Journal Article

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

Lina Chiuccariello, Robert G Cooke, Laura Miler, Robert D Levitan, Glen B Baker, Stephen J Kish, Nathan J Kolla, Pablo M Rusjan, Sylvain Houle, Alan A Wilson and Jeffrey H Meyer

in International Journal of Neuropsychopharmacology

Published on behalf of Collegium Internationale Neuro-Psychopharmacologicum

Volume 19, issue 1 ISSN: 1461-1457
Published online August 2015 | e-ISSN: 1469-5111 | DOI:

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  • Clinical Pharmacology and Therapeutics
  • Neurology
  • Psychiatry
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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.


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


Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45–60mg 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 (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01].


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-A; monoamine oxidase inhibitors; phenelzine; positron emission tomography

Journal Article.  7909 words.  Illustrated.

Subjects: Clinical Pharmacology and Therapeutics ; Neurology ; Psychiatry ; Neuroscience

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