Biomarkers of Neuroinflammation and Anti-Inflammatory Treatments in Major Depressive Disorder

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.

Eligibility Criteria:
Group 1 - Current major depressive episode (MDE) secondary to MDD

Inclusion Criteria:

* good physical health with no active medical conditions
* non-cigarette smoking
* no past or current substance abuse or dependence
* negative urine pregnancy test at screening and scan days (for women)
* primary diagnosis of current major depressive episode (MDE) and major depressive disorder (MDD) verified by SCID for DSM IV
* score greater than 19 on the 17 item HDRS
* non-response to a clinical trial of at least one antidepressant given at appropriate clinical dose
* willing to take medication for the duration of the trial and has previously taken antidepressants for the duration of the trial
* presently taking an antidepressant at a standard clinical dose.

Exclusion Criteria:

* history of neurological illness or autoimmune disorders
* never taken a tricyclic antidepressant or an antidepressant that raises norepinephrine
* received treatment with electroconvulsive therapy or mechanical brain stimulation in the previous 6 months
* currently taking medication contraindicated or that may possibly interact with either minocycline or celecoxib
* known intolerance or allergy to minocycline, other tetracyclines, sulfonamides or NSAIDs
* taken diazepam or other benzodiazepine use within the past month, except for lorazepam and clonazepam
* use of anti-inflammatory drugs or tetracyclines lasting ≥1 week within the past month
* history of severe hepatic or renal insufficiency, asthma, allergies, gastrointestinal disease, ischemic heart disease, cerebrovascular disease or congestive heart failure
* lactose intolerance

Group 2 - Healthy Controls - Phase 1 (baseline scan) only

Inclusion criteria:

* score below 8 on the 17 item HDRS
* good physical health
* non-cigarette smoking
* negative urine pregnancy test at screening and scan days (for women)
* negative urine screen for drugs of abuse

Exclusion criteria:

* past or current diagnosis of axis I or axis II disorder as determined by the SCID I and SCID II for DSM IV
* history of psychotropic medication use
* history of neurological illness or autoimmune disorder