Monoamine oxidase B (MAO-B) is a highly abundant protein in the brain that generates oxidative stress, removes monoamines such as dopamine and norepinephrine that support normal mood, and influences the predisposition towards apoptosis. MAO-B levels and activity are highly correlated and increase after chronic stress hormone exposure. MAO-B activity is increased in rodent brain after chronic unpredictable stress, however, MAO-B has not been studied in the most common early onset (age<45 years) major depressive disorder (MDD). Using [11C]SL25.1188 positron emission tomography, we propose to study whether MAO-B VT is elevated in key brain regions in early onset MDD during medication free major depressive episodes; (MDE; n=31), and in medication free major depressive episodes with a history of treatment resistance (n=31) as well as age matched healthy controls (from n=46). The intention is to make a convincing case that MAO-B levels are frequently elevated in key affect modulating regions during MDE, especially treatment resistant MDE. Such results could be applied to develop strategies for matching MDE cases of elevated MAO-B level towards MAO-B inhibitor treatments in the clinic through identifying low cost predictors of elevated MAO-B level (such as the clinical and RDOC measures proposed and/or additional peripheral protein or genetic biomarkers in future study).

Public Health Relevance

The proposed study is the first to determine whether a protein in the brain called MAO-B is increased in the most common early onset type clinical depression (starting before age 45). MAO-B creates oxidation (the opposite of an antioxidant), removes some brain chemicals that support normal mood, and can influence death/survival of brain cells. Using positron emission tomography, we propose to measure MAO-B VT, an index of MAO-B level, in medication free clinical depression (n=31), medication free clinical depression with a history of treatment resistance (n=31), and age matched healthy controls (n=46). If this study identifies a therapeutic target of elevated MAO-B level in key affect regulating regions in MDE, and in treatment resistant MDE, then such results could be advanced towards matching MDE cases of elevated MAO-B level towards MAO-B inhibitor treatments in the clinic. For example, low cost predictors of elevated MAO-B level could then be developed (such as the clinical and RDOC measures proposed and/or additional peripheral biomarkers in future study). It is plausible that MDE response to MAO-B inhibitors would be improved if cases with elevated MAO-B levels were selected for this treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH115014-01
Application #
9422139
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2017-11-10
Project End
2022-10-31
Budget Start
2017-11-10
Budget End
2018-10-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Centre for Addiction and Mental Health
Department
Type
DUNS #
207855271
City
Toronto
State
ON
Country
Canada
Zip Code
M5S2S1