Monoamine Oxidase Inhibitors MAOIs

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Monoamine Oxidase Inhibitors MAOIs

Definition

Monomanie oxidase inhibitors (MAOIs) are a class of antidepressants most often used to treat atypical depression . MAOIs carry the risk of dangerous dietary side effects, so they are prescribed only after other antidepressants prove ineffective.

Purpose

The mood-altering effects of MAOIs were initially discovered in the 1940s during efforts to use the first MAOI as a tuberculosis therapy. The drug was ineffectual against tuberculosis, but the patients taking it reported enhanced mood. Based on these results, MAOIs were used in the 1950s in clinical trials for patients with depression. It was discovered that the drugs’ common property was inhibition of monoamine oxidase (also called MAO), an enzyme that breaks down mood-regulating neurotransmitters , including dopamine , serotonin, and norepinephrine and epi-nephrine (also known as noradrenaline and adrenaline ). By inhibiting the enzyme that breaks down these chemicals, MAOIs allow these neurotransmitters to persist and exert their mood-enhancing effects longer. One class of MAOIs also has recently been developed as a therapy for Parkinson’s symptoms.

MAOIs were in widespread use from the 1960s through the 1980s, but fell out of favor as newer drugs with fewer potentially severe side effects and interactions (see below) came on the market. However, the interest in them has been renewed, especially as therapy for major depressive disorder with atypical features and for treatment-resistant depression.

Description

MAOIs can be divided into two main groups. The first group encompasses the nonselective, systemic, irreversible MAOIs, and includes phenelzine (Nar-dil), isocarboxazid (Marplan), and tranylcypromine (Parnate), which are approved by the U.S. Food and Drug Administration for treatment of depression. They are considered nonselective because they target both types of MAOs: MAO-A and MAO-B. Their action is called “irreversible” because they bind the enzyme so strongly that even after a person stops taking them, two or three weeks must pass before the drugs degrade and normal enzymatic activity resumes.

The second group consists of the selective inhibitors, which inhibit either MAO-A or MAO-B, as the name implies. Those that inhibit MAO-A, which include moclobemide (Aurorix, Manerix) and brofar-omine (Consonar) are also known as RIMAS (reversible inhibitors of MAO-A). As discussed below, the use of a selective inhibitor can help prevent some of the food-drug interactions associated with the nonselec-tive inhibitors. RIMAS are not approved for use in the United States.

Also in the second group are inhibitors of MAO-B. These drugs, which include selegiline (Eldepryl) and rasagiline (Azilect), are not used orally for treatment of depression but instead are used in very low doses for treatment of Parkinson’s symptoms. Because low dop-amine levels are associated with Parkinson’s symptoms, and these drugs block the MAO that breaks down dopamine, their effect of increasing dopamine levels has proved beneficial. At higher dosages, however, these MAO-B–inhibiting drugs become nonselective inhibitors, targeting both MAO-A and MAO-B and exerting antidepressant effects. In addition to their potential use in Parkinson’s treatment, these MAO-B inhibitors hold promise as therapies for attention deficit/hyperactivity disorder , stimulant abuse , and smoking cessation .

A low-dose, transdermal selegiline patch (Emsam) has recently been approved by the FDA for treatment of depression.

Recommended dosage

Dosages of MAOIs vary depending on the specific drug. Most are taken orally, but selegiline has been tested in the form of a transdermal patch that lessens exposure in the gastrointestinal tract, preventing some of the food-drug interactions associated with MAOIs (see “Interactions” for more information).

Nonselective MAOIs

Isocarboxazid as antidepressant: oral tablets. Adults will initially take 10 mg/2x/day. The health care provider may gradually increase the dose, but the recommended maximum is no more than 60 mg/day. Dosage for children under the age of 16 will be determined by their doctors.

Phenelzine as antidepressant: oral tablets. The adult dose is based on body weight; initially, it is 0.45 mg/lb (1 mg/kg) per day to a maximum dose of no more than 90 mg/day. The dosage for children under age 16 years is to be determined by their doctors. For older adults, the initial dose is 15 mg in the morning. This dosage can be increased but to no more than 60 mg/day.

