Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

Abstract

Background: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing.

Methods: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine.

Results: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01].

Conclusions: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

Keywords: Moclobemide; monoamine oxidase inhibitors; monoamine oxidase-A; phenelzine; positron emission tomography.

Figure 1.

Relationship between monoamine oxidase-A occupancy and dose of moclobemide. The data were fit using the hyperbolic equation F_(0,0) = a(x/[b + x]). (A) Depicted here are a selected number of brain regions; however, the model significantly fit the data in each brain region tested. (B) Relationship between monoamine oxidase-A occupancy and dose of moclobemide for each brain region fit using the hyperbolic equation F_(0,0) = a(x/[b + x]).

Figure 2.

Monoamine oxidase-A occupancy higher in high doses of moclobemide (900–1200mg) and phenelzine (45–60mg) than low doses of moclobemide (300–600mg). There was a significant main effect of doses of moclobemide (1200mg and 900mg) and phenelzine (45 and 60mg) on occupancy across brain regions sampled when compared to the average clinical doses of moclobemide [300, 450, and 600mg; MANOVA, F_(7,16) = 3.94, p = 0.01].