The Use of MAOIs in Primary Care

Larry Culpepper, MD, MPH

Department of Family Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts

Once the mainstay of antidepressant treatment, MAOIs have largely been abandoned in favor of newer medications with improved safety profiles. Although MAOIs have proven efficacy for treating depression, primary care physicians have avoided them, mainly due to dietary restrictions and the potential for serious side effects and drug interactions. However, despite the use of newer antidepressants, about 30% of patients with MDD do not reach remission after 1 year and several treatment steps,1 and continuing subsyndromal symptoms, chronicity, and recurrent episodes remain problems for many patients.2–4 Adverse effects such as weight gain and sexual dysfunction also may limit the usefulness of some antidepressants.

From the 1960s until the early 1990s, evaluating for depressive subtype was a tool for guiding treatment choice because research had shown that some subtypes of depression responded better to certain antidepressants than to others. Atypical depression, for example, was considered more responsive to MAOIs than to TCAs. With the introduction of SSRIs, which were seen as useful for all depressive subtypes, the interest in depressive subtypes waned. But, with the continued presence of patients who do not respond to first-line therapies, the increased knowledge and skill of primary care physicians in managing depression, and the availability of a safer MAOI formulation, a re-examination of the usefulness of MAOIs is warranted.

Understanding MAOI Mechanisms of Action

MAO is a mitochondrial enzyme that deaminates and inactivates excess dopamine, serotonin, and norepinephrine neurotransmitters; the therapeutic effect of MAOIs is achieved through inhibition of MAO in the brain.5 One of the 2 identified isomers of MAO, MAO-A, is found primarily in the intestine and in brain regions with serotonin, norepinephrine, dopamine, and tyramine substrates, whereas MAO-B is concentrated in platelets and in the brain regions that are rich in serotonergic neurons.

Nonselective MAOIs (phenelzine, isocarboxazid, and tranylcypromine) and the selective MAOI selegiline are effective for depression (moclobemide is also an effective selective MAOI but is not available in the United States).5 MAOIs that are available in the United States have irreversible action, meaning that they permanently bind MAO for the life of the enzyme, and a period of 7 to 10 days is needed for the enzyme to be regenerated.

MAOI Adverse Effects

AV 1. Medications Contraindicated With MAOIs (00:26)

aFound in cold products, weight-reducing preparations, general anesthesia, and some local anesthetics
Abbreviations are defined before the References

The most frequently reported side effects of oral MAOIs include insomnia, sedation, and hypotension.6 Long-term adverse effects include weight gain and sexual dysfunction, although the literature is inconclusive about whether these effects occur to the same extent as with SSRIs.

A serious adverse effect, serotonin syndrome, has been reported as a result of the interaction between MAOIs and other serotonergic agents (AV 1).7 When using MAOIs, a washout period of about 2 weeks is recommended before switching to or from contraindicated medications, and a washout period of 5 weeks is required when switching from fluoxetine, which has a long half-life.8 Care should also be taken when prescribing MAOIs with drugs containing vasoconstrictors or other medications that can increase the risk of hypertensive crisis.


AV 2. Dietary Restrictions with MAOI Use: Some Foods to Avoid (00:48)

Based on Gardner et al9
Dietary restrictions not required for 6 mg/24 h dose of transdermal selegiline
Abbreviations are defined before the References

Both selective and nonselective MAOIs require dietary restrictions that limit tyramine intake (AV 2).9 In the intestines, MAO-A metabolizes dietary tyramine and thus restricts the uptake of tyramine into the circulatory system. Orally administered MAOIs inhibit this protective effect, so dietary tyramine is absorbed in larger quantities. Once in the systemic circulation, tyramine triggers norepinephrine release, causing a rapid increase in blood pressure; high levels of dietary tyramine entering the circulatory system can lead to hypertensive crisis.6

To avoid the potential for hypertensive crisis, a transdermal formulation of the MAOI selegiline was developed. Transdermal delivery via an adhesive skin patch allows the drug to be directly absorbed into the blood stream, which lowers the dosage needed for an antidepressant effect and minimizes exposure of the GI tract to the drug.10 The selegiline transdermal system also provides a marked reduction in absorption peaks and valleys compared with oral selegiline. No hypertensive crises have been reported at any dose of the selegiline patch, and dietary restrictions are not required at the lowest dose (6 mg/24 h); due to limited data documenting safety, however, dietary restrictions are still required at higher dosages. Except for application site reactions and insomnia, the tolerability profile of transdermal selegiline (including the potential for weight gain and sexual side effects) is similar to that of placebo.11

Patients for Whom MAOIs Should Be Considered

Based on the perceived difficulty of using MAOIs, APA treatment guidelines12 recommend their use only for patients who have not responded to other treatments. Studies13,14 have shown that MAOIs are effective in patients with TCA-resistant depression. However, data support the usefulness of MAOIs for other subgroups of patients, as well. For instance, a meta-analysis13 showed that MAOIs were more effective than TCAs for patients with atypical depression, which is generally characterized by persistent vegetative symptoms (hyperphagia, hypersomnia, and leaden paralysis) coupled with sensitivity to rejection.15 Atypical symptoms are present in as many as 40% of patients with depression and appear to be stable over repeated episodes of major depression.16 MAOIs have also demonstrated efficacy for anxiety disorders, including panic disorder, and for anergic bipolar depression.5 Patients with treatment-resistant depression should be evaluated for features of atypical depression, anxiety/phobias, and anergic bipolar depression because MAOIs may help to bring about remission in these patients.

Transdermal selegiline should also be considered for patients who have experienced intolerable adverse effects, particularly weight gain or sexual side effects, with other medications. Additionally, transdermal selegiline has a more favorable metabolic profile than other evidence-based second- or third-line medications (ie, atypical antipsychotics).


Over the past decade, primary care physicians have become more experienced and skilled in treating MDD, but they continue to have patients who either do not respond or who only partially respond to newer antidepressants. MAOIs have proven efficacy for depression, particularly for patients with treatment-resistant depression, atypical depression, high levels of anxiety, and anergic bipolar depression. MAOIs have declined in use because of their potential for severe side effects and drug interactions, but newer formulations avoid the need for dietary restrictions due to the possibility of hypertensive crises and have fewer metabolic and sexual side effects than some newer medications. Due to its ease of administration and low prevalence of side effects, transdermal selegiline may be particularly suited for use in primary care.

For Clinical Use


  • Understand the mechanism of action of MAOIs in order to minimize serious side effects and drug interactions
  • Consider MAOIs for patients who have treatment-resistant depression, atypical depression, high levels of anxiety, or anergic bipolar depression or who have experienced intolerable side effects from other antidepressants
  • Use a transdermal delivery system for patients who are concerned about dietary restrictions or metabolic and sexual side effects


Drug Names

bupropion (Wellbutrin, Aplenzin, and others), cyclobenzaprine (Amrix, Flexeril, and others), fluoxetine (Prozac and others), isocarboxazid (Marplan), meperidine (Demerol and others), mirtazapine (Remeron and others), phenelzine (Nardil), selegiline oral formulation (Eldepryl, Zelapar, and others), selegiline transdermal system (EMSAM), tranylcypromine (Parnate and others)


APA = American Psychiatric Association, GI = gastrointestinal, MAO = monoamine oxidase, MAOI = MAO inhibitor, MDD = major depressive disorder, SNRI = selective norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant

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