Evidence-Based Reviews

Monoamine oxidase inhibitors: Forgotten treatment for depression

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Increased knowledge of MAOIs has made these agents worthy of reconsideration


 

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For patients with major depressive disorder (MDD), monoamine oxidase inhibitors (MAOIs) have efficacy comparable to that of other antidepressants. However, concerns about side effects—particularly hypertensive crisis—and drug-drug interactions have led clinicians to prescribe MAOIs less often than newer antidepressants. A 1999 survey of 573 Michigan psychiatrists found that 30% had not prescribed an MAOI within the past 3 years, and 12% had never prescribed an MAOI.1 Although there are challenges to using these agents, we prefer prescribing MAOIs to depressed patients who have not responded to previous antidepressant trials over trying untested antidepressant combinations.

Currently, MAOIs are used primarily for patients who have not responded to other antidepressant trials and are considered treatment resistant. Treatment-resistant depression (TRD) typically is defined as nonresponse to ≥3 adequate antidepressant trials. TRD is a major cause of disability and loss of productivity. These patients tend to do poorly over the long term, with high rates of hospitalization and suicide attempts. Several controlled trials have shown that patients who fail other antidepressants may respond to MAOIs.2-4

Our knowledge regarding MAOIs has grown considerably. We have learned more about depression subtypes that MAOIs may help. As we learned more about dietary restrictions for patients taking MAOIs, the list of “forbidden foods” has decreased. Advances in treating a hypertensive crisis have decreased the need for hospitalization. By educating ourselves and our patients about MAOIs, we can provide another option for treating MDD.

An older antidepressant class

MAOIs were introduced approximately 60 years ago. Their potential for treating depression was discovered when a tuberculosis treatment—iproniazid—was found to reduce depressive symptoms. Researchers determined iproniazid’s antidepressant effects were the result of blocking removal of the amine group by monoamine oxidase (MAO) from dopamine, norepinephrine, and serotonin.5 A second MAOI, tranylcypromine, was discovered when it was found to be ineffective for treating decongestion.6

MAOI use in psychiatric practice has undergone significant changes since these medications were introduced. The discovery of hypertensive crises related to tyramine consumption led to decreased MAOI use, as did the rise of tricyclic antidepressants (TCAs) shortly thereafter. In the 1960s, research compared the relative efficacy of MAOIs to TCAs, and they became second-line antidepressants after the TCAs. In the late 1980s, the introduction of fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) resulted in a significant drop-off in MAOI use.

Pharmacologic effects

MAO is a class of enzymes that initiate oxidation of extracellular neurotransmitters such as serotonin, norepinephrine, and dopamine. MAOIs can be classified based on their relative affinity to MAO as well as their enzyme selectivity. The first distinguishing characteristic is whether the drug binds to MAO in a reversible or irreversible manner. Currently, all MAOIs that are FDA-approved for treating depression bind irreversibly to MAO. As a result, the body must renew its MAO levels before a patient is no longer at risk for a hypertensive crisis, a process that may take up to 2 weeks. Clinicians must take care to ensure their patients avoid foods that contain tyramine and medications contraindicated with MAOIs during this period.

MAOIs also differ from each other in enzyme selectivity. There are 2 subtypes of MAO enzymes—MAOA and MAOB. Generally, the antidepressant activity of MAOIs appears to be directed toward MAOA inhibition. MAOA has been found to be more specific for binding to serotonin and norepinephrine and MAOB to be more specific for phenylethylamine. Dopamine is equally deaminated by both MAOA and MAOB.

Reversible MAOA inhibitors require fewer restrictions on diet or concurrent medications, but efficacy data of reversible MAOA inhibitors is mixed.

Clinical use of MAOIs

Four MAOIs are available in the United States: tranylcypromine, phenelzine, isocarboxazid, and selegiline. Selegiline is the only MAOI available as a transdermal patch. Transdermal administration results in fewer effects on MAO in the gastrointestinal tract, which means no dietary restrictions at the 6 mg/d starting dose, although the manufacturer recommends patients follow the MAO diet at 9 mg/d and 12 mg/d doses.7 Although selegiline is selective for MAOB at low doses, it becomes nonselective at therapeutic doses for depression. Recommended dosages for MAOIs can be found in Table 1.8

Table 1

Recommended dosages of monoamine oxidase inhibitors

MedicationStarting dosagesUsual therapeutic dosage
Isocarboxazid10 mg twice a day30 to 60 mg/d
Phenelzine15 mg twice a day45 to 90 mg/d
Selegiline transdermal6 mg patch/d6 to 12 mg patch/d
Tranylcypromine10 mg, 2 or 3 times a day30 to 60 mg/d
Source: Adapted from reference 8
Depression subtypes. Researchers have observed that MAOIs are effective for treating atypical depression.9 Atypical depression is characterized by significant increases in sleep, appetite, or weight; leaden paralysis; and a pattern of extreme sensitivity to interpersonal loss often referred to as “rejection sensitivity.” Other subtypes of depression—such as depression with melancholic features and dysthymia—respond to MAOIs.

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