Monoamine Oxidase Inhibitors: An Old-School Treatment Option for Depression

Brief Overview

Just like SSRIs are considered a “class of antidepressants,” MAOIs, or Monoamine Oxidase Inhibitors, are in a class of their own. MAOIs work by blocking the enzyme responsible for the breakdown of certain neurotransmitters, such as norepinephrine and serotonin. There are two forms of this enzyme (MAO-A and MAO-B), and drugs can block one or both of them. MAOIs are shown to increase serotonin, norepinephrine, dopamine, and tyramine. There is not a large selection of antidepressants work on all three of these neurotransmitters and even fewer are available that increase dopamine specifically. MAOI’s are generally under-utilized in practice due to so many other treatment options, as well as common myths and misinformation about these powerful medications.

Function

Oral Mechanism of Action: At recommended doses, MAOI function to selectively and irreversibly inhibits the action of MAO-B, which boosts neurotransmission of dopamine in the brain. Above recommended doses, MAOIs function to irreversibly blocks both MAO-A and MAO-B by decreasing the degradation of serotonin, norepinephrine, and dopamine in the brain and gastrointestinal system while simultaneously inhibiting the metabolism of tyramine in the gastrointestinal system (Stahl, 2017). This inability to metabolize tyramine coupled with ingesting moderate amounts of foods and beverages containing tyramine is what can lead to the life-threatening reaction called “hypertensive crisis.”

Transdermal Mechanism of Action: At recommended doses, irreversibly inhibits both MAO-A and MAO-B from degradation of serotonin, norepinephrine, and dopamine which boost the levels of these neurotransmitters in the brain. While in the gastrointestinal system, irreversibly blocks both MAO-B reducing the chances of dietary interactions (Stahl, 2017).

MAOIs Currently Available in the United States:

Isocarboxazid (Marplan): Tablet Strength: 10 mg. Usual Dosing Range: 40–60 mg/day
Phenelzine (Nardil): Tablet Strength: 15 mg. Usual Dosing Range: 45–75 mg/day
Tranylcypromine (Parnate): Tablet Strength: 10 mg. Usual Dosing Range: 30 mg/day in divided doses
Selegiline (Emsam): Transdermal Patch Strength: 6 mg/24 hr, 9 mg/24 hr, 12 mg/24 hr. Capsule Strength: 5 mg. Tablet Strength: 5 mg. Orally disintegrating tablet: 1.25 mg. Usual Dosing Range: 6 mg/24 hr–12 mg/24 hr. or 30-60 mg/day (oral tablet).

Why Use MAOIs?

MAOIs are typically only used as a second- or third-line option for managing treatment-resistant depression or atypical depression, after the following options have been tried and failed: SSRIs, SNRIs, and combinations of new antidepressants. MAOIs can help address some somatic symptoms of depression, eating and sleeping disturbances, and psychomotor disturbances. There is less risk of weight gain and sexual dysfunction with MAOIs (Stahl, 2017). The most common reason a MAOI would be prescribed is for treatment resistant depression, but other less common indications include: Atypical Depression, Bipolar Depression, Treatment-Refractory Depression, Treatment-Resistant Depression, Treatment-Resistant Panic Disorder, Treatment-Resistant Social Anxiety Disorder. MAOI medication is not typically prescribed as a first line treatment for psychiatric illness such as MDD, Bipolar Depression, Panic Disorder, or Social Anxiety (Culpepper, 2013; Fiedorowicz & Swartz, 2004).

Foods To Know

There are several foods containing tyramine that should be completely avoided due to the increased risk of having a hypertensive crisis. High doses of a MAOI, especially MAOI-A, may interact with tyramine-containing foods and beverages and can result in potentially lifethreatening adverse reactions such as a hypertensive crisis (Stahl, 2017).