Tranylcypromine as antidepressant: oral tablets. The adult dose is 30 mg/day to start. It can be increased, but to no more than 60 mg/day. The doctor should determine dosages for children under the age of 16. In older adults, the regimen is 2.5–5 mg/day to start. This dosage can be increased as needed, but usually to no more than 45 mg/day.

Selective MAOIs

Transdermal selegiline patch as antidepressant: The patch is available in three sizes that deliver 6, 9, or 12 mg/day through the skin. It should be applied to dry, intact skin on the upper torso (below the neck and above the waist), upper thigh, or outer surface of the arm every 24 hours.

Oral selegiline: This low-dose MAOI is intended for management of Parkinson’s symptoms. The drug is not to be used at daily doses exceeding 10 mg/day, and this dose should be split into two doses of 5 mg each, taken at breakfast and lunch. Exceeding the 10-mg limit can shift the drug’s activity into nonselective inhibition, precipitating food interactions (see “Interactions” below). Oral selegiline is usually taken in conjunction with dopamine-boosting drugs, such as levodopa (also called L-dopa), although it also appears to be effective when used alone.

Oral rasagiline: This MAOI is intended for management in Parkinson’s disease. The recommended dose is 1 mg once daily if taken alone. If taken in conjunction with levodopa, the recommended starting dose is 0.5 mg once a day, which can be increased to 1 mg a day if necessary.

Precautions

Dietary

For systemic, nonselective MAOIs (isocarboxazid, phenelzine, tranylcypromine) used as antidepres-sants, certain foods should be avoided. These include foods high in tyramine (see “Interactions” below), a chemical found in foods that have been fermented or aged, including cheeses, fava beans, yeast- or meat-based extracts, meat that has been smoked or pickled, some kinds of sausages (for example, pepperoni or salami), sauerkraut, and overripe fruit. The health care provider should supply anyone prescribed these MAOIs with a list of foods to avoid. Also avoid alcohol and large amounts of caffeine.

For people using the selegiline patch with the lowest level of delivery (6 mg/day) or taking oral selegiline at low doses for Parkinson’s disease, dietary adjustment is not indicated; however, people using the 9 or 12 mg/day patches should observe dietary restrictions to avoid foods containing tyramine, like those required for the nonselective MAOIs.

Other medications

People taking MAOIs must be sure to let their health care provider know if they are taking any other medications or drugs, especially the following:

other antidepressant medications, such as fluoxetine (Prozac) or sertraline (Zoloft)
some anticonvulsants, such as carbamazepine (Eque-tro and oxcarbazepine (Trileptal)
opioids, such as meperidine (Demerol)
dextromethorphan, a component of many cough suppressant medications
decongestants or appetite suppressants containing ephedrine, pseudoephedrine, phenylephrine, or pheny-lpropanolamine
antihypertensive medications
ciprofloxacin (Cipro)
stimulants, especially amphetamines
asthma medication
insulin or antidiabetic medication
cocaine
tryptophan as a supplement or as a sleep aid (see “Interactions,” below)
St. John’s wort

Medical problems

People taking MAOIs must tell their health care provider of other medical problems, especially:

alcohol abuse
chest pain
headaches asthma
diabetes
kidney disease
epilepsy
heart or blood vessel disease, recent heart attack or stroke, high blood pressure
mental illness or a history of mental illness
Parkinson’s
hyperthyroidism

Pregnancy

There is an increased risk of birth defects when the nonselective, classic MAOIs are taken during the first three months of pregnancy. Selegiline is classified as a pregnancy category C drug (this category indicates that animal reproduction studies showed an adverse effect on the fetus and that adequate and well-controlled studies in humans are lacking; however, potential benefits may outweigh potential risks for pregnant women in some cases).

Breastfeeding

Tranylcypromine passes into the breast milk; the status of the other two nonselective MAOIs is unknown. Selegiline passes into the milk of rodents, but it is unknown whether or not it passes into human breast milk. No studies on rasagiline in human breast milk have been done.

Children

In clinical trials, these antidepressants increased the risk of suicidal thinking and behavior in children and adolescents with psychiatric disorders, including major depressive disorder. The average risk in pediatric trials for patients taking these drugs was twice that of patients taking placebo (4% vs. 2%, respectively).

Note

It is important to remember that even after a patient has stopped taking an MAOI, he must continue to exercise precautions for at least two weeks because of the irreversible nature of these inhibitors.

