MAO-B Occupancy in Depressed Patients
Condition: Major Depressive Disorder; Treatment Resistant Depression
MeSH terms: Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
Study type: Interventional

Summary: 
      The study is looking at assessing monoamine oxidase B (MAO-B) occupancy in depressed patients
      before and after medication treatment using positron emission tomography (PET) scan.
    

Detailed description: 
      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. 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%. MDD is also often treatment resistant, with 50% of people
      having inadequate responses. 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, hence the investigators prioritize this region in
      our objectives. As detailed in the introduction, the investigators 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. The investigators 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
      purposed to treat MDD. The investigators 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

        1. To measure MAO-B occupancy of tranylcypromine at a standard treating dose (30 to 60mg
           total per day) in the prefrontal cortex.

        2. 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

        3. To evaluate the effect of duloxetine 60mg daily on MAO-B VT in the prefrontal cortex.

        4. To evaluate the relationship between changes in symptoms of MDE and cognition (primarily
           assessed with the Hamilton Rating Scale and the Cognitive Failure Questionnaire) and
           baseline MAO-B VT in the regions most altered in MDE, and MDE post COVID-19.

      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, investigators 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. With respect to objective 4, it is expected that participants with more elevated
      MAO-B VT will have a greater response to rasagiline.
    

Intervention name(s): [11C]SL25.1188 PET radiotracer
Intervention type(s): Other
Intervention description(s): Monoamine oxidase B (MAO-B) occupancy before and after medication treatment using [11C]SL25.1188 PET
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other