Clin Psychopharmacol Neurosci 2014; 12(3): 180-188
Protocol and Rationale-The Efficacy of Minocycline as an Adjunctive Treatment for Major Depressive Disorder: A Double Blind, Randomised, Placebo Controlled Trial
Olivia May Dean1,2,3*, Michael Maes4, Melanie Ashton1, Lesley Berk4, Buranee Kanchanatawan5, Atapol Sughondhabirom5, Sookjareon Tangwongchai5, Chee Ng6, Nathan Dowling6, Gin S. Malhi7,8, and MIchael Berk1,2,3,9,10

1Innovations in Mental and Physical Health and Clinical Treatments Strategic Research Centre, Deakin University, School of Medicine, Geelong, Australia.

2Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia.

3Department of Psychiatry, University of Melbourne, Parkville, Australia.

4Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand.

5Centre for Mental Health and Wellbeing Research, Deakin University, School of Psychology, Burwood, Australia.

6Department of Psychiatry, University of Melbourne, The Melbourne Clinic, Richmond, Australia.

7Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, Australia.

8Department of Psychiatry, CADE Clinic, St. Leonards, Australia.

9Orygen Youth Health Research Centre, Parkville, Australia.

10Centre of Youth Mental Health, University of Melbourne, Parkville, Australia.

Correspondence to: Olivia May Dean, PhD. Innovations in Mental and Physical Health and Clinical Treatments Strategic Research Centre, Deakin University, School of Medicine, Kitchener House, P.O. Box 281, Geelong VIC 3220, Australia. Tel: +61-3-4215-3300, Fax: +61-3-4215-3491,
Received: March 21, 2014; Revised: April 29, 2014; Accepted: April 30, 2014; Published online: December 26, 2014.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Minocycline, Depression, Clinical research protocol, Inflammation, Oxidative stress


Using a randomised placebo controlled trial, we aim in this pilot study to test the efficacy of adjunctive minocycline (100 mg twice daily) in the acute treatment of unipolar depression to determine if:

1. Twelve weeks treatment of 200 mg/day minocycline treatment reduces severity of depression compared to individuals taking treatment as usual: Primary aim.

2. Twelve weeks with 200 mg/day minocycline treatment will improve self-reported symptom burden, quality of life, overall functioning and clinical impression and reduce symptoms of anxiety.

3. There are continued benefits following cessation of trial treatment assessed at 4 weeks following discontinuation.

4. Whether 12-weeks treatment with 200 mg/day minocycline reduces serum markers of inflammation.

5. Whether the change in immune-inflammatory and nitro-oxidative markers correlates with change in depressive symptomatology.

Primary Hypothesis

1. Twelve-weeks of adjunctive minocycline treatment will be superior to placebo for reducing symptoms of depression using the Montgomery-Asberg Depression Rating Scale (MADRS).

Secondary Objectives/Hypotheses

2. Twelve weeks of adjunctive minocycline treatment will be superior to placebo for reducing clinical global status, and improving quality of life and functioning based on validated rating scales.

3. Those who were taking the minocycline treatment will have better outcomes 4 weeks post-treatment discontinuation, based on symptomology, quality of life and functioning than those taking the placebo.

4. Those taking minocycline treatment will have reduced levels of inflammatory and oxidative stress (lipid peroxidation) levels in peripheral (blood) samples.

5. Clinical change will correlate with discernible changes in inflammatory and oxidative stress levels in the peripheral sample.


Study Design

This is a 12-week, parallel group, double-blind, randomised-control trial in which 60 participants with moderate-to-severe MDD will be allocated receive either 200 mg/day minocycline or placebo, in addition to treatment as usual (medication, psychotherapy or any other treatment).

Assessments are completed at baseline and weeks 0, 2, 4, 8 and 12. A follow-up (post-treatment discontinuation) assessment is completed at week 16. Randomisation is carried out according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines by an independent researcher. Participants are allocated to treatment groups using randomly permuted blocks (4×2) to maintain approximately equal group sizes over time.

Identity of Investigational Product and Comparators

Minocycline: 200 mg/day of minocycline (given as 100 mg twice daily) will be used in the study.

Placebo: Placebo tablets (starch) matched in appearance and taste will be used.


The current study is being led by Dr. Olivia Dean from Deakin University, in collaboration with Professor (Prof.) Michael Berk from Deakin University/Barwon Health, Prof. Chee Ng from the Univesrity of Melbourne/The Melbourne Clinic and Profs. Michael Maes and Buranee Kanchanatawan from Chulalongkorn University. The study will be conducted at three sites; Barwon Health and The Melbourne Clinic, both based in Victoria, Australia and Chulalongkorn University, Bangkok, Thailand.


Selection of Study Population

Potential participants are identified through referral by both the private and public treating sectors and by community advertisements. Participants expressing interest in the trial are contacted and invited to participate in a screening interview. Informed consent is obtained at the initial interview, prior to any study procedures commencing.