Side effects

A person taking MAOIs must watch for symptoms of very high blood pressure. These include chest pain, enlarged pupils, fast or slow heartbeat, sensitivity to light, increased sweating, nausea or vomiting, and stiff or sore neck.

Other potential side effects include nervous system effects, such as dizziness or lightheadedness (can be common), headache, drowsiness, sleep disturbances, fatigue , weakness, and tremors. Gastrointestinal side effects can include either constipation or diarrhea, and dry mouth. A person taking an MAOI may experience weight gain, or, in the case of selegiline, weight loss. A sudden drop in blood pressure with a change in posture is possible, as is swelling in the feet or lower legs. Some people have reported sexual disturbances, including impotence or an inability to experience orgasm. Urinary changes may include decreased fluid volume or more frequent urination.

Specific to the selegiline patch, the only commonly reported side effect was an occasional skin reaction at the application site. A less commonly seen side effect of the patch was lightheadedness related to low blood pressure.

Interactions

Food-drug

One important role of MAO is breaking down tyramine, the compound in foods that have undergone

KEY TERMS

Cheese reaction —Common term for the high blood pressure crisis that can occur when nonse-lective monoamine oxidase inhibitors are combined with dietary tyramine, a chemical often associated with aged cheeses.

Dopamine —A neurotransmitter involved in maintaining mood; low levels play a role in the manifestation of symptoms of Parkinson’s disease.

MAO —Monoamine oxidase, an enzyme that degrades signaling molecules involved in mood maintenance.

MAOI —Monoamine oxidase inhibitor, a class of drugs that inhibits the enzyme monoamine oxidase.

Tyramine —A chemical found in aged and fermented foods that is normally broken down by monoamine oxidase; when the enzyme’s activity is blocked, tyramine passes into the body system and can cause a critical high blood pressure event.

aging or fermentation. Normally, because MAO is active, consuming these foods does not result in much tyramine entering the system. However, when an MAOI interferes with the activity of MAO, tyramine from these foods does enter the system and can elicit what has been called the “cheese reaction” (related to the association of tyramine with aged cheeses). This response can be life-threatening because of tyramine’s effects on heart rate and blood pressure; the cheese reaction can produce a severe spike in blood pressure, leading to a hypertensive crisis. For this reason, people taking classic, nonselective MAOIs must avoid foods that contain tyramine and continue this avoidance for at least two weeks after they stop taking the drug. As mentioned above, people on the lowest dose (6 mg) of the selegiline patch do not need to exercise any tyramine-related dietary modifications.

Users of MAOIs also will be advised about limiting tryptophan consumption, especially in the form of supplements.

Drug-drug interaction

The drugs listed in the precautions section, especially other antidepressants, anticonvulsants, opioids, dextromethorphan, decongestants, and amphetamines, should be avoided. Patients using MAOIs should be sure to mention any drugs they are taking to their doctor.

Resources

PERIODICALS

Amsterdam, Jay D., M.D., and J. Alexander Bodkin. “Selegiline transdermal system in the prevention of relapse of major depressive disorder. A 52-week, double-blind, placebo-substitution, parallel-group clinical trial.” Journal of Clinical Psychology26 (2006): 579-586.

Howland, Robert H. “MAOI antidepressant drugs.” Journal of Psychosocial Nursing44 (2006):9-12.

Youdim, Moussa B. H., Dale Edmondson, and Keith F. Tipton. “The therapeutic potential of monoamine oxidase inhibitors.” Nature Reviews Neuroscience 7(2006):295-309.

PRODUCT LABELING

Eldepryl® capsule product labeling. Somerset Pharmaceuticals, Inc. (1998).

Emsam® product labeling. Somerset Pharmaceuticals, Inc. (2006).

Nardyl® product labeling. Pfizer/Parke-Davis. (2006).

WEB SITES

“Antidepressants, Monoamine Oxidase (MAO) Inhibitor (Systemic).” Mayo Clinic. Available online at http://www.mayoclinic.com/health/drug-information/DR202054 (accessed January 06, 2007).

“FDA approves Emsam (selegiline) as first drug patch for depression.” US Food and Drug Administration new release. Available online at http://www.fda.gov/bbs/topics/NEWS/2006/NEW01326.html (accessed January 06, 2007).