Depression can occur if some of the neurotransmitters (chemicals that carry messages between nerve cells) in the brain are not functioning effectively. Released by one part of nerve cells, the neurotransmitters float across the synapse (the space between nerve cells) to stick on specific places known as receptors on other cells. Occupying the receptors activates the second nerve cell to release additional neurotransmitters that keep the message going along the nervous system. Once they have delivered their messages, neurotransmitters are either broken down by enzymes or taken back into the nerves in a process known as reuptake.

The three main neurotransmitters involved in depression are dopamine, norepinephrine, and serotonin (also known as 5-HT). In Canada, Europe, and other areas of the world, norepinephrine is known as noradrenaline. When brain levels of one or more neurotransmitter are low or unbalanced, depression and other conditions can result. Generally, antidepressant drugs work by increasing the production or decreasing the breakdown of one or more neurotransmitter.

For example, monoamine oxidase inhibitors (MAOIs) block the effects of monoamine oxidase (MAO), one of the main enzymes that break down neurotransmitters. MAO has two major subtypes?MAO-A (concentrated mostly in the intestines, liver, and stomach) and MAO-B (found mainly in the brain and blood platelets). MAO-A is known to break down norepinephrine and serotonin as well as some components in food. Both MAO-A and MAO-B break down dopamine. The older MAOIs (isocarboxazid, phenelzine, and tranylcypromine) block both subtypes of MAO, while selegiline works mainly on MAO-B. Blocking MAO causes the concentrations of dopamine, norepinephrine, and/or serotonin to remain at higher levels, relieving depression.

Although many different types of depression are known, two main categories are atypical depression and melancholic depression. Atypical depression is more common. Individuals who have it are more sensitive to rejection or insults; they may gain weight and sleep more than usual; and they become happier when something positive happens. On the other hand, patients with depression of the melancholic type generally are sad all the time; their moods are worse in the morning; and they lose weight. MAOIs are more effective for atypical depression than for melancholic depression. Patients with very severe depression may not respond as well to MAOIs as they do to other types of antidepressants.

Due to their many interactions and to their relatively high potential for causing side effects, MAOIs typically are used after other types of antidepressants have been tried. They may even be added to therapy with another kind of antidepressant. Many foods that contain a chemical known as tyramine (including alcohol, bananas, caffeine, aged cheese, chocolate, nuts, smoked or salted meats, and yogurt) must be avoided when an older MAOI is taken because the combination can lead to a dangerously fast increase in blood pressure. In addition, isocarboxazid, phenelzine, and tranylcypromine have a high probability of causing side effects such as blurry vision, constipation, dizziness, headache, muscle aches, nausea, shaking, sleep disturbances, and weight gain. Individuals taking an older MAOI have also experienced heart rhythm changes, sexual problems, a rapid drop in blood pressure, and other possibly serious side effects. Using selegiline patches does not have limits on foods and fewer side effects are attributed to using them.

Currently, no strong evidence firmly recommends any individual antidepressant or even any of the antidepressant classes for every situation. Not all patients will respond to the same antidepressant and an individual?s response may change over time. Often, a different antidepressant in the same class will be effective, but sometimes a change to a different type of antidepressant is needed. Patients with resistant or recurring depression may need to take two or more antidepressants from different classes at the same time. The choice of an antidepressant depends on multiple factors that include:

• the type of depression being treated
• the doctor's experience
• any other medical conditions the patient may have
• other medications the patient takes
• the patient?s response to previous therapy
• the patient?s prescription formulary

Drugs in this Class
Isocarboxazid (Marplan)
Tranylcypromine (Parnate)
Phenelzine Tablets (Nardil Tablets, Phenelzine Sulfate Tablets)

Summarizing the Evidence

Only a few studies have compared MAOIs with each other for the treatment of depression. One analysis revealed generally comparable overall effectiveness for isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate) for depressed patients who were not hospitalized.

For 67 patients with severe depression that was not relieved by a tricyclic antidepressant (TCA) or the selective serotonin reuptake inhibitor (SSRI), fluvoxamine, both phenelzine and tranylcypromine worked for about half the patients taking them during a 5-week study. About one-fifth of the patients in each group had serious side effects such as dizziness and insomnia, however.

Phenelzine

• Based on studies done in the 1980s, phenelzine produces a response in more than 60 percent of the patients who take it to treat atypical depression. Side effects and interactions limit its use, however.
• A study of 105 patients compared the effects of phenelzine with the tricyclic antidepressant (TCA), amitriptyline. Both drugs treated depression about equally well and their side effects were similar. Patients taking phenelzine also felt their anxiety was relieved, but patients taking amitriptyline had more relief of sleeping problems and weight loss.
• When compared in a 3-week study of 43 patients, phenelzine was as effective for relieving depression and anxiety as imipramine (a tricyclic antidepressant or TCA).
• In a one-year long follow-up of 51 older patients whose depression had been treated successfully, 15 patients took phenelzine, 13 took nortriptyline (a tricyclic antidepressant or TCA), and 23 others took inactive placebo pills. Only 13 percent of the patients taking phenelzine experienced a return of depression, but 54 percent of the nortriptyline group and 65 percent of the placebo group did.
• One 7-week long study compared the effects of phenelzine, placebo (inactive sugar pills), and nortriptyline (a tricyclic antidepressant or TCA) for elderly patients with depression. Generally, both phenelzine and nortriptyline produced results in about 60 percent of the patients taking them. Only about 13 percent of the placebo-treated patients achieved relief.

Selegiline

• Newer than the other MAOIs, selegiline (Emsam) is more targeted for MAO-B. Since it does not affect MAO-A as much, it does not cause gastrointestinal (GI) side effects and it has fewer interactions with food or other drugs than the older MAOIs. Additionally, because selegiline for treating depression comes as a transdermal patch instead of an oral tablet, it enters the blood directly, which also limits its side effects and prevents its inactivation in the liver.
• One study involved 322 patients who had responded to 10 weeks of treatment with selegiline patches (Emsam). For the following year, half of the patients used selegiline patches and half used identical, but inactive placebo patches. Depression, which was relieved for longer amounts of time for the patients using selegiline, came back for about 17 percent of the patients in the selegiline group as compared to about 31 percent in the placebo group.
• In an analysis of safety studies that included over 2,000 patients who used selegiline patches and 668 patients who used inactive placebo patches, selegiline was found to have no interactions with food. The most common side effects were insomnia and irritation at the sites where the patches were placed.

Tranylcypromine

• Results of several small studies done in the 1970s and 1980s suggest that tranylcypromine was effective for about half of the patients who did not respond to treatment with a tricyclic antidepressant (TCA). Many of the TCAs used in the studies are not available in the United States; however, and newer antidepressants may be as effective with fewer side effects and less chance of interfering with other drugs. Patients with a particular type of bipolar disorder seemed to be especially responsive to tranylcypromine. Bipolar disorder (formerly known as manic-depressive disorder) includes periods of depression and episodes of excessive happiness.

Dosing and Administration

• The usual initial adult dose of isocarboxazid is 20 mg per day (taken as two doses of 10 mg each) and it may be increased to a maximum of 60 mg per day divided into two, three, or four equal doses.
• Generally, 15 mg phenelzine tablets are taken three times daily when therapy is started. The recommended total daily maintenance dose for adult patients is 60 mg to 90 mg daily, but some patients may be maintained on as little as 15 mg once every other day.
• Selegiline comes as patches that are applied to the skin once daily. Available dosages are 6 mg per 24 hours, 9 mg per 24 hours, and 12 mg per 24 hours.
• Typically, tranylcypromine tablets are taken twice daily. The recommended effective dose for adults is 30 mg per day, but as much as 60 mg per day may be needed to control depression for some patients.

Generic Availability

Currently, only tranylcypromine is available generically.

Drug Interactions

Some interactions between medications can be more severe than others. The best way for you to avoid harmful interactions is to tell your doctor and/or pharmacist what medications you are currently taking, including any over-the-counter products, vitamins, and herbals. For specific information on how the drugs interact and the severity of the interaction, please use our Drug Interactions Checker.

Side Effects

To view specific side effect information, please use our Side Effect Checker.

Additional Information

In the last few years, some study results and case reports suggested that taking antidepressants was linked with an increase in suicides, attempted suicides, and thinking about suicide?especially in young individuals. Generally, the risk is higher in first month or so and then appears to decrease as the body adjusts to the medication. Whether depressed individuals are more likely to attempt or commit suicide despite therapy is unknown. Nevertheless, in 2004, the FDA required the manufacturers of all antidepressants to include on their labels the following safety warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.

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Last Updated: March 2008

Note: The above information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist, or other healthcare professional. It should not be construed to indicate that the use of the product is safe, appropriate, or effective for you. Consult your healthcare professional before taking any medication.

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