Table 1 Inclusion and exclusion criteria

Inclusion Criteria

 1) are voluntary outpatients who are competent to consent to treatment;

 2) have a DSM–5 diagnosis of non-psychotic MDD, single or recurrent, based on the Structured Clinical Interview for DSM-5 (SCID-5) (R. L. Spitzer et al., 2015);

 3) are male or female between the ages of 18–80;

 4) total score of > 3 on the Antidepressant Treatment History Form (ATHF) (M. A. Oquendo et al., 1999; Maria A. Oquendo et al., 2003)

 5) have a baseline Hamilton Rating Scale for Depression (HRSD-17) > 14;

 6) if a woman of child-bearing potential, are on a medically acceptable form of birth control such as oral contraceptives, contraceptive injections (Depo-Provera), intrauterine devices (IUD), contraceptive patch, male partner sterilization, abstinence, or barrier methods (condom or diaphragm) plus spermicide,

 7) are currently taking one of the following antidepressants: Escitalopram, Citalopram, Sertraline, Venlafaxine, Duloxetine, Mirtazapine or Bupropion

Exclusion Criteria

 1) meet DSM-5 substance use disorder criteria within the past 3 months;

 2) have a concomitant major unstable medical illness;

 3) are pregnant or intend to get pregnant during the study;

 4) have a SCID-5 diagnosis of any psychotic disorder, bipolar disorder, obsessive compulsive disorder, or post-traumatic stress disorder (current or within the last year). While patients with psychotic depression subtype have been shown to respond and remit with minocycline treatment, we exclude these patients in order to pursue a conservative study with a homogeneous non-psychotic TRD sample first and will use such information to guide future research development with patients with psychotic features;

 5) Have a DSM-5 diagnosis of borderline personality disorder as assessed by a study investigator;

 6) have possible or probable dementia (based on the Informant Questionnaire on Cognitive Decline in the Elderly (Jorm & Jacomb, 1989) that will be administered to any subject with a baseline score of < 26 on the Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005);

 7) prior history of intolerance to any of the tetracyclines or presence of any contraindication to tetracyclines;

 8) abnormal readings in hematology (Hemoglobin, White Blood Cell count, platelet count), liver functions (ALT, AST, bilirubin) or renal function test (BUN, creatinine);

 9) patients with Myasthenia Gravis;

 10) concomitant treatment with anticoagulants, diuretics, retinoids, ergot alkaloids, antacids containing aluminium, calcium or magnesium, bismuth and zinc salts, quinapril