What is a Hypertensive Crisis? A hypertensive crisis is defined as a systolic blood pressure >180 mm Hg or a diastolic blood pressure >120 mm Hg. A hypertensive crisis can either be classified as a hypertensive urgency or hypertensive emergency, depending on end-organ involvement – including cardiac, renal, and neurological injury (Rodriquez et al., 2010). If you suspect you are having a hypertensive crisis, you should call 911 or seek immediate medical attention.

Dietary Guidelines- Foods and Beverages to Avoid:

Meat: Beef/Chicken Liver, Fermented/Dry Sausages (Pepperoni, Salami, Mortadella), Summer Sausage, Improperly Stored/Spoiled/Dry/Aged Meat and Poultry
Fish: Caviar, Cured Fish, Dried or Pickled Herring, Shrimp Paste Products, Improperly Stored/Spoiled/Dry/Aged Fish
Fruits and Vegetables: Fava Beans, Broad Bean Pods, Banana Peel (Not actual Banana), Overly Ripe Fruits and Vegetables
Milk Products: Matured and Aged Cheese
Yeast: Homemade Yeast Bread, Sourdough Bread, Concentrated Yeast Food Products
Pickled and Fermented Products: Kimchee, Sauerkraut, Pickles, Kefir, Tofu, Tempeh, Kombucha
Desserts: Soy Based Ice Cream, Marmite/Vegemite
Alcohol: Tap/Draft Beer, Home Brewed Beer, Red Wine, Chianti, Vermouth, Sherry
Beverages: Coffee (Limited Consumption) and Milk Alternatives
Miscellaneous: Meat Extract Bouillon Cubes or Broth and Soy Based Meat

Medications To Know

There are several types of medications that should be completely avoided due to the increased risk of Serotonin Syndrome! All medications, including over the counter medications, should be discussed with the provider prescribing the MAOI.

What is Serotonin Syndrome? - A potentially life-threatening syndrome caused by an over activation of serotonin receptors, which can occur when multiple serotonergic medications are taken (Volpi-Abadie et al., 2013). MAOIs pose the highest risk for causing serotonin syndrome, especially when combined with a SSRI. Serotonin syndrome is most likely to occur between two and seventy-two hours after initiation of treatment. Symptoms of serotonin syndrome typically fall into three categories: neuromuscular hyperactivity (e.g., myoclonus, rigidity, tremors, incoordination), altered mental status (e.g., agitation, confusion, hypomania), and autonomic instability (e.g., hyperthermia, diaphoresis). If you suspect you might have serotonin syndrome after starting or new drug or increasing the dose of a drug you’re already taking, call your doctor right away or go to the emergency room. If you have severe or rapidly worsening symptoms, seek emergency treatment immediately (Sub Laban & Saadabadi, 2021).

Prescription Medication to Avoid:

Antidepressants (SSRIs, SNRIs, most Tricyclics, Clomipramine, and other MAOIs)

Stimulants (ADHD stimulant medications, Modafinil, Armodafinil, and Phentermine)

Pain Medications (Tramadol, Meperidine, Fentanyl, Methadone, cyclobenzaprine)

OTC Medication to Avoid: St. John’s Wort, Dextromethorphan, Decongestants (pseudoephedrine and phenylephrine), Chlorpheniramine, Brompheniramine

Other Medications to Avoid: Carbamazepine, Oxycarbazepine, Non-subcutaneous sumatriptan

[Avoid stimulant drugs of abuse: Cocaine, MDMA, Methamphetamine]

[Use Antihypertensive and Diuretics with caution]

Side Effects

The most common side effects of MAOIs are dry mouth, nausea, diarrhea, constipation, headache, drowsiness, insomnia, dizziness or lightheadedness, sedation, fatigue, and skin reaction at the patch site (Mayo Foundation for Medical Education and Research, n.d.).

Less serious but notable side effects can include: involuntary muscle jerks, tremor, low blood pressure (orthostatic hypotension), weakness, blurred vision, increased sweating, change in appetite, weight gain, muscle cramps, prickling or tingling sensation in the skin (parenthesis), difficulty starting the flow of urine, and sexual dysfunction (reduced sexual desire or difficulty reaching orgasm) (Stahl, 2017).

