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The purpose of this study is to determine if translocator protein total distribution volume (TSPO VT) is elevated in major depressive disorder that is not responding to medication and if adding minocycline can affect TSPO VT. Many remain treatment resistant with common antidepressant treatments and the investigators think it may be due to poor targeting of brain pathologies.
There will be three Phases in the study. Only MDE subjects will be invited to continue to Phase 2 and 3. Subjects will be invited to continue to the subsequent Phase given they meet entry criteria described below:
Phase 1: The investigators will evaluate whether TSPO is elevated in individuals during a current MDE compared to healthy controls. Eligible participants will receive one [18F]FEPPA PET scan and one MRI scan. Other measures will include urine sample, blood samples for genetic and peripheral biomarker analysis, a neurocognitive battery, mood scales and questionnaires.
Phase 2: Participants who have elevated TSPO VT in Phase 1 and are agreeable to receiving minocycline will be invited to participate in Phase 2. Based on our previous results participants will be considered candidates for Phase 2 if TSPO VT ≥ 10.5 (HAB) or ≥8.5 (MAB) in any of the primary regions of interest (prefrontal cortex, anterior cingulate cortex or insula). Eligible participants will be invited to participate in a randomized, double blind, placebo controlled trial, to receive either minocycline or placebo. After the eight weeks of treatment, participants will receive one [18F]FEPPA PET scan. Other measures will include urine samples, blood samples, mood scales and questionnaires.
Phase 3: If, after the initial eight week treatment period with either minocycline or placebo, any participant continues to have depressive symptoms (17-item Hamilton Depression Rating Scale score ≥ 8) they will be invited to participate in an eight week open label trial of celecoxib. Participants not eligible for Phase 2 may also be invited to participate in Phase 3 directly from Phase 1.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Minocycline | Experimental | The dose of minocycline would be 50mg per day on week 1, 50mg bid on week 2 and 100mg bid weeks 3-8. For tapering, the dose will be reduced to 50mg bid for a week, and then stopped. |
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| Placebo | Placebo Comparator | The number and appearance of the pills would be identical to those in the minocycline arm. |
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| Celecoxib | Other | This will be an open label trial for those with Hamilton Depression Rating Scale score ≥ 8 following the minocycline v. placebo trial or those not eligible for Phase 2. Dose of celecoxib will be 100 mg bid for the first week and 200mg bid for weeks 2-8. For tapering, the dose of celecoxib will be reduced to 100mg bid for one week, and then stopped. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Minocycline | Drug | 50 mg and 100 mg capsule, oral administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| Translocator total distribution volume (TSPO VT): Treatment Effect of Minocycline in MDE Subjects | TSPO VT will be measured using [18F]FEPPA positron emission tomography brain scans. Eligible MDE participants will be randomized to either minocycline or placebo. Following 8 weeks of either minocycline or placebo treatment, MDE participants will have a second PET scan . | Pre- and post-minocycline or placebo treatment= 8 weeks total between pretreatment and posttreatment scans |
| Translocator total distribution volume (TSPO VT): Difference between MDE and healthy subjects | Compare baseline TSPO VT prior to treatment between MDE group and healthy group | Pre-treatment scan will take place up to 8 weeks from initial assessment |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Hamilton Depression Rating Scale Score | Change in HDRS score following minocycline vs. placebo treatment. Change in HDRS score following celecoxib treatment. | Pre- and post-minocycline treatment (8 weeks total between pre- and post-treatment). Pre- and post-celecoxib treatment (8 weeks total between pre- and post-treatment). |
| Measure | Description | Time Frame |
|---|---|---|
| Hopkins Verbal Learning Test-Revised | To assess verbal memory we will administer the Hopkins Verbal Learning Test-Revised to MDE participants before and after treatment. | Pre- and post-minocycline or placebo treatment (8 weeks between pre- and post-treatment measure) |
| Brief Visuospatial Memory Test-Revised |
Group 1 - Current major depressive episode (MDE) secondary to MDD
Inclusion Criteria:
Exclusion Criteria:
Group 2 - Healthy Controls - Phase 1 (baseline scan) only
Inclusion criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey H Meyer, MD, PhD | Centre for Addiction and Mental Health; University of Toronto | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre for Addiction and Mental Health | Toronto | Ontario | M5T 1R8 | Canada |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D008911 | Minocycline |
| D000068579 | Celecoxib |
| ID | Term |
|---|---|
| D013754 | Tetracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| Placebo | Drug | Lactose monohydrate in identical gel capsules to minocycline, oral administration. |
|
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| Celecoxib | Drug | 100 mg and 200 mg capsules, oral administration. |
|
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To assess visuospatial memory we will administer the Brief Visuospatial Memory Test-Revised to MDE participants before and after treatment. |
| Pre- and post-minocycline or placebo treatment (8 weeks between pre- and post-treatment measure) |
| Comprehensive Trails Making Test | To assess psychomotor speed and attention we will administer the Comprehensive Trails Making Test to MDE participants before and after treatment. | Pre- and post-minocycline or placebo treatment. |
| Genetic sample | The priority of the genetic sample is to analyze the alleles of polymorphism rs6971 which has an association with the affinity of most second generation TSPO ligands including [18F]FEPPA. The genetic sample will also be used to study sequences of genes that are believed to affect TSPO expression, inflammation, mood and conditions that may predispose to mood disorders. | Phase 1-single sample |
| Blood samples (serum and plasma) | Analyses will include complete blood cell count (CBC), ESR, hepatic and renal function. Peripheral marker analyses will include proteins related to TSPO expression and inflammation. Plasma minocycline and celecoxib levels will be analyzed. | Pre- and post-minocycline or placebo treatment (8 weeks between measures). Pre- and post-celecoxib treatment (8 weeks between measures). |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D001555 | Benzene Derivatives |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011720 | Pyrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |