Major depressive disorder (MDD) is a leading cause of disability worldwide. Up to 50% of patients experience treatment resistant depression (TRD), which accounts for a vast majority of disease burden. Current medications for TRD have limited efficacy and can be associated with intolerable side effects. Therefore, there is a need for finding new treatment targets. Accumulating evidence suggests some patients with MDD including those with TRD, display brain inflammation. Thus, patients with TRD may benefit from medications that can reduce this inflammation. Minocycline is an antibiotic which can cross the blood-brain barrier and has effects on several systems implicated in depression. The principal investigator led the first pilot study of minocycline as an add-on treatment in TRD demonstrating that it led to a significant reduction in depressive symptoms compared to placebo and these findings require replication in a larger sample to confirm the efficacy and tolerability of this treatment approach.

This study is a 12 week, double-blind, placebo-controlled trial of minocycline as add-on treatment for patients suffering from a major depressive episode who have failed to respond to antidepressant treatment, confirmed by the Structured Clinical Interview for DSM-5 (SCID-5) and the Antidepressant Treatment History Form (ATHF) at screening. After screening and randomization to the two parallel arms of the trial, 50 patients will receive minocycline added to treatment as usual (TAU) and 50 patients will receive placebo added to TAU. Clinical assessment will include the Hamilton Depression Rating Scale (HRSD-17), Clinical Global Impression scale (CGI), World Health Organization Quality of Life Short Form (WHOQOL-BREF), and Generalized Anxiety Disorder scale (GAD-7), administered at each study visit (baseline, week 2, 6, and 12). Side effects checklists will be undertaken at each visit. Minocycline will be started at 100 mg once daily and will be increased to 100 mg twice daily at two weeks. Secondary outcomes include inflammatory biomarkers measured at baseline, weeks 6 and 12.

This trial will provide further evidence of minocycline's efficacy and acceptability as a treatment option for patients with TRD and provide insights into its mechanism of action.

Inclusion Criteria:

1. Outpatients
2. Voluntary and competent to consent to treatment
3. DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the SCID-5
4. Male or female aged between 18-80
5. Total score > 3 on ATHF
6. Baseline HRSD-17 score > 14
7. Able to adhere to study schedule
8. If female of childbearing potential, currently on a medically acceptable form of birth control (oral contraceptives, contraceptive injections, IUD, contraceptive patch, male partner sterilization, abstinence, or barrier methods plus spermicide)
9. Currently taking one of the following standard antidepressants: Escitalopram, Citalopram, Sertraline, Venlafaxine, Duloxetine, Mirtazapine or Bupropion
10. Been on same dose of all psychotropic medications for > 4 weeks prior to enrolment

Exclusion Criteria:

1. DSM-5 substance use disorder within past 3 months, moderate or severe, based on SCID-5
2. Concomitant major unstable medical illness
3. Pregnancy or intent to become pregnant during study period
4. DSM-5 diagnosis of psychotic disorder, bipolar disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) within last year
5. DSM-5 diagnosis of borderline personality disorder (BPD)
6. Possible or probable dementia
7. Prior or current intolerance or contraindication to tetracyclines
8. Abnormal readings in hematology, liver, or renal function tests
9. Have Myasthenia Gravis
10. Concomitant treatment with anticoagulants, diuretics, retinoids, ergot alkaloids, antacids containing aluminium/calcium/magnesium, bismuth and zinc salts, or quinapril

Patients, their families, referring clinicians, lab workers and research assistants carrying out assessments will be concealed from allocation. Once randomized, pharmacy at the Centre for Addiction and Mental Health (CAMH) will be informed by email and deliver medication to the patient. An independent study psychiatrist will manage any clinical concerns and will be blind to treatment allocation. To assess the integrity of blinding procedures, participants and independent raters will be asked to complete a conventional guess form asking whether they believe participants received Minocycline or placebo as a treatment after the final ratings have been completed.