Serotonin syndrome and a hypertensive crisis are the most serious and potentially life-threatening adverse side effects an individual would potentially experience from taking MAOIs. Other dangerous side effects can also include induction of mania, seizures, hepatotoxicity, and rare activation of suicidality (Stahl, 2017).

Initiating Therapy

Prior to initiating therapy with MAOI medication, a review of all current prescriptions, herbal supplements, and over the counter medications should be performed. Medications contraindicated with the use of a MAOI should be discontinued or tapered off prior to initiation of therapy, known as the “wash-out” period. Patients should be off any contraindicated medications, including antidepressants for at least 2 weeks prior to starting the MAOI. A longer time is needed for tapering off medications, such as Fluoxetine, that have a longer half-life. This transition period should be carefully explained by the prescribing provider, as severely depressed individuals may be more susceptible to an exacerbation of symptoms and risk of suicide.

A general rule when transitioning from an antidepressant to an MAOI, is to be titrated completely off the serotonergic drug for 5-7 half-lives before starting the MAOI.

Phenelzine (Nardil) is manufactured in a dosage form of 15 mg tablets and is initially started in 3 divided doses of 45 mg/day. Depending on effectiveness, the clinician may increase the dosage to 60-90 mg/day. Maximum Dosage: 90 mg/day.
Isocarboxazid (Marplan) is manufactured in a dosage form of 10 mg tablets and initially started in divided doses twice daily. Every 2-4 days, the clinician can increase the dosage by 10 mg/day divided twice to four times daily. Maximum Dosage: 60 mg/day.
Tranylcypromine (Parnate) is manufactured in a dosage form of 10 mg tablets and initially started in divided doses of 30 mg/day. After 2 weeks, the clinician, depending on effectiveness, can increase the dosage by 10 mg/day every one to three weeks. Maximum Dosage: 60 mg/day.
Selegiline (Emsam) is manufactured in a transdermal patch and comes in 6 mg/24 hours, 9 mg/24 hours, and 12 mg/24 hours. Selegiline (Emsam) is initially started transdermal 6 mg/24 hours. Every 2 weeks, the clinician, depending on effectiveness, can increase the dosage by 3 mg/24 hours. Maximum Dosage: 12 mg/24 hours (Fiedorowicz & Swartz, 2004). Selegiline (Emsam) is the first transdermal treatment option for depression.

References

Culpepper, L. (2013). Reducing the burden of difficult-to-treat major depressive disorder. The Primary Care Companion For CNS Disorders. https://doi.org/10.4088/pcc.13r01515

Fiedorowicz, J. G., & Swartz, K. L. (2004). The role of monoamine oxidase inhibitors in current psychiatric practice. Journal of Psychiatric Practice, 10(4), 239–248. https://doi.org/10.1097/00131746-200407000-00005

Mayo Foundation for Medical Education and Research. (n.d.). Monoamine oxidase inhibitors (maois). Mayo Clinic. Retrieved June 29, 2021, from Https://www.mayoclinic.org/diseases-conditions/depression/in-depth/MAOIs/art20043992

Rodriguez, M., Kumar, S. K., & De Caro, M. (2010). Hypertensive crisis. Cardiology in Review, 18(2), 102–107. https://doi.org/10.1097/crd.0b013e3181c307b7

Stahl, S. M. (2017). Stahl's essential psychopharmacology: Prescriber's guide (6th ed.). Cambridge University Press. Sub Laban, T., & Saadabadi, A. (2021). Monoamine oxidase inhibitors (maoi). In StatPearls [Internet]. StatPearls Publishing. https://doi.org/https://www.ncbi.nlm.nih.gov/books/NBK539848/

Volpi-Abadie, J., Kaye, A. M., & Kaye, A. D. (2013). Serotonin syndrome. The Ochsner Journal, 13(4), 533–540. https://doi.org/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865832