Minocycline as Adjunctive Treatment for Treatment Resistant Depression (MINDEP2)

Minocycline as Adjunctive Treatment for Treatment Resistant Depression: a Double Blind, Placebo-controlled, Randomized Trial

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.

Study Overview

• Status: Completed
• Conditions: Treatment Resistant Depression
• Intervention / Treatment: Drug: Minocycline

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M6J 1H4
      • Centre for Addiction and Mental Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active; Minocycline will start at an oral dose of 100mg daily and will be increased after one week to 100mg twice daily.	Drug: Minocycline; Participants will be randomized to receive either Minocycline or placebo added to standard oral antidepressants.; Other Names: Apo-Minocycline
Placebo Comparator: Placebo; Placebo capsules will start at one capsule daily, and will be increased after one week to one capsule twice daily	Drug: Minocycline; Participants will be randomized to receive either Minocycline or placebo added to standard oral antidepressants.; Other Names: Apo-Minocycline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depressive symptoms	Changes from baseline to week 12 on the 17-item Hamilton Rating Scale for Depression (HRSD-17).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	Reduction of 50% or more in HRSD score from baseline to week 12	12 weeks
Remission rate	Final HRSD score < 8	12 weeks
Anxiety symptoms	Changes from baseline to week 12 in Generalized Anxiety Disorder scale (GAD-7)	12 weeks
Self-reported perception of quality of life	Changes from baseline to week 12 in World Health Organization Quality of Life Short Version (WHOQOL-BREF)	12 weeks
Clinician-rated illness severity	Changes from baseline to week 12 in Clinical Global Impression scale (CGI)	12 weeks

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: The Physicians' Services Incorporated Foundation
• Investigators: Principal Investigator: Ishrat Husain, MBBS, MD(Res.), CAMH

Publications and helpful links

General Publications

• Husain MI, Cullen C, Umer M, Carvalho AF, Kloiber S, Meyer JH, Ortiz A, Knyahnytska Y, Husain MO, Giddens J, Diniz BS, Wang W, Young AH, Mulsant BH, Daskalakis ZJ. Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2). BMC Psychiatry. 2020 Apr 15;20(1):173. doi: 10.1186/s12888-020-02553-9.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Actual): January 7, 2025
• Study Completion (Actual): January 7, 2025

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: May 9, 2019
• First Posted (Actual): May 13, 2019

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Biomarker; Neuroinflammation; Treatment Resistant Depression; Minocycline; Microglial Activation
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Pathologic Processes; Inflammation; Mood Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Neuroinflammatory Diseases; Depressive Disorder, Treatment-Resistant; cyclopia sequence; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Naphthacenes; Tetracyclines; Minocycline
• Other Study ID Numbers: 135/2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No