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 [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 300–600mg 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].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.

The effect of electroconvulsive therapy on cerebral monoamine oxidase A expression in treatment-resistant depression investigated using positron emission tomography

“…This was further underlined by a direct comparison (paired t-test) of change scores of MAO-A V T between PET1 and PET2 (both baseline scans) and those between PET2 and PET3 which was not significant. A reduction of MAO-A V T of 3e4% is unlikely to have clinically meaningful effects given that MAO-A occupancies range between 74 and 87% for moclobemide at different dosages and around 87% for phenelzine [37]. Therefore, our finding does not effectively support the hypothesis of a clinically relevant mechanism of action of ECT based on cerebral MAO-A expression.…”

“…Furthermore, increased MAO-A expression has been associated with the early postpartum period [33], perimenopause [34], and severe, atypical depression [35]. Brain MAO-A availability was shown to be affected by moclobemide and MAO-A occupancy levels of 74% were proposed as a desirable threshold level to have therapeutic impact in MDD [36,37].…”

Kinetics, mechanism, and inhibition of monoamine oxidase

“…Moclobemide, a reversible inhibitor (Bonnet 2002), requires twice daily administration to give a therapeutic occupancy rate of about 74% for MAO A, whereas a single daily dose (10 mg/kg) of the irreversible inhibitor tranylcypromine gave 58% occupancy (reviewed in (Fowler et al 2015)). Effective antidepressant effect is evident at around 80% for both moclobemide and phenelzine (Chiuccariello et al 2016)…”

Harmine and its derivatives: Biological activities and therapeutic potential in human diseases

“…Harmine treatment (20 mg/kg) improved BDNF expression on hippocampal neurogenesis and up-regulated GLT-1 activity . Accumulated data by the researchers acclaim that inhibition of monoamineoxidase A (MAO-A) is associated with antidepressant efficacy of harmine (Chiuccariello et al, 2015;Sacher et al, 2015;Balint et al, 2017;Hamid et al, 2017;Meyer, 2017). Harmine (300 nM) was also reported to augment dopamine efflux by an innovative and 5 -HT(2A) receptor-dependent mechanism (Brierley and Davidson, 2013).…”