title: 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.
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Lina
authors: L
authors: Chiuccariello
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Robert G
authors: RG
authors: Cooke
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Laura
authors: L
authors: Miler
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Robert D
authors: RD
authors: Levitan
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Glen B
authors: GB
authors: Baker
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Stephen J
authors: SJ
authors: Kish
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Nathan J
authors: NJ
authors: Kolla
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Pablo M
authors: PM
authors: Rusjan
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Sylvain
authors: S
authors: Houle
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker).
authors: Alan A
authors: AA
authors: Wilson
authors: CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusjan, Houle, Wilson, and Meyer, and Ms Miler); Department of Psychiatry (NRU) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada (Dr Baker). jeff.meyer@camhpet.ca.
authors: Jeffrey H
authors: JH
authors: Meyer
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006247:Harmine / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D020912:Moclobemide / Q000494:pharmacology*; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics*; D015999:Multivariate Analysis; D010624:Phenelzine / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D055815:Young Adult
chemical_list: D002247:Carbon Isotopes; D008996:Monoamine Oxidase Inhibitors; D006247:Harmine; D008995:Monoamine Oxidase; D010624:Phenelzine; D020912:Moclobemide
keywords: Moclobemide; monoamine oxidase inhibitors; monoamine oxidase-A; phenelzine; positron emission tomography