacy may, in part, explain their usefulness in treating major depressive disorder with atypical features. Results of moclobemide treatment of social anxiety disorder have been mixed. In comparative studies, moclobemide was equally effective as fluoxetine or clomipramine in the treatment of panic disorder (30).

Other Disorders

Phenelzine and tranylcypromine have also been used successfully in the treatment of narcolepsy not responsive to stimulants. The MAOIs significantly reduced sleep paralysis, cataplexy, and hypnagogic hallucinations; excessive daytime sleepiness was somewhat less responsive. These drugs’ property of significant, prolonged, almost complete suppression of rapid eye movement (REM) sleep is believed to be responsible for their therapeutic effect in narcolepsy (31).

Tranylcypromine and moclobemide have been studied for the treatment of ADHD and have shown efficacy (32,33). They were shown to be as effective as stimulants and, like stimulants, to have a rapid onset of therapeutic effect. Children with ADHD responded to low doses of tranylcypromine (10 mg/day) and tolerated the medication well (33).

Treatment Guidelines

MAOIs are considered 2^nd to 4^th line antidepressants and antianxiety agents (34-37). Both evidence-based treatment guidelines and expert opinion recommend that these agents not be used as initial treatments. Nevertheless, there are experts who encourage wider, more liberal use of MAOIs and point out that their potential benefits in difficult to treat cases may outweigh concerns regarding drug-drug and drug-food interactions (1,2,4,14).