MAO-B Occupancy in Depressed Patients

Summary

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BACKGROUND 1.1 Problem of Treatment Resistant Depression and a Proposed Solution Problem of Major Depressive Disorder: Major depressive disorder (MDD) known to the layperson as clinical depression, is an illness composed of repeated major depressive episodes of variable length and persistence (MDE)....

BACKGROUND 1.1 Problem of Treatment Resistant Depression and a Proposed Solution Problem of Major Depressive Disorder: Major depressive disorder (MDD) known to the layperson as clinical depression, is an illness composed of repeated major depressive episodes of variable length and persistence (MDE). MDD is the leading cause of death and disability in moderate to high income countries 1. MDD is common with 5% of adults in the midst of a major depressive episode (MDE) and the lifetime prevalence of MDD is 10 to 20%2. MDD is also often treatment resistant, with 50% of people having inadequate responses3. Plausible Mechanism of Treatment Resistance: It is generally believed that there are multiple underlying pathologies in MDD and the mismatch of treatment to pathology results in treatment resistance. Hence it is important to determine whether common brain pathologies are targeted by common treatments like serotonin and norepinephrine reuptake inhibitors, and to establish the degree to which alternative treatments might better target such brain pathologies. Then with this information matching of treatment to identified disease pathologies can be optimized. STUDY OBJECTIVES Overview Rationale for Objectives The abnormal elevation in MAO-B level in MDE of MDD was most prominent in the prefrontal cortex (see section 1), hence we prioritize this region in our objectives. As detailed in the introduction, we will assess MAO-B occupancy of tranylcypromine because it is a MAO-B inhibitor, albeit non-selective, that is approved in Canada for clinical use to treat MDD. We assess rasagiline as a selective MAO-B inhibitor that does not require stringent dietary restriction of tyramine at the 1mg dose, which is approved for Parkinson's Disease in Canada and has potential to be repurposed to treat MDD. We will also include assessment of MAO-B VT before and after duloxetine to verify the widespread assumption that the commonly prescribed medications that inhibit the reuptake of serotonin and norepinephrine, do not affect MAO-B level. Primary Objectives To measure MAO-B occupancy of tranylcypromine at a standard treating dose (30 to 60mg total per day) in the prefrontal cortex. To measure MAO-B occupancy of rasagiline at 1mg total daily, a dose not requiring stringent tyramine dietary restriction in the prefrontal cortex. Secondary Objective To evaluate the effect of duloxetine 60mg daily on MAO-B VT in the prefrontal cortex. The methods to quantitate more exact occupancy inherently require some MAO-B occupancy to occur, so in the case of objective 3, the related measure of change in MAO-B VT will be assessed. In addition, we will evaluate MAO-B occupancy of the interventions listed in objectives 1 and 2 within other brain regions with either reasonably high MAO-B density or whose dysfunction is implicated in the pathophysiology of MDD, including the anterior cingulate cortex, ventral striatum, dorsal striatum, thalamus, hippocampus, and midbrain.

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