Inclusion criteria

For inclusion in the study, participants must fulfil all of the following criteria:

  1. Aged 18 years or over
  2. Capacity to consent to the study and to follow its instructions and procedures
  3. Fulfil the Diagnostic and Statistical Manual of Mental Disorders 4th edition, text revision (DSMIV-TR) diagnostic criteria for MDD, single episode or recurrent scoring 25 or over on the MADRS, at the baseline visit
  4. Participants on antidepressant therapy need to have been on the same treatment for at least two weeks prior to randomisation
  5. Utilising effective contraception (other than the contraceptive pill due to drug interactions) if female of child-bearing age and sexually active

Exclusion criteria

Participants are ineligible to enter the trial under the following conditions:

  1. Concurrent diagnosis of bipolar disorder I, II or not otherwise specified
  2. Three or more failed adequate trials of antidepressant therapy for the current major depressive episode or electroconvulsive therapy for the current major depressive episode
  3. Known or suspected clinically unstable systemic medical disorder (including a pre-existing infectious illness requiring tetracycline antibiotic treatment)
  4. Pregnancy or breastfeeding
  5. Contraindications to tetracyclines, including allergy or other intolerance; prior tetracycline use within 2 months of baseline visit
  6. Current treatment with >5 mg beta caretone or >300?g retinol equivalent
  7. Current treatment with isotretinoin or etretinate
  8. Current treatment with anticoagulants (excluding aspirin)
  9. Current treatment with methoxyflurane
  10. Current treatment with penicillin
  11. Females of childbearing age currently relying solely on the contraceptive pill as contraception
  12. Current enrolment in another clinical trial
  13. Participants requiring treatment with antacids containing aluminium, calcium or magnesium and preparations containing iron must take these preparations at least 2 hours before or after minocycline administration. This should be clearly stated at each visit.

Withdrawal of patients from treatment or assessment

Participants will be withdrawn from the trial under the following conditions:

  1. Failure to take the trial medication for seven consecutive days
  2. Cessation of effective contraception or confirmed pregnancy
  3. Withdrawal of consent
  4. Emergence of serious adverse events suspected to be associated with the trial medication
  5. Unavoidable commencement on anticoagulants (other than aspirin), >5 mg beta caretone or >300 ?g retinol equivalent, isotretinoin or etretinate, the contraceptive pill, methoxyflurane or penicillin.
  6. Participants who require tetracycline antibiotic treatment during the course of the study will be withdrawn.

Note: In cases of the emergence of adverse effects of minocycline treatment (such as vertigo), trial medication will be stopped for five days and then recommenced. Participants will be contacted two days following recommencement to determine if adverse effects have returned.

Randomisation - Method of Assigning Patients to Treatment Groups

After the baseline assessment has been completed, the participant will be randomised to one of the two treatment groups. Randomisation is enabled by a computer-based random number generator. Participating pharmacies have the randomisation code, to unblind participants if required. The randomisation will be double-blind and only the pharmacist will know which group the participant has been allocated to. Blindness will be maintained by ensuring that the packaging, appearance and colour of minocycline and placebo capsules are identical. Additionally, a third blinding aspect has been included, whereby all data analysis conducted by the statistician is conducted blind to treatment arms.

Participants are randomised strictly sequentially, as they are eligible for randomisation. Randomisation schemes are organised and administered centrally by the Innovations in Mental and Physical Health Aand Clinical Treatments Strategic Research Centre (IMPACT SRC). Each participant will have a unique identification number (Participant ID#) for anonymous data analysis.


The study treatments will only be used as directed in the protocol. From visit 1, participants will be requested to return all unused investigational products and empty containers to the investigator or research assistants. Records of overall dispensing and returns will be calculated and documented by the pharmacist involved in the study. Adherence to medication will be assessed by self-report and a pill count. This data will be used to calculate compliance with medication for analysis purposes.


Assessment of Inclusion and Exclusion Criteria

  1. Unipolar depression (and the absence of bipolar disorder) will be confirmed using the Mini International Neuropsychiatric Interview for DSM-IV (MINIPlus) version 5.
  2. Depressed severity will be established with the MADRS (moderate-to-severe depression defined as MADRS ≥25).
  3. Stability of current treatment and use of previous antidepressants and contraindicated medications will be assessed at the screening visit by the researcher based on questions in the case report form.
  4. Urine pregnancy tests will be conducted on females of child-bearing age to exclude pregnancy.

Enrolment and Demographic Variable(s)

The following variables will be assessed for enrolment in the study and for demographic purposes:

  1. Medical history
  2. Previous medication
  3. Basic physical examination (pregnancy test for females, height and weight)
  4. Family history
  5. Demographics (age, gender, socioeconomic status, educational attainment)

Efficacy Measure(s)

A battery of validated outcome measures, focussing on both depressive symptomatology and global clinical and functional status, will be used at baseline and at weeks 2, 4, 8 and 12 post-baseline intervals. Efficacy measures include:

  1. MADRS (primary outcome)
  2. Clinical Global Impression - Improvement (CGI-I) and - Severity (CGI-S) scales
  3. Patient Global Impression - Improvement (PGI-I) scale
  4. Hamilton Anxiety Rating Scale (HAMA)

Functioning and Quality of Life Measures

  1. Quality of life will be assessed using the Quality of life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF). We will look at change in score over time at 12 and 16 weeks.
  2. The Social and Occupational Functioning Scale (SOFAS) will be used to measure of psychosocial (social and occupational) functioning over time at 12 and 16 weeks.
  3. The Range of Impaired Functioning Tool (LIFE-RIFT) will also be used to measure levels of functioning over time at 12 and 16 weeks.

