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

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 [(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.

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.

Fig. 1

Monoamine oxidase A (MAO-A) binding pre- and posttreatment. Regional MAO-A binding in depressed patients after moclobemide treatment (300 mg twice daily) for 6 weeks (black triangles), and after St. John’s wort administration (600 mg twice daily) for 6 weeks (grey triangles), and in healthy controls (test–retest data; empty triangles). Monoamine oxidase A V_T values from the first positron emission tomography (PET) scan are displayed on the left, and those from the second PET scan are displayed on the right for each group. The line connecting the values indicates which values were for the same participant. The black bars represent the mean for groups of values. The change in MAO-A binding (MAO-A V_T) was significantly greater after moclobemide treatment compared with the other groups for every region (repeated-measures analysis of variance [ANOVA], effect of group on change in MAO-A V_T, F_1,15 = 71.08–130.06, p < 0.001 for all regions). There was no significant change in MAO-A V_T in the St. John’s wort group (repeated-measures ANOVA, regional MAO-A V_T repeated-measure, group effect assessed, F_1,15 = 0.002–3.38, p = 0.09–0.96, mean difference 5%, standard deviation 5%).

Fig. 2

An [¹¹C]-harmine positron emission tomography (PET) scan of a representative depressed patient at baseline and after 6 weeks of moclobemide treatment. Each image is in the transverse view and represents [¹¹C]-harmine V_T, an index of [¹¹C]-harmine binding in tissue relative to plasma concentration at equilibrium. The [¹¹C]-harmine V_T values are displayed on the rainbow scale and rank as follows: red > orange > yellow > green > blue > black. The [¹¹C]-harmine V_T values are greater in (left) the baseline condition, whereas (right) values are considerably reduced after 6 weeks of moclobemide treatment.