title: Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: an [11C]-harmine PET study.
abstract: BACKGROUND
  Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John's wort, an herb purported to have MAO-A inhibitor properties.
  
  
  METHODS
  Participants underwent 2 [(11)C]-harmine positron emission tomography scans. Healthy controls completed a test-retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John's wort for 6 weeks at the assigned dose. We measured MAO-A VT, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus.
  
  
  RESULTS
  We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A VT decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F1,15 = 71.08-130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John's wort did not significantly alter MAO-A VT.
  
  
  CONCLUSIONS
  The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%-78%, and we can estimate with 95% certainty that the occupancy of St. John's wort is less than 5%.
  
  
  CONCLUSIONS
  For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John's wort should not be classified as an MAO-A inhibitor. The magnitude of MAO-A blockade during moclobemide treatment exceeds the elevation of MAO-A binding during illness by at least 30%, suggesting that the treatment effect should exceed the disease effect when designing selective antidepressants for this target.
authors.affiliation: Vivian M. Rakoff PET Imaging Centre, University of Toronto, Toronto, Ont.
authors.forename: Julia
authors.initials: J
authors.lastname: Sacher
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Jun
authors.initials: J
authors.lastname: Parkes
authors.forename: Pablo
authors.initials: P
authors.lastname: Rusjan
authors.forename: Sandra
authors.initials: S
authors.lastname: Sagrati
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Meyer
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D002250:Carbon Radioisotopes; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D006247:Harmine; D006801:Humans; D020902:Hypericum; D008297:Male; D008875:Middle Aged; D020912:Moclobemide / Q000494:pharmacology* / Q000627:therapeutic use; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008517:Phytotherapy / Q000523:psychology; D028321:Plant Preparations / Q000494:pharmacology* / Q000627:therapeutic use; D049268:Positron-Emission Tomography / Q000379:methods / Q000523:psychology; D011869:Radioligand Assay / Q000379:methods
chemical_list: D002250:Carbon Radioisotopes; D008996:Monoamine Oxidase Inhibitors; D028321:Plant Preparations; D006247:Harmine; D008995:Monoamine Oxidase; D020912:Moclobemide