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- Title
Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.
- Authors
Chiuccariello, Lina; Cooke, Robert G.; Miler, Laura; Levitan, Robert D.; Baker, Glen B.; Kish, Stephen J.; Kolla, Nathan J.; Rusjan, Pablo M.; Houle, Sylvain; Wilson, Alan A.; Meyer, Jeffrey H.
- 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 [11C]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 doseoccupancy 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 (45-60 mg) 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 300-600 mg 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.
- Subjects
MONOAMINE oxidase; MOCLOBEMIDE; PHENELZINE (Drug); MONOAMINE oxidase inhibitors; PARKINSON'S disease
- Publication
International Journal of Neuropsychopharmacology, 2016, Vol 19, Issue 1, p1
- ISSN
1461-1457
- Publication type
Article
- DOI
10.1093/ijnp/pyv078