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MAO-B Occupancy in Depressed Patients (MOCP)

Primary Purpose

Major Depressive Disorder, Treatment Resistant Depression

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
[11C]SL25.1188 PET radiotracer
Sponsored by
Centre for Addiction and Mental Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Major Depressive Disorder

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • age 18 to 80
  • DSM-5 diagnosis of current MDE and MDD verified by the research version of SCID for DSM-5
  • early onset type MDD with first MDE prior to age 40
  • score greater than or equal to 17 on the 17 item Hamilton Depression Rating Scale (HDRS)28
  • antidepressant free for at least 2 weeks (by self report)

Exclusion Criteria:

  • history of psychotic symptoms
  • history of antisocial or borderline personality disorders (screened with the Structured Clinical Interview for Personality Disorders (SCID) for Diagnostic and Statistical Manual-5 (DSM-5) 30
  • history of neurodegenerative illness
  • cigarette smoking for the past 6 months (there are reports that cigarette smoking lowers monoamine oxidase B 31, 32.)
  • currently abusing street drugs
  • current alcohol use disorder
  • diagnosis of liver or kidney disease
  • positive for hepatic dysfunction as measured by aspartate transaminase (AST) and alanine transaminase (ALT) tests
  • diagnosis of cardiovascular disease such as hypertension/hypotension, angina or tachycardia
  • electroconvulsive therapy or mechanical brain stimulation treatment within the previous 6 months (the effects of these on MAO-B level are unknown but since they could stimulate astrogliosis which could influence MAO-B level these are included as exclusionary)
  • positive pregnancy test (in our Centre women up to 65 years of age are given a urine pregnancy test prior to every PET scan)
  • currently breastfeeding
  • recent use of MAO-B inhibitor treatments (within the previous 4 weeks)
  • disorders of coagulation, blood or ongoing use of anticoagulant medication
  • presence of metal objects or implanted electrical devices in the body that would preclude MRI scanning
  • claustrophobia
  • weight over 400lbs and height over 7ft (requirements for fitting in the scanners and hospital gowns)
  • the total radiation dose over the currently approved guideline of 20 millisievert (mSv) in a 12-month period. Note: The sievert is a derived unit of ionizing radiation dose in the International System of Units (SI) and is a measure of the health effect of low levels of ionizing radiation on the human body.
  • history of undergoing a number of PET scans that, including the number of PET scans under this protocol, will bring the total to more than 8 PET scans/lifetime, exceeding permissible limit for subjects participating in research set by our centre's guidelines
  • elevated liver transaminases AST and ALT levels as shown by the laboratory test results

Additional Requirements for Receiving Tranylcypromine :

  • not taking any anesthetics, meperidine (Demerol), anti-asthmatics, anti-hypertensives, dextromethorphan, buspirone, narcotics, codeine (e.g. found in Tylenol), over the counter medication for colds, hay fever, sinus decongestants, eye drops that contain tetrahydrozoline hydrochloride (Visine); SSRI medication including selective reuptake inhibitors (SSRI), amitriptyline, nortriptyline, protriptyline, desipramine, imipramine, doxepin, perphenazine, carbamazepine, cyclobenzaprine, amoxapine, maprotiline, trimipramine; stimulant medication such as: amphetamines, ephedrine, cocaine, methylphenidate, methyldopa, dopamine, levodopa, tryptophan as well as energy-enhancing and weight-reducing preparations for at least 2 weeks
  • not taking fluoxetine for at least 6 weeks
  • inadequate response to serotonin reuptake inhibitor medication
  • inadequate response to medication that raises norepinephrine
  • inadequate response to lithium addition to an antidepressant or patient does not want to take lithium due to side effects (such as intention tremor or hypothyroidism risk)
  • inadequate response to a medication that raises both serotonin and norepinephrine
  • inadequate response to wellbutrin or participant is not able to take wellbutrin due to a contraindication or side effect or participant does not wish to take wellbutrin
  • inadequate response to wellbutrin added to a second antidepressant or participant is not able to take wellbutrin due to a contraindication or side effect or participant does not wish to take wellbutrin
  • awareness and willingness to follow medication and substance use requirements required of taking tranylcypromine or rasagiline

