Effects of electroconvulsive therapy on Monoamine Oxidase A

Background: In treatment-resistant depression, electroconvulsive therapy (ECT) has been shown to effectively reduce depressive symptoms. However, the underlying neurobiological mechanisms remain uncertain. Recent neuroimaging findings underline the involvement of the serotonergic system. Here, the aim of the study is to assess the effects ECT on monoamine oxidase A (MAO-A), the main serotonin degrading enzyme, in humans using positron emission tomography (PET) and the radiotracer [11C]harmine. Additionally, grey matter volume (GMV) alterations caused by ECT using structural magnetic resonance imaging (sMRI) will be assessed. Outcome measures: (1) Change in MAO-A DVs induced by a treatment course of 6 to 14 ECTs in depressed patients (2) Change in GMV caused by ECT. (3) Comparison of MAO-A DVs/GMV of patients and healthy subjects before ECT (4) Correlation of therapeutic efficacy (=decrease in the HAM-D scores of at least 50%) with MAO-A DVs and GMV. Study design: Longitudinal mono-centre study including 18 depressed patients, age 18-60 years, and 18 age- and sex-matched healthy subjects. Overall study duration of 36 months. Measurements: Each patient will be measured 3 times using a GE Advance PET scanner and the radioligand [11C]harmine. The 1st and 2nd measurements determine baseline changes in MAO-A DVs while the 3rd scan is used to quantify changes induced by ECT. Similarly, patients will undergo 3 structural (T1-weighted) MRI temporally coordinated to the PET scans. Healthy subjects will be measured once with PET and MRI. ECT: Patients will be treated in 8 unilateral ECT sessions within a time interval of 2 to 4 weeks using Thymatron System IVTM). Psychotropic medication is allowed if steady state has been reached > 10 days prior to inclusion. Data analysis: The MAO-A DVs will be determined using a region of interest and a whole brain voxel-wise approach. A repeated-measures analysis of variance (ANOVA) will compare the change in the MAO-A DVs before and after ECT (PET2-PET3) with the change between the baseline PET scans (PET1-PET2). Secondly, MAO-A DVs from PET1 will be compared to the scans of healthy subjects (cross-sectional part). Besides, the correlation between treatment effects reflected in HAM-D score and changes in MAO-A DVs will be computed. Similar statistical analyses will be done with sMRI data. Relevance of this study: This study would be the first to demonstrate an effect of ECT on MAO-A DVs in humans in vivo. Given the involvement of the MAO-A in the pathophysiology of mood disorders, the present study would be an important step towards a better understanding of the antidepressant effect of ECT. Additionally, this study might contribute in substantiating potential effects of ECT on brain structure and help to identify biomarkers that distinguish patients who are likely to benefit from ECT from patients who will rather be non-responders.

Electroconvulsive therapy (ECT) constitutes the most effective treatment options in major depression, notably when it comes to conditions that are resistant to pharmacological therapy. During ECT a generalized seizure is induced under controlled circumstances and leads to the improvement of various mental symptoms. Despite the successful use of ECT for more than 80 years, the neurobiological mechanisms underlying its effect are still insufficiently understood. Current research findings point towards in involvement of the serotonergic system. For instance, a global increase of serotonin-1A receptor density was shown after ECT in depressed patients, which is similar to observations reported after the administration of antidepressant drugs. The monoamine oxidase A (MAO-A) is the major serotonin-degrading enzyme in the human brain and was shown to be increased in depressed patients as compared to healthy subjects. Therefore, the aim of the present study was to assess MAO-A expression before and after ECT in patients suffering from major depression and to compare the latter with healthy subjects. To do so patients were measured three-times using positron emission tomography (PET), an imaging method allowing for the visualization of MAO-A density in the brain: twice before (during continuous pharmacological treatment, to test the reliability of the PET method) and once after ECT. Simultaneously, patients underwent magnetic resonance imaging to investigate whether ECT is accompanied by brain volume changes. Healthy subjects were scanned only once. In patients antidepressant drugs were continued in unchanged dosage during the whole study participation. ECT was performed under generalized anaesthesia and using a unilateral (right temporal) treatment modality. Overall 16 depressed patients and 16 healthy subjects (12 women, 4 men, mean age 46 years, respectively) were examined for this study. In the patients group the ECT response rate was 81%. ECT did not lead to a relevant alteration of MAO-A expression in depressed patients. This suggests that the enzyme MAO-A does not play a role in the mechanism of action of ECT. No differences of MAO-A density could be detected in patients compared with controls which might be attributable to the continued pharmacological treatment. The MR based analysis of changes in brain structure over the course of ECT has indicated increases in the volume of the right amygdala, the right hippocampus and the right putamen. Further, increases in the cortical thickness were found in the temporal, parietal, insular and precuneus cortices of the right hemisphere. The novel analysis of subfields of the hippocampus and nuclei of the amygdala has allowed allocating the increases in volume to specific substructures of these regions. Specifically, increases were found in the granule-cell molecular-layer of the dentate gyrus region in the hippocampal head, the hippocampo- amygdala transition area, and basal, lateral nuclei, as well as cortico-amygdalar transition areas of the amygdala. These regions are known to possess a high potential for plastic changes in adult brains and were implicated by decreased neuroplasticity in depression and stress-related disorders. The current results add to the understanding of the mechanism of action of ECT which appears to restore some of the structural alterations reported in depressed patients.