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

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.

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