The U.S. Food and Drug Administration (FDA) granted final approval February 28 to market the skin-patch formulation of the monoamine oxidase inhibitor (MAOI) selegiline for the treatment of major depression.

The new skin patch, developed by Somerset Pharmaceuticals, will be marketed in the U.S. by Bristol-Myers Squibb Company under the brand name Emsam.

In announcing the approval, Steven Galson, M.D., M.P.H., director of the FDA's Center for Drug Evaluation and Research, noted, "Emsam provides a significant advance because, at least in the lowest dose, patients can use the drug without the usual dietary restrictions associated with these types of drugs."

MAOIs have long been considered highly effective, particularly in patients with atypical depression, which DSM-IV-TR characterizes as presenting with "mood reactivity, increased appetite or weight gain, hypersomnia, leaden paralysis, and a long-standing pattern of extreme sensitivity to perceived interpersonal rejection."

However, use of MAOIs has also been limited by the drugs' ability to block the monoamine oxidase enzyme (MAO) not only in the central nervous system, but throughout the body.

The highest concentrations of MAO are found in the liver, kidney, stomach, intestinal wall, and brain. MAOs are subclassified into two types, A and B, which differ in their specificity and actions, as well as where each is found in the body. In humans, most of the MAO in the brain is type B, while in the digestive tract, for example, MAO is predominantly type A.

In brain neurons, MAO plays an important role in the metabolism of the catecholamines dopamine, norepinephrine, and epinephrine, and to a lesser extent serotonin. As such, MAOIs are commonly referred to as "triple amine drugs." MAOs are also important in the metabolism of various amines found in a variety of foods and drugs.

MAO in the GI tract and liver (primarily type A), for example, is thought to provide protection from high blood levels of the amine, tyramine. Tyramine has the capacity, if absorbed intact, to cause a "hypertensive crisis," also known as the "cheese reaction," because tyramine is found in large amounts in fermented cheese, red wine, herring, and over-the-counter cough/cold medications. High amounts of tyramine lead to the release of excessive amounts of norepinephrine from adrenergic neurons throughout the body. It is this release of norepinephrine that causes the rise in systemic blood pressure.

In theory, at the doses of selegiline used therapeutically in the skin patch (for example, 10 mg a day), MAO-A in the gut is not inhibited, which would free patients from having to watch diet and other medications that could also increase tyramine levels or stimulate release of norepinephrine. At higher doses, selegiline inhibits both MAO-A and MAO-B.

The Emsam patch will be available in doses equivalent to 6 mg, 9 mg, and 12 mg absorbed in a 24-hour period. Clinical trials data on the 6 mg dose showed no inhibition of MAO-A, and therefore the lowest dose will not be labeled with patient warnings regarding diet. However, both the 9 mg and 12 mg patches will carry dietary warnings.

In addition, Somerset and BMS have agreed to develop a patient-education campaign regarding dietary modifications necessary when using the two higher doses. The companies have pledged to monitor reports of adverse events.

In clinical trials, the most common treatment-emergent adverse events included skin reaction to the patch (24 percent with Emsam, 12 percent with placebo), headache (18 percent versus 17 percent), insomnia (12 percent versus 7 percent), and diarrhea (9 percent versus 7 percent).

Alexander Bodkin, M.D., chief of the Clinical Psychopharmacology Research Program at Harvard University/McLean Hospital, noted that the need for other treatment options "is indeed great: some 30 percent of all patients who seek treatment and receive SSRIs or SNRIs do not respond to the medication. Many then end up taking combinations of two or more antidepressants in an attempt to get an effect on all three monoamines, such as an SSRI plus bupropion or CNS stimulants. With selegiline, all three monoamines are covered, and the data show onset of action is very quick—within the first day to seven days." Bodkin was a principal investigator on several clinical trials of the Emsam patch.

More information is posted at<www.bms.com>.▪