During the past decade, a spate of monoamine oxidase–B (MAO-B) inhibitors has been investigated for use in the treatment of Parkinson’s disease (PD). Since PD is characterized by the death of dopaminergic neurons and MAO-B is responsible for the breakdown of dopamine, MAO-B inhibitors have been explored both as stand-alone therapies and as adjuncts to standard levodopa therapy. While MAO inhibitors (MAOIs) are useful drugs that show promise in treating PD, ingestion of these agents can be associated with considerable risks, necessitating close monitoring of patients’ diets and other drug regimens. In this article, 3 MAO-B inhibitors are reviewed, including those already approved (selegiline, rasagiline) and one that has shown potential benefit in PD (safinamide).

Parkinson’s disease (PD) is an aging-related movement disorder that results from a deficiency of the neurotransmitter dopamine (DA) in the striatum of the brain.¹ This reduction in DA is due to a decrease in the number of dopaminergic neurons in the substantia nigra, causing depletion of DA along the nigrostriatal pathway.^1,2 Although the molecular mechanism of DA cell death in sporadic PD remains undetermined, the enzyme MAO-B is believed by some investigators to play a pivotal role.¹ With aging, the activity of MAO-B increases, likely because of increases in numbers of glial cells, and the number of DA neurons diminishes.^1,3 Type B is also the primary MAO isoform responsible for the metabolic degradation of DA released from neurons.⁴ MAOIs that have selectivity and specificity for MAO-B inhibit DA metabolism, increasing synaptosomal DA concentrations, enhancing striatal dopaminergic activity, and improving motor symptoms.^5,6

Two MAO-B inhibitors—selegiline and rasagiline—are currently approved for the treatment of PD in the United States. Therapeutic doses of these agents have similar degrees of selectivity for inhibition of MAO-B vs MAO-A, and this selectivity diminishes in a dose-dependent fashion.^7,8

Selegiline is indicated as adjunctive therapy to levodopa for individuals with PD who exhibit deterioration in the quality of their response to levodopa treatment.⁹ Although initial studies of selegiline did not demonstrate an improvement in motor function, its modest symptomatic effect has complicated later studies of possible effects on disease progression beginning with the pivotal DATATOP trial in early PD.^10,11 However, the most recent of several studies of long-term outcomes in patients with early PD found that selegiline was associated with slower disease progression (according to scores on the Unified Parkinson Disease Rating Scale [UPDRS]) as well as lower dose of levodopa compared to placebo at 7 years.¹² In more advanced PD, the use of selegiline as an adjunct to levodopa has been shown to extend “on” time with patients with wearing off, but the data have been inconsistent, perhaps due to the poor and erratic bioavailability of the parent drug.^7,13 Conventional oral selegiline tablets undergo extensive hepatic first-pass metabolism, which reduces bioavailability and produces high levels of the metabolites L-methamphetamine and L-amphetamine.^14,15 A new orally disintegrating tablet (ODT) formulation, designed for transmucosal absorption, avoids first-pass hepatic metabolism, increases bioavailability of the parent drug, and reduces the formation of amphetamine metabolites. 7 In 2 identically designed 3-month trials, selegiline ODT significantly improved both “off” and “on” time, without dyskinesia, in 1 study but failed to improve “on” time in the other (“off” time was not a primary endpoint).^16,17

Rasagiline is indicated for use as either initial monotherapy or as an adjunct to levodopa in patients with PD.¹⁸ The pivotal trial of this agent as monotherapy was the Rasagiline (TVP-1012) in Early Monotherapy for Parkinson’s Disease Outpatients (TEMPO) study.¹⁹ Patients with early PD were randomized to receive rasagiline 1 or 2 mg once daily or placebo for 6 months, at which point the placebo group switched to rasagiline 2 mg once daily (“delayed-start” cohort) and all participants received active treatment for the next 6 months.^19,20 The “delayed-start” design of TEMPO was used to separate symptomatic effects of therapy from potential disease-modifying effects.⁴ Both rasagiline doses produced significantly greater improvements in total scores on the UPDRS than placebo did at 6 months (P<0.001).¹⁹ At 1 year, UPDRS scores were significantly better in the “early-start” than in the “delayed-start” cohort (P<0.05).²⁰ If the effects of the rasagiline were purely symptomatic, no significant difference in UPDRS scores would be expected after 6 months of comparable therapy in the 2 groups.²⁰ Therefore, the observations suggested a disease-modifying effect of rasagiline therapy.

Recently, an analysis of long-term outcomes in an open-label extension of TEMPO revealed an adjusted mean difference in change from baseline in total UPDRS scores of 2.5 units (P=0.021), or 16% (P=0.0006), at 6.5 years, favoring early-start vs delayed-start rasagiline.²¹ The participants were allowed to receive any additional approved PD medications (except selegiline) at the investigator’s discretion. The authors commented that the findings suggest early initiation of rasagiline therapy may offer clinical advantages over delaying treatment for 6 months, and these benefits may be enduring as well as apparent even when patients are treated with other medications for PD.²¹