Monoamine oxidase a inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: An [11C]-harmine PET study

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 [11c]-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. limitations: 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%. conclusion: 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 dring 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 anti-depressants for this target. © 2011 canadian medical association.