Exclusion

  • previous hypersensitivity to monoamine oxidase inhibitors
  • previous history of hypersensitivity to tyramine
  • self report of previous diagnosis of cerebrovascular or cardiovascular disorders
  • self report history of recurrent or frequent headaches
  • diagnosis of phaeochromocytoma and catecholamine-releasing paragangliomas
  • systolic blood pressure not between 91 and 139 mmHg (inclusive)
  • diastolic blood pressure not between 51 and 90 mmHg (inclusive)
  • a decrease in systolic blood pressure of 20 mm Hg or diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with BP from the sitting position
  • use of triptans or tryptamines (e.g. sumatriptan or rizatriptan) in the past 2 weeks.

Additional Requirements for Taking Rasagiline

Inclusion

● Participant does not wish to take tranylcypromine due to concerns regarding side effects or the strict dietary restrictions of reduced tyramine intake required for taking tranylcypromine.

Additional Requirements for Taking Duloxetine:

Inclusion

  • Participants must be antidepressant free for at least 4 weeks prior to scanning (most antidepressants affect monoamines as does duloxetine so a longer period of being medication free is required to be able to separate effect of duloxetine from previous medication).
  • Participant must not have a history of non-response to duloxetine at a daily dose of 60mg daily or higher.

Sites / Locations

  • CAMH

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

Duloxetine

Rasagiline

Tranylcypromine

Arm Description

Assessment of MAO-B distribution volume in the prefrontal cortex before and after duloxetine at 60 mg daily.

Assessment of regional MAO-B distribution volume before and after rasagiline at 1.0 mg daily.

Assessment of regional MAO-B distribution volume before and after tranylcypromine at 30 to 60 mg daily.

Outcomes

Primary Outcome Measures

MAO-B occupancy of tranylcypromine at standard treating dose
MAO-B Occupancy is an overall occupancy measure that is intended to be derived from Lassen Plot. The Lassen Plot will include MAO-B total distribution volume (VT) values before and after treatment in regions that optimize the plot. It is expected that these will include prefrontal cortex, anterior cingulate cortex, dorsal putamen, ventral striatum, hippocampus, and cerebellum. To quantify the regional monoamine oxidase B (MAO-B) occupancy we use a measure called the total distribution volume (VT) an index of MAO-B density. The percent change, termed occupancy can range from 0% to 100%.
MAO-B occupancy of rasagiline at standard treating dose
MAO-B Occupancy is an overall occupancy measure that is intended to be derived from Lassen Plot. The Lassen Plot will include MAO-B total distribution volume (VT) values before and after treatment in regions that optimize the plot. It is expected that these will include prefrontal cortex, anterior cingulate cortex, dorsal putamen, ventral striatum, hippocampus, and cerebellum. To quantify the regional monoamine oxidase B (MAO-B) occupancy we use a measure called the total distribution volume (VT) an index of MAO-B density. The percent change, termed occupancy can range from 0% to 100%.

Secondary Outcome Measures

Rasagiline effect on MAO-B distribution volume (VT) in the prefrontal cortex
Rasagiline effect on MAO-B distribution volume (VT) in the prefrontal cortex. To quantify the regional monoamine oxidase B (MAO-B) occupancy we use a measure called the total distribution volume (VT) an index of MAO-B density. The percent change, termed occupancy can range from 0% to 100%.
Rasagiline effect on MAO-B distribution volume (VT) and cognition in MDE post COVID-19
Rasagiline effect on the total Hamilton Depression Rating Scale (HDRS). The Hamilton Rating Scale for Depression (HRSD) scoring is based on the 17-item scale. Scores of 0-7 are considered as being normal, 8-13 higher than normal, 14-16 modestly clinical, 17-19 mild depression, 20-23 moderate depression and scores 24 or greater are considered severe depression. The maximum sore being 52. Higher scores represent worse outcomes.

Full Information

First Posted
April 8, 2021
Last Updated
July 25, 2023
Sponsor
Centre for Addiction and Mental Health
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1. Study Identification

Unique Protocol Identification Number
NCT04841798
Brief Title
MAO-B Occupancy in Depressed Patients
Acronym
MOCP
Official Title
Monoamine Oxidase B Occupancy in Depressed Patients
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
April 15, 2021 (Actual)
Primary Completion Date
July 1, 2023 (Actual)
Study Completion Date
July 3, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre for Addiction and Mental Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Treatment Resistant Depression

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Duloxetine
Arm Type
Other
Arm Description
Assessment of MAO-B distribution volume in the prefrontal cortex before and after duloxetine at 60 mg daily.
Arm Title
Rasagiline
Arm Type
Other
Arm Description
Assessment of regional MAO-B distribution volume before and after rasagiline at 1.0 mg daily.
Arm Title
Tranylcypromine
Arm Type
Other
Arm Description
Assessment of regional MAO-B distribution volume before and after tranylcypromine at 30 to 60 mg daily.
Intervention Type
Other
Intervention Name(s)
[11C]SL25.1188 PET radiotracer
Intervention Description
Monoamine oxidase B (MAO-B) occupancy before and after medication treatment using [11C]SL25.1188 PET
Primary Outcome Measure Information:
Title
MAO-B occupancy of tranylcypromine at standard treating dose
Description
MAO-B Occupancy is an overall occupancy measure that is intended to be derived from Lassen Plot. The Lassen Plot will include MAO-B total distribution volume (VT) values before and after treatment in regions that optimize the plot. It is expected that these will include prefrontal cortex, anterior cingulate cortex, dorsal putamen, ventral striatum, hippocampus, and cerebellum. To quantify the regional monoamine oxidase B (MAO-B) occupancy we use a measure called the total distribution volume (VT) an index of MAO-B density. The percent change, termed occupancy can range from 0% to 100%.
Time Frame
3 years
Title
MAO-B occupancy of rasagiline at standard treating dose
Description
MAO-B Occupancy is an overall occupancy measure that is intended to be derived from Lassen Plot. The Lassen Plot will include MAO-B total distribution volume (VT) values before and after treatment in regions that optimize the plot. It is expected that these will include prefrontal cortex, anterior cingulate cortex, dorsal putamen, ventral striatum, hippocampus, and cerebellum. To quantify the regional monoamine oxidase B (MAO-B) occupancy we use a measure called the total distribution volume (VT) an index of MAO-B density. The percent change, termed occupancy can range from 0% to 100%.
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Rasagiline effect on MAO-B distribution volume (VT) in the prefrontal cortex
Description
Rasagiline effect on MAO-B distribution volume (VT) in the prefrontal cortex. To quantify the regional monoamine oxidase B (MAO-B) occupancy we use a measure called the total distribution volume (VT) an index of MAO-B density. The percent change, termed occupancy can range from 0% to 100%.
Time Frame
3 years
Title
Rasagiline effect on MAO-B distribution volume (VT) and cognition in MDE post COVID-19
Description
Rasagiline effect on the total Hamilton Depression Rating Scale (HDRS). The Hamilton Rating Scale for Depression (HRSD) scoring is based on the 17-item scale. Scores of 0-7 are considered as being normal, 8-13 higher than normal, 14-16 modestly clinical, 17-19 mild depression, 20-23 moderate depression and scores 24 or greater are considered severe depression. The maximum sore being 52. Higher scores represent worse outcomes.
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: age 18 to 80 DSM-5 diagnosis of current MDE and MDD verified by the research version of SCID for DSM-5 early onset type MDD with first MDE prior to age 40 score greater than or equal to 17 on the 17 item Hamilton Depression Rating Scale (HDRS)28 antidepressant free for at least 2 weeks (by self report) worsening of MDE symptoms or new onset MDE symptoms after COVID-19 may receive rasagiline and complete all procedures except the second [11-C]SL25.1188 PET scan - participants with this criteria will be enrolled in the alternative criteria that is similar to the general criteria except for the second PET scan. Exclusion Criteria: history of psychotic symptoms history of antisocial or borderline personality disorders (screened with the Structured Clinical Interview for Personality Disorders (SCID) for Diagnostic and Statistical Manual-5 (DSM-5) (unless occuring after COVID) history of neurodegenerative illness cigarette smoking for the past 6 months (there are reports that cigarette smoking lowers monoamine oxidase B 31, 32.) currently abusing street drugs current alcohol use disorder diagnosis of liver or kidney disease positive for hepatic dysfunction as measured by aspartate transaminase (AST) and alanine transaminase (ALT) tests diagnosis of cardiovascular disease such as hypertension/hypotension, angina or tachycardia electroconvulsive therapy or mechanical brain stimulation treatment within the previous 6 months (the effects of these on MAO-B level are unknown but since they could stimulate astrogliosis which could influence MAO-B level these are included as exclusionary) positive pregnancy test (in our Centre women up to 65 years of age are given a urine pregnancy test prior to every PET scan) currently breastfeeding recent use of MAO-B inhibitor treatments (within the previous 4 weeks) disorders of coagulation, blood or ongoing use of anticoagulant medication presence of metal objects or implanted electrical devices in the body that would preclude MRI scanning claustrophobia weight over 400lbs and height over 7ft (requirements for fitting in the scanners and hospital gowns) the total radiation dose over the currently approved guideline of 20 millisievert (mSv) in a 12-month period. Note: The sievert is a derived unit of ionizing radiation dose in the International System of Units (SI) and is a measure of the health effect of low levels of ionizing radiation on the human body. history of undergoing a number of PET scans that, including the number of PET scans under this protocol, will bring the total to more than 8 PET scans/lifetime, exceeding permissible limit for subjects participating in research set by our centre's guidelines elevated liver transaminases AST and ALT levels as shown by the laboratory test results Additional Requirements for Receiving Tranylcypromine : not taking any anesthetics, meperidine (Demerol), anti-asthmatics, anti-hypertensives, dextromethorphan, buspirone, narcotics, codeine (e.g. found in Tylenol), over the counter medication for colds, hay fever, sinus decongestants, eye drops that contain tetrahydrozoline hydrochloride (Visine); SSRI medication including selective reuptake inhibitors (SSRI), amitriptyline, nortriptyline, protriptyline, desipramine, imipramine, doxepin, perphenazine, carbamazepine, cyclobenzaprine, amoxapine, maprotiline, trimipramine; stimulant medication such as: amphetamines, ephedrine, cocaine, methylphenidate, methyldopa, dopamine, levodopa, tryptophan as well as energy-enhancing and weight-reducing preparations for at least 2 weeks not taking fluoxetine for at least 6 weeks inadequate response to serotonin reuptake inhibitor medication inadequate response to medication that raises norepinephrine inadequate response to lithium addition to an antidepressant or patient does not want to take lithium due to side effects (such as intention tremor or hypothyroidism risk) inadequate response to a medication that raises both serotonin and norepinephrine inadequate response to wellbutrin or participant is not able to take wellbutrin due to a contraindication or side effect or participant does not wish to take wellbutrin inadequate response to wellbutrin added to a second antidepressant or participant is not able to take wellbutrin due to a contraindication or side effect or participant does not wish to take wellbutrin awareness and willingness to follow medication and substance use requirements required of taking tranylcypromine or rasagiline Exclusion previous hypersensitivity to monoamine oxidase inhibitors previous history of hypersensitivity to tyramine self report of previous diagnosis of cerebrovascular or cardiovascular disorders self report history of recurrent or frequent headaches diagnosis of phaeochromocytoma and catecholamine-releasing paragangliomas systolic blood pressure not between 91 and 139 mmHg (inclusive) diastolic blood pressure not between 51 and 90 mmHg (inclusive) a decrease in systolic blood pressure of 20 mm Hg or diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with BP from the sitting position use of triptans or tryptamines (e.g. sumatriptan or rizatriptan) in the past 2 weeks. Additional Requirements for Taking Rasagiline Inclusion ● Participant does not wish to take tranylcypromine due to concerns regarding side effects or the strict dietary restrictions of reduced tyramine intake required for taking tranylcypromine. Additional Requirements for Taking Duloxetine: Inclusion Participants must be antidepressant free for at least 4 weeks prior to scanning (most antidepressants affect monoamines as does duloxetine so a longer period of being medication free is required to be able to separate effect of duloxetine from previous medication). Participant must not have a history of non-response to duloxetine at a daily dose of 60mg daily or higher.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey H Meyer, MD, PhD
Organizational Affiliation
CAMH
Official's Role
Principal Investigator
Facility Information:
Facility Name
CAMH
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 1L8
Country
Canada

12. IPD Sharing Statement

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MAO-B Occupancy in Depressed Patients

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