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Evaluating the Efficacy of Adjunctive Minocycline for the Treatment of Bipolar Depression

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01403662
Recruitment Status : Completed
First Posted : July 27, 2011
Last Update Posted : December 19, 2016
Information provided by (Responsible Party):
Roger McIntyre, University Health Network, Toronto

Brief Summary:
Long-term studies have emphasized that depressive symptoms and episodes account for majority of the illness burden experienced by individuals with bipolar disorder (BD). Previous studies have shown that blood levels of proteins called pro-inflammatory cytokines are abnormal in individuals with bipolar depression. The investigators hypothesize that preventing the production or release of pro-inflammatory cytokines will result in improvement of depressive symptoms in individuals with bipolar depression. Minocycline is a medication that inhibits the activation of immune cells (i.e. microglia) in the brain and reduces the production of pro-inflammatory cytokines. Treatment with minocycline has been shown to have antidepressant-like effects in animal studies and improve symptoms of individuals with schizophrenia. In this study, minocycline (100 mg twice a day) will be administered for 8 weeks to determine if it is an efficacious antidepressant for individuals with bipolar depression.

Condition or disease Intervention/treatment Phase
Bipolar Disorder Bipolar Depression Bipolar I Depression Bipolar II Depression Drug: Minocycline Phase 3

Detailed Description:

Bipolar disorder (BD) is associated with a high-rate of non-recovery, recurrence, and inter-episodic dysfunction. Depressive symptoms and episodes dominate the longitudinal course of BD and differentially account for overall illness burden. During the past decade, substantial developments have been made in the pharmacological and psychosocial treatment of bipolar mania and maintenance, with relatively few treatments proven efficacious for bipolar depression. The absence of an explanatory disease model in bipolar disorder has limited the development and evaluation of genuinely novel agents for bipolar disorder.

Several lines of evidence implicate the inflammatory system as consequential and causative to mood disorder. Bipolar disorder is marked by alterations in inflammatory cytokines (e.g. TNF-alpha, IL-6). Moreover, pro-inflammatory activation in both healthy and medically ill individuals is associated with disturbances in affective, cognitive, and somatic function.

The clinical use of cytokine-based therapy has been demonstrated to induce and/or intensify affective symptomatology in non-psychiatric medical patients. Conventional pharmacological treatments (e.g. lithium) for bipolar disorder affects the production of pro-inflammatory cytokines as well as their gene expression. The encompassing aim of the study herein is to develop a novel treatment for bipolar depression based on a model of disease pathophysiology. Minocycline is a semisynthetic second-generation tetracycline, which exerts anti-inflammatory effects that are distinct from its antimicrobial properties.

Minocycline is a potent inhibitor of microglial activation and decreases expression of pro-inflammatory cytokines, chemokines and their receptors and suppresses the activity of matrix metalloproteinases. Minocycline has been shown to exert antidepressant-like properties in preclinical studies. Rats treated with minocycline monotherapy as well as combination treatment with an antidepressant (desipramine) exhibited significantly improved performance on the forced swim test. Adjunctive minocycline has been shown to be efficacious for the treatment of schizophrenia in a double-blind, randomized, placebo-controlled study. Subjects receiving minocycline exