Journal
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
Volume 19, Issue 1, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ijnp/pyv078
Keywords
Moclobemide; monoamine oxidase-A; monoamine oxidase inhibitors; phenelzine; positron emission tomography
Funding
- Canadian Institutes of Health Research (CIHR)
- Ontario Mental Health Foundation (OMHF)
- CIHR
Ask authors/readers for more resources
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 [C-11] 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,F-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,F-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available