This is a randomised, double-blind, placebo-controlled clinical trial in which patients with major depressive disorder will receive augmentation through minocycline (MCO), celecoxib (CXB) or placebo.

This project aims to repurpose two established anti-inflammatory compounds as adjuvant therapy for immune-mediated depression, in line with state-of-the-art research of the last 10 years. Immune-mediated depression represents a subtype which accounts for approximately 30% of depressive disorders. Patients with this immunosubtype are more likely to have a higher severity of depression, a lower quality of life and more somatic symptoms. Furthermore it is accompanied by a high incidence of treatment resistance. While their mechanisms of action completely differ from those of existing antidepressant treatment options, immunomodulatory drugs celecoxib and minocycline have proven their merit as add-on treatment in depressive episodes. They have been on the Belgian market for years and come with a known pharmacological and safety profile. Patient stratification at baseline based on inflammatory status will reveal which inflammatory subpopulation benefits most from each of the two investigated anti-inflammatory compounds. Additionally, our distinctive study design allows head-to-head comparison of both add-on therapies and will as such provide the last stepping stones towards clinical implementation of individualised treatment strategies in depression.

Inclusion Criteria:

• Male or female, 18-65 years inclusive.
• Able and willing to give informed consent and take oral medication.
• Physically healthy.
• Diagnosis of Major Depressive Disorder by DSM-5 criteria, confirmed by the Mini International Neuropsychiatric Interview (MINI).
• The current episode of depression has failed to remit to the current antidepressant treatment at the adequate dose (as defined in the Maudsley Prescribing guidelines). Relapse while taking an antidepressant is also considered a treatment failure.
• Tolerant to the current antidepressant and having no planned changes in their current therapy for the duration of the study.
• Stable on current treatment for a minimum of 4 weeks (6 weeks for fluoxetine) prior to baseline.
• If female and of childbearing age, willing to use adequate contraceptive precautions and willing to take a pregnancy test at baseline.

Exclusion Criteria:

• Primary diagnosis of a bipolar disorder, psychotic spectrum disorder, obsessive-compulsive disorder, eating disorder, post-traumatic stress disorder, or alcohol and/or substance use disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (< 4 weeks before screening, excl. nicotine and caffeine).
• Use of immunosuppressant or immunostimulant drugs within 21 days of screening (e.g., glucocorticoid treatment, methotrexate, etc.).
• History of peptic ulcer disease or gastrointestinal (GI) bleeding.
• Having an acute infection or inflammatory bowel disorder.
• Current severe cardiovascular disease, congestive heart failure (NYHA-class II-IV), ischemic or thrombotic events or unstable coronary artery (incl. coronary artery bypass graft (CABG) surgery),
• Liver impairment (alanine aminotransferase > 2x upper limit, serum albumin < 25 g/l or Child-Pugh Score ≥ 10)
• Renal impairment (creatinine clearance < 30 mL/min).
• Having received >14 days of tetracycline or non-steroidal anti-inflammatory medication within the previous 2 months, or having a history of sensitivity or intolerance to these classes of drugs.
• Chronic severe hypertension (systolic BP > 170 mmHg).
• Serology positive for hepatitis-B surface antigen, hepatitis-C antibodies or HIV antibodies.
• Received electroconvulsive therapy < 2 months prior to screening.
• Blood donation in 30 days prior to screening.
• Pregnancy or breastfeeding.
• Currently enrolled in an intervention study.