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

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Sacher,  Julia
Vivian M. Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, ON, Canada;
Mood and Anxiety Disorders Division, Centre for Addiction and Mental Health, University of Toronto, ON, Canada;
Department of Psychiatry, University of Toronto, ON, Canada;
Clinic for Cognitive Neurology, University of Leipzig, Germany;
Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society;

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Citation

Sacher, J., Houle, S., Parkes, J., Rusjan, P., Sagrati, S., Wilson, A. A., et al. (2011). Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: An [(11)C]-harmine PET study. Journal of Psychiatry & Neuroscience, 36(6), 375-382. doi:10.1503/jpn.100117.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0011-594E-B
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 [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 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 anti-depressants for this target.