J Psychiatry Neurosci 2011;36(6):375-82
Julia Sacher, MD, PhD; Sylvain Houle, MD, PhD; Jun Parkes, MSc; Pablo Rusjan, PhD; Sandra Sagrati, PhD; Alan A. Wilson, PhD; Jeffrey H. Meyer, MD, PhD
Sacher, Houle, Parkes, Rusjan, Sagrati, Wilson, Meyer — Vivian M. Rakoff PET Imaging Centre; Sacher, Sagrati, Meyer — Mood and Anxiety Disorders Division, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Toronto, Ont.; Sacher — Day Clinic of Neurology, University of Leipzig, and Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
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 antidepressants for this target.
Submitted July 14, 2010; Revised Oct. 29, Nov. 12, 2010; Accepted Nov. 16, 2010.
Acknowledgments: This research received project support from the Canadian Institutes of Health Research (CIHR), the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Canada Foundation for Innovation (CFI), the Alexander von Humboldt Foundation (AvH), the Ontario Mental Health Foundation (OMHF), the Ontario Ministry of Research and Innovation, and GlaxoSmith Kline.We thank research analysts Leslie Jacobs and Laura Miler, secretary Jinoos Sotodeh, technicians Alvina Ng and Jeannie Fong, chemistry staff Armando Garcia, Winston Stableford and Min Wong, physicist Peter M. Bloomfield, and engineers Terry Bell and Ted Brandts-Harris for their assistance with this project and Dr. Dana Tudorascu for help with R software.
Competing interests: See above. Dr. Sacher declares having received a University of Toronto Faculty of Psychiatry Travel Award and an Alexander von Humboldt Foundation postdoctoral fellowship salary award. Drs. Meyer, Wilson and Houle have received operating funding from Lundbeck, Bristol-Myers Squibb and GlaxoSmithKline in the past 12 months, and it is likely that companies that make antidepressants that affect monoamine receptor or monoamine oxidase binding will seek collaborations with these investigators in the future. None of these companies participated in the design or execution of this study or writing the manuscript. Dr. Meyer declared having consulted for SK Life Sciences, Sepracor, Bristol-Myers Squibb, GlaxoSmithKline, Lundbeck and Eli Lilly. He has received grants from SK Life Sciences, Lundbeck, Eli Lilly, Bristol-Myers Squibb and GlaxoSmithKline. None declared for Drs. Houle, Rusjan, Sagrati and Wilson and Mrs. Parkes.
Contributors: Drs. Sacher, Houle and Meyer designed the study. Drs. Sacher, Houle, Sagrati, Wilson and Meyer and Mrs. Parkes acquired the data, which Drs. Sacher, Houle, Rusjan and Meyer and Mrs. Parkes analyzed. Dr. Sacher wrote the article, which Drs. Houle, Rusjan, Sagrati, Wilson and Meyer and Mrs. Parkes reviewed. All authors approved its publication.
Correspondence to: Dr. J.H. Meyer, College Street Site, Centre for Addiction and Mental Health, PET Centre, 250 College St., Toronto ON M5T 1R8; firstname.lastname@example.org