Monoamine oxidase inhibitors: Forgotten treatment for depression
Increased knowledge of MAOIs has made these agents worthy of reconsideration
Discuss this article at www.facebook.com/CurrentPsychiatry
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.
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
Recommended dosages of monoamine oxidase inhibitors
Usual therapeutic dosage
10 mg twice a day
30 to 60 mg/d
15 mg twice a day
45 to 90 mg/d
6 mg patch/d
6 to 12 mg patch/d
10 mg, 2 or 3 times a day
30 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.10,11
Several controlled trials have found a better response rate to MAOI therapy in outpatients with MDD who have not responded to other antidepressants.2,12 In a 6-week, double-blind trial, Vallejo et al10 reported that the TCA imipramine and high-dose phenelzine were equally efficacious in 32 patients with major depression with melancholia. In 32 dysthymic patients, high-dose phenelzine was superior to imipramine. Himmelhoch et al13 compared efficacy of tranylcypromine with that of imipramine in treating anergic bipolar depressive illness. Patients receiving tranylcypromine experienced significantly greater symptomatic improvement and higher global response without increased risk of treatment-emergent hypomania or mania.
Serum monitoring of MAOIs is not clinically indicated and there are no correlations between drug levels and effectiveness.14 In a study that examined the correlation of inhibiting platelet MAO and MAOIs’ antidepressant effects, researchers found that a higher dose of phenelzine (60 mg/d) was significantly better in treating depression and anxiety than a lower dose (30 mg/d), and only the higher dose achieved 80% of platelet MAO inhibition.15 Further studies with other MAOIs did not reproduce this effect and platelet MAO inhibition is not regularly used to assess adequate dosing.
A refined view of side effects
Clinicians often consider hypertensive crisis to be the most serious side effect of MAOIs. Many clinicians recommend that their patients wear bracelets stating they are taking MAOIs in case they become unconscious in an emergency. Consumption of tyramine, a substrate for the MAO enzyme, may trigger a hypertensive crisis. Although the exact mechanism by which tyramine causes hypertensive crises is unknown, it is thought that if a patient with depleted MAO levels ingests tyramine, it may displace intracellular norepinephrine, leading to a rapid rise in blood pressure. Hypertensive crises are rare among patients who adhere to a tyramine-free diet.
In a hypertensive crisis, patients experience significant hypertension, headaches, tachycardia, diaphoresis, and vomiting. Intravenous phentolamine—an α-adrenergic receptor blocker—can be used as an antidote; often a single dose is effective.16 Alternatively, calcium channel blockers such as nifedipine can be prescribed. A patient can take 10 mg/hour and be observed in the emergency room until symptoms are relieved (usually only 1 or 2 doses are needed) without being admitted to the hospital.
Dietary restrictions. In the 1970s and 1980s, the “MAOI diet” list of prohibited foods contained >70 items. As patients on an overly inclusive diet began to “cheat,” they struggled to differentiate foods that were moderately safe from those that were highly dangerous. Over time, in addition to foods that contained tyramine, foods that contained compounds that caused symptoms similar to those of a hypertensive crisis were added to many MAOI diets. For example, chocolate, which contains phenylethylamine, is associated with migraine headaches, which can be confused with MAOI-related emergencies. Likewise, tannic acids found in red wines caused similar symptoms. In recent years, the number of “forbidden foods” on the MAO diet has decreased. Table 24,17,18 contains an up-to-date list of foods with elevated tyramine content, based on systematic reviews and more rigorous evaluations of tyramine content of foods.
Food restrictions with MAOIs
Use in moderation (≤2 servings/d)
Red wine (4 oz)
Mild to none
Potential drug-drug interactions. Concomitant use of SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), opioids, clomipramine, epinephrine, local anesthetics containing sympathomimetic agents, and decongestants with MAOIs could cause serotonin syndrome. Serotonin syndrome is characterized by hypertonicity, autonomic signs, hallucinations, rhabdomyolysis, and hyperthermia, and can be fatal if not promptly treated. Treatment is guided by presentation severity and discontinuing the causative medications is of utmost importance. Interventions include aggressive treatment for hyperthermia, including external cooling and hydration, and supportive care such as administering IV fluids.
Orthostatic hypotension is a common cardiovascular side effect of MAOIs that may lead to dizziness or syncope. Typically this is seen 2 to 3 weeks after initiating MAOI treatment. If hypotension remains a problem, mineralocorticoids can be prescribed with monitoring of serum potassium for hypokalemia. Increasing doses of tranylcypromine can increase supine—but not standing—diastolic blood pressure.19 Distinguish this type of blood pressure elevation from a hypertensive crisis by monitoring blood pressure with the patient sitting and standing and before and after he or she walks for 60 seconds.
Insomnia and day-night shifting—sleeping during the day and staying awake at night—are common and patients often cite these as reasons for discontinuing MAOIs. Many patients who respond to MAOIs report periods of substantial sleepiness in the mid to late afternoon. Table 320 provides a more complete list of reported side effects and their frequencies.
MAOIs: Stay vigilant for side effects
Common side effects
Anxiety, blurred vision, constipation, dizziness, headache, insomnia, mania, somnolence, weight gain, xerostomia
Constipation, disorder of ejaculation and/or orgasm, dizziness, edema, fatigue, headache, hyperreflexia, impotence, elevated values on liver function tests, orthostatic hypotension, sleep disorders, somnolence, tremor, weight gain, xerostomia
Application site reaction, decreased systolic blood pressure, diarrhea, headache, indigestion, insomnia, orthostatic hypotension, weight loss, xerostomia
Agitation, anxiety, constipation, diarrhea, dizziness, headache, impotence, insomnia, loss of appetite, mania, nausea, orthostatic hypotension, somnolence, weight gain, xerostomia
MAOIs: monoamine oxidase inhibitors
The American Psychiatric Association’s practice guidelines for treating major depression state that MAOIs are effective in treating subgroups of patients with MDD with atypical features who have failed TCA trials.21 These guidelines also state that MAOIs have been shown to be effective treatment for some patients who have failed other antidepressants. However, for TRD patients who have not responded to SSRIs or SNRIs, the effectiveness of MAOIs compared with other strategies is unclear.22
One study found adding lithium to an MAOI may provide more rapid or more efficacious response than MAOI monotherapy.23 Guze et al24 evaluated the effects of high-dose MAOI treatment for 2 TRD patients; both patients improved without any side effects.
MAOIs have been used for >6 decades, and published studies continue to document their efficacy and safety when patients are monitored appropriately.11,12,14,15,25 However, based on our observations we suspect MAOIs are underutilized in clinical practice today. We are concerned that such practices can trickle down into residency training programs. Psychiatric residents typically do not receive adequate training in prescribing MAOIs, largely because many training faculty are not prescribing MAOIs themselves. Despite MAOIs’ limitations, concerns about an increased risk of suicide in patients with TRD26 and the high likelihood of a poor outcome associated with persistent nonresponse to prior treatments must be weighed against the relatively low risk of a hypertensive event with MAOIs.6