Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. Johns wort an 11C-harmine PET study.
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. Johns wort, an herb purported to have MAO-A inhibitor properties. 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. Johns 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. 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. Johns wort did not significantly alter MAO-A VT. 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. Johns wort is less than 5%. For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. Johns 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.