AAN 2011: Novel Selegiline Delivery Can Inhibit Brain MAO-A with Lower Tyramine Risk -- Implications for Parkinson's Disease

Selegiline delivered either transdermally or in an orally dissolving tablet can inhibit monoamine oxidase A in the brain without elevating the risk of hypertensive crisis from dietary tyramine, according to a study presented at the 63rd Annual Meeting of the American Academy of Neurology.

The imaging study, while performed in normal volunteers, has important implications for treatment of depression in Parkinson's disease (PD), according to lead investigator Stanley Fahn, MD, of Columbia University Medical Center in New York.

Monoamine oxidase occurs in two forms, A and B. Monoamine oxidase B (MAO-B) in the brain breaks down dopamine, and selective MAO-B inhibitors, including selegiline, have been used in PD for many years based on their ability to prevent dopamine breakdown and provide motor benefit. The brain also contains MAO-A, and nonselective MAO inhibitors are established treatments for depression.

At high enough doses, selective MAO-B inhibitors also spill over to inhibit MAO-A, but at the standard doses used in PD, oral selegiline in pill form has never been shown to inhibit MAO-A in the brain. Fahn said it may be clinically valuable to increase the dose of selegiline, in order to allow it to have a spillover effect on MAO-A in the brain, to alleviate depression, which occurs in up to half of PD patients.

But MAO-A is also active in the GI tract in processing dietary tyramine. Inhibition of MAO-A in the gut can lead to hypertensive crisis, the so-called “cheese effect,” because aged cheeses, along with fermented meats and red wine, contain large amounts of tyramine.

Delivery forms that avoid the GI tract have the potential to allow higher doses to reach the brain without triggering the cheese effect, Fahn said. EMSAM is a transdermally delivered form of selegiline, approved for treatment of depression. It has not been tested for its use in PD. Zelepar is an orally dissolving tablet approved for adjunctive therapy in PD.

In order to explore whether higher doses of selegiline may safely allow MAO-A inhibition in the brain, Fahn enrolled 21 normal, healthy volunteers to undergo PET scanning before and after treatment with a standard dose of EMSAM or with Zelepar at one of three doses. MAO-A brain activity was measured using an MAO-A specific radioactive tracer, clorgyline.

After treatment, MAO-A activity declined by 33% in subjects treated with 6 mg EMSAM, and by 5%, 9%, and 37% in subjects treated with 2.5 mg, 5 mg, and 10 mg Zelepar, respectively. The standard starting dose of EMSAM in treatment of depression is 6 mg, and for Zelepar in treatment of PD is 2.5 mg. Treatment did not lead to hypertension in any subjects.

These results suggest that non-pill forms of selegiline can achieve significant brain inhibition of MAO-A while avoiding the cheese effect, Fahn said, pointing out their potential for treatment of depression in PD. The next direction for the research is to expand it to PD patients, including those on levodopa, he said.

The study was funded by Valeant Pharmaceuticals