Predictors and Moderators of Response

  1. The Standardised Assessment of Personality-Abbreviated Scale (SAPAS) will be used to identify those with suspected personality disorders and this will be used as a covariate in the analysis and also used as a variable of interest in examining treatment response.
  2. Analysis of biomarkers of oxidative and inflammatory markers will be used to determine how treatment response (if present) correlates to changes in biological markers.
  3. Changes in biomarkers will be used to explore the underlying pathophysiology of depression.

Assessment of Safety

Side-effects will be assessed with open questions and recorded using the standardised adverse events sheet included in the CRF.


Participants will also be asked to provide two blood samples for research analysis. The provision of the blood samples is optional and does not affect participation in the clinical trial. These samples will be collected at baseline and the end of the treatment phase (week 12) and will involve the collection of a 3 tubes of blood (approximately 30 ml, 2 tablespoons) at each collection. This sample will be processed (centrifuged and aliquoted into 500 ?l aliquots) and frozen at -80℃ until the time of analysis.

The research sample will be collected to investigate inflammatory and oxidative stress markers to determine if and how these treatments are impacting at a biological level (in addition to the subjective perception of symptom change). These markers will include inflammatory cytokines, c-reactive protein, oxidative stress markers such as malondialdehyde, oxidised low-density lipoprotein, measures of antioxidant levels, markers of DNA damage (8-hydroxy-2-deoxyguanosine), and growth factors including insulin-like growth factor, epidermal growth factor and BDNF.


Description of Analysis Sample

The sample to be included in the analyses will be all the participants who give consent to participate in the study and who meet all inclusion criteria and no exclusion criteria. Participants must also complete at least one post-baseline visit for their data to be included in the analysis.

Method of Statistical Analysis

All analyses will be conducted in accordance with the ICH E9 statistical principles, and are based on all randomised participants with at least one post-baseline observation (intention to treat population). Primary analyses will be undertaken on an intention-to-treat basis, including all participants as randomised, regardless of treatment actually received. Mixed- model repeated measures (MMRM) analyses will be used to analyse change in MADRS score because it has been demonstrated to be superior to the last observation carried forward method for handling missing data in longitudinal designs. The MMRM model includes the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. The MMRM includes all available data at each time point. Results from the analysis of dichotomous data will be presented as proportions, with 95% confidence interval, and Fisher's exact p-value where appropriate. Non-parametric statistics will be used when assumptions for parametric methods are violated. Effect sizes will be calculated using Cohen's guidelines. All tests of treatment effects will be conducted using a two-sided alpha level of 0.05 and 95% confidence intervals. Significance will be defined as p≤0.05.

Sample Size and Power

A total of 60 participants meeting the DSM-IV-TR criteria for MDD, and experiencing moderate to severe illness symptomatology, will be recruited. The primary outcome measure will be change in MADRS score at week 12. For a two tailed analysis42) with α=0.05, Zα = 1.96 and with β=0.2, Zβ = 0.842, N=60 (n=30 in each arm), the study will be powered at 80% to detect a true difference in rating scale score between placebo and minocycline treated groups if the difference of the means is not less than 0.724 times the standard deviation in the control group (effect size).

An effect size of 0.4 or greater for difference in MADRS scores in randomised controlled trials of antidepressants versus placebo has been suggested as necessary to suggest clinical utility for an antidepressant used as monotherapy. Effect sizes of 0.28 to 0.51 have been reported for difference in MADRS score in trials of citalopram and escitalopram after 8 weeks of treatment.43) This suggests that at N=60 the proposed depression study may not be sufficiently powered to detect small effect size differences between placebo and minocycline treated groups for changes in MADRS score if the efficacy of minocycline is not greater than conventional antidepressant monotherapy. However, for a pilot study a sample size of 60 should be sufficient to demonstrate trends that would indicate a need for a larger trial.


The study is currently being conducted at the two Victorian sites and has relevant approval from the Human Research and Ethics Committees. The study is planned to begin recruitment at the Thailand site in May 2014, with the relevant aprpovals in place.

The study has recruited 15 participants to date and is planning to complete the recruitment phase in 2014.


Given the paucity of new therapies for unipolar depression and the burden the illness costs not only at a personal level, but for the wider community and the associated health-economics concerns, this trial is timely. The study may not only provide evidence of a novel therapy for unipolar depression, but may also assist in driving new targets of therapeutic pursuit through the exploration of biomarkers. Overall, we are hopeful that this study may have significant benefit for those with unipolar depression.

The authors would like to acknowledge the support of the Brain and Behavior Foundation, the Australasian Society of Bipolar and Depressive Disorders and the Alfred Deakin Postdoctoral Research Fellowship. We would also like to acknowledge the service support of Barwon Health, Deakin University, The Melbourne Clinic, The University of Melbourne and Chulalongkorn University.
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