A good explanation of how MAOIs work, what makes them different from other antidepressants, and some of the side effects you might want to watch out for.

"MAO inhibitors worked much better for me than tricyclics. But for a chocoholic, the dietary restrictions were torture. That's why I finally stopped taking them."

-- Marie, 42

Soon after scientists developed tricyclic antidepressants, another group of chemicals very different from the tricyclics rolled out of the laboratory -- the monoamine oxidase (MAO) inhibitors. These new drugs affected the same neurotransmitters (serotonin and norepinephrine) that the tricyclics did, but they also affected dopamine.

How They Work

Once the brain's three neurotransmitters, known as monoamines (serotonin, norepinephrine, and dopamine), have played their part in sending messages in the brain, they get burned up by a protein in the brain called monoamine oxidase, a liver and brain enzyme.

Antidepressants known as monoamine oxidase inhibitors work by blocking this cleanup activity. When the excess neurotransmitters don't get destroyed, they start piling up in the brain. And since depression is associated with low levels of these monoamines, it's not surprising that increasing the monoamines ease depressive symptoms.

Unfortunately, monoamine oxidase doesn't just destroy those neurotransmitters; it's also responsible for mopping up another amine called tyramine, a molecule that affects blood pressure. So when monoamine oxidase gets blocked, levels of tyramine begin to rise, too. And that's when the trouble starts.

While a hike in neurotransmitters is beneficial, an increase in tyramine is disastrous. Excess tyramine can cause a sudden, sometimes fatal increase in blood pressure so severe that it can burst blood vessels in the brain.

Every time you eat chicken liver, aged cheese, broad-bean pods, or pickled herring, tyramine floods into your brain. Normally, MAO enzymes take care of this potentially harmful tyramine excess. But if you're taking an MAO inhibitor, the MAO enzyme can't stop tyramine from building up. This is exactly what happened when the drugs were introduced in the 1960s. Because no one knew about the tyramine connection, a wave of deaths from brain hemorrhages swept the country. Other patients taking MAO inhibitors experienced severe headaches caused by the rise in blood pressure. These early side effects were particularly disturbing because nobody knew why they were happening.

The mystery was solved when a British pharmacist noticed that his wife, who was taking MAO inhibitors, got headaches when she ate cheese. But the early MAOIs were considered so dangerous (they also can damage the liver, brain, and cardiovascular systems) that even after the MAO-tyramine connection was finally understood, these drugs were taken off the American market for a time. (A related European antidepressant drug, Deprenyl, is marketed in this country as an anti-Parkinson's medication; it requires less stringent dietary cautions.)

Eventually the MAOIs were reintroduced in this country despite the tyramine risk because some depressed people don't respond to any other medication. Nevertheless, MAO inhibitors are usually the antidepressant of last resort.

"I call it the 'St. Jude' drug," says psychiatrist Andy Myerson. "It's the drug I use when nothing else works and someone is willing to give up anything in the hope that something will help their depression."

Types of MAO Inhibitors and Their Dosages

MAO Inhibitor

isocarboxazid (Marplan)

Usual Starting Dose: 30 mg/day

Maximum Dose: 30 mg/day

phenelzine (Nardil)

Usual Starting Dose: 15 mg/day

Maximum Dose: 60 mg/day

tranylcypromine (Parnate)

Usual Starting Dose: 30 mg/day

Maximum Dose: 60 mg/day