MAO inhibitors: Risks, benefits, and lore
ABSTRACTMonoamine oxidase (MAO) inhibitors were the first antidepressants introduced, but their use has dwindled because of their reported side effects, their food and drug interactions, and the introduction of other classes of agents. However, interest in MAO inhibitors is reviving. Here, we discuss their use, risks, and benefits in clinical medicine.
KEY POINTS
- Data from multiple studies suggest the efficacy of MAO inhibitors in the management of major depressive disorder and, in particular, major depressive disorder with atypical features and in treatment-resistant depression.
- When using oral MAO inhibitors, patients must follow a low-tyramine diet to avoid the “cheese reaction,” ie, tyramine-induced hypertensive crisis. However, recent studies suggest that traditional dietary advice may be unnecessarily restrictive.
- The selegiline transdermal system (Emsam) is the first approved transdermal patch for treatment of major depression. Unlike oral MAO inhibitors, the patch can be used without the dietary restrictions at its lowest effective dose of 6 mg/24 hours. Because of its transdermal delivery, it has the advantage of not inhibiting the metabolism of dietary tyramine by MAO subtype A in the gut, while providing antidepressant effect in the brain. The patch may be a promising alternative to existing strategies for the management of major depressive disorder.
EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE
Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,43–48 treatment-resistant major depressive disorder,49,50 and bipolar depression.51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.53
MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.54
Major depressive disorder
In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.55 When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.56 Thase et al,57 in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.
Atypical depression
Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.58 An estimated 30% of outpatients with unipolar depression meet these criteria.59
Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.43 Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.49 Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.50 Another report48 indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.
A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.60 Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.61
The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.60 However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford59 compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).59
Treatment-resistant depression
The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,62,63 as is the risk of more severe future depressive episodes63 and death from any cause.64 Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.
The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.49,50,65–67 MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.
Bipolar depression
Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.
Efficacy of the selegiline patch
The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.69–72 There were three short-term studies (a 6-week study of 177 patients,69 an 8-week study of 265 patients,72 and an 8-week study of 289 patients70) and a fixed-dose 1-year relapse prevention study of 322 patients.71 The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,71 patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.71
DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?
MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.
