Supplemental Material
Elevated Monoamine Oxidase A Binding During Major Depressive Episodes is Associated WithGreater Severity and Reversed Neurovegetative Symptoms
Running Title: Monoamine Oxidase A and Subtypes of Depression
Lina Chiuccariello, M.Sc.1, Sylvain Houle, M.D. Ph.D.1,Laura Miler H.BSc.1,
Robert G. Cooke, M.D.1, Pablo M. Rusjan, Ph.D.1, Grazyna Rajkowska, Ph.D.2,
Robert D. Levitan, M.D.1, Stephen J. Kish, Ph.D.1, Nathan J. Kolla, M.D., M.A., M.Sc.1, Xiaoming Ou, Ph.D.2, Alan A. Wilson, Ph.D.1, Jeffrey H. Meyer, M.D., Ph.D.1.
1CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5T 1R8, Canada, 2Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216
Corresponding Author:
Dr. Jeffrey H. Meyer
Centre for Addiction and Mental Health
250 College Street, Toronto, ON, M5T 1R8, Canada
Tel. 416-535-8501 x4007, Fax. 416-979-4656
Methods
PET Imaging: [11C]harmine PET has been modeled in humans and is an excellent technique for quantifying MAO-A level in the brain: [11C]harmine is a selective and reversible radiotracer for MAO-A; it has high affinity for the MAO-A enzyme, high brain uptake in humans, and polar metabolites that do not cross the blood- brain barrier (for review of [11C]harmine properties see Meyer et al. (Meyer et al, 2006; Meyer et al, 2009)). The specific binding of [11C]harmine may be fully blocked in baboons (Bergstrom et al, 1997) and 85% of the specific binding can be blocked with clinically tolerated doses of MAO-A inhibitors in humans (Sacher et al, 2011).
Motion Correction:All individuals were fitted with the thermoplastic head fixation system to minimize movement (Orfit Industries, USA) while in the scanner. All time activity curves were visually inspected for motion throughout the scan. Although no scans were corrected for movement in the data presented here, the standard procedure employed was to visually inspect denoised dynamical PET images for potential head movement. If motion is visible, a correction technique which relies on frame-to-frame realignment as described by (Mawlawi et al, 2001) (implemented under ROMI) is applied.Specifically, the method involves registration of the frames prior to attenuation correction using the Automatic Image Registration (AIR) algorithm (Woods et al, 1993), which is then applied to the frames after attenuation correction.
Results
Additional Information Regarding Relationship of MAO-A VT with Severity as a Continuous Variable: The relationship between severity and MAO-A VT was also present in the group with reversed neurovegetative symptoms. For example, within the group with reversed neurovegetative symptoms, the MAO-A VT in the PFC and ACC was highly correlated with severity (pearson correlation coefficient, PFC, r=0.83, p=0.003, ACC, r=0.83, p=0.003) and this was not due to outliers (spearman’s rho, PFC, r=0.90, p<0.001, ACC, r=0.88, p=0.001).
Plasma Free Fraction: The plasma free-fraction of the parent metabolite was collected in 73 of 79 participants. There were no significant differences between those with a greater severity of symptoms and those without (t= 0.184, p=0.855) or those with reversed neurovegetative symptoms of depression and those without (t=0.967, p=0.340).
Discussion
The results of the present study and other investigations of indices of MAO-A level, suggest that elevated MAO-A level, particularly in the PFC and ACC, represents a central biomarker of vulnerability to mood dysregulation. The present study demonstrates that MAO-A level is more elevated when severity is greater, which is consistent with a role towards generating symptoms of depression. During other conditions associated with dysphoric mood, such as the postpartum blues, or early withdrawal from cigarette smoking this marker is also elevated(Bacher et al, 2011; Sacher et al, 2010), suggesting that elevations in this marker may occur during times of sad mood, and times of high risk for MDE. Future clinical trials should develop a personalized medicine approach, such that when this marker is present across pathological conditions, it can be targeted with treatments to lower available MAO-A so as to either normalize mood or protect against risk for onset of major depressive episodes when MDE is not present.
References
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