Transdermal Patch Could Herald Renewed Popularity for MAOIs

Bodkin and Jay Alexander, M.D., director of the Depression Research Unit at the University of Pennsylvania School of Medicine, compared 177 adult outpatients with major depression, randomly assigning 89 to receive the active selegiline patch, and 88 randomly assigned to receive a placebo patch. After a one-week washout during which all subjects wore a placebo patch, the subjects completed a six-week blinded comparison. All subjects followed dietary restrictions commonly used when taking MAO inhibitors.

Response to medication or placebo was primarily gauged by the 17-item Hamilton Depression Rating Scale (HamD), with the Montgomery-Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) severity and improvement subscales as additional outcome measures.

At the end of the six weeks, patients wearing the selegiline patch saw greater improvement on all measures compared with placebo. Average scores on the HamD improved by 38 percent for those on selegiline versus 26 percent for those on placebo. A similar difference was seen in the Montgomery-Asberg ratings, with a 34 percent reduction for subjects taking selegiline and a 19 percent reduction for those on placebo. Thirty-seven percent of those on selegiline achieved remission, characterized by a 50 percent reduction in their HamD score or a final HamD score below 8, compared with 22 percent on placebo. In addition, 42 percent of those wearing the selegiline patch were rated as “much improved” or “better” on the CGI compared with 27 percent of those wearing the placebo patch.

MAO inhibitors have generally been considered to have robust efficacy in depression, especially in cases of atypical or treatment-resistant depression. Their use has been severely limited, however, by adverse effects tied to interactions with enzymes in the gastrointestinal tract.

The MAO family of enzymes are found throughout the body, with high concentrations in the liver, kidney, stomach, intestinal wall, and brain. They are generally broken down into two types, MAO-A and MAO-B. Type A is predominantly found in the gastrointestinal tract, while type B is predominant in brain tissues. Both types are responsible for the breakdown of catecholamines, including dopamine, epinephrine, norepinephrine, and serotonin in brain tissues.

In the GI tract, MAO is responsible for breaking down amines absorbed through dietary intake. When the process is inhibited in the GI tract, potentially high amounts of amines—in particular dietary tyramine, found in most cheeses, beer, wine, and many vegetables and fruits—can be absorbed.

High blood levels of these amines can lead to hypertensive crisis, stroke, and heart attack and can be fatal.

Administering an MAO through a transdermal patch offers several benefits. First, according to Bodkin, lower doses of the drug are required because bypassing the GI tract allows the drug to be absorbed directly into the blood without undergoing “first-pass metabolism,” the initial metabolism of the drug as it is processed in the liver after absorption.

Second, in the case of selegiline, at lower doses, Bodkin said, the drug is a fairly selective MAO-B inhibitor. As such, the MAO-A necessary for dietary amine control is not affected, greatly reducing the risk of hypertensive adverse effects.

In the present study, the only common significant side effect was a local skin irritation or reaction at the site of application of the selegiline patch (36 percent of those with selegiline compared with 17 percent wearing placebo). Notably, no subjects experienced any clinically significant elevations of blood pressure.

“So, now we have a way of getting an MAO inhibitor antidepressant to the brain without interfering with the MAO in the digestive system,” Bodkin said in a press release. “Close to 20 percent of treated patients with depression do not do as well as they could. With selegiline in patch form, there will be a significant number of people who can get much better.”