Vivian M. Rakoff PET Imaging Centre, University of Toronto, Toronto, Ont.
J Psychiatry Neurosci. 2011 Nov;36(6):375-82. doi: 10.1503/jpn.100117.
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.
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.
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.
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%.
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.
单胺氧化酶 A（MAO-A）抑制剂抗抑郁药会提高多种单胺类物质的水平，而选择性 5-羟色胺再摄取抑制剂（SSRIs）仅提高细胞外 5-羟色胺水平。尽管 MAO-A 抑制剂有这样的优势，但与 SSRIs 相比，MAO-A 抑制剂的开发频率要低得多。我们试图在接受临床有效剂量的选择性 MAO-A 抑制剂治疗的抑郁症患者中测量 6 周后的大脑 MAO-A 占有率，并测量重复给予贯叶连翘（一种据称具有 MAO-A 抑制剂特性的草药）后 MAO-A 占有率。
参与者接受了 2 次[11C]- harmine 正电子发射断层扫描。健康对照者完成了一项测试-重测条件，而抑郁症患者在接受重复莫昔康或贯叶连翘治疗 6 周后，在指定剂量下接受扫描。我们测量了前额叶、前扣带回和前颞叶皮质、纹状体、丘脑、中脑和海马的 MAO-A VT，这是 MAO-A 密度的指标。
我们的研究包括 23 名参与者（10 名对照者和 13 名患有重度抑郁症[MDD]的患者）。与对照组相比，接受莫昔康治疗的 MDD 患者的 MAO-A VT 在所有区域均显著降低（重复测量方差分析，F1，15=71.08-130.06，p<0.001 所有区域，平均占有率 74%[6%]）。贯叶连翘的治疗并未显著改变 MAO-A VT。
占有率估计受到每个治疗组样本量的限制；因此，我们对莫昔康总占有率 74%的估计置信区间为 70%-78%，我们可以有 95%的把握估计贯叶连翘的占有率小于 5%。
对于新的 MAO-A 抑制剂，在稳态给药时达到 74%的占有率是理想的。与这一结论一致，贯叶连翘不应被归类为 MAO-A 抑制剂。莫昔康治疗期间 MAO-A 阻断的幅度至少比疾病期间 MAO-A 结合增加 30%，这表明在设计针对该靶点的选择性抗抑郁药时，治疗效果应该超过疾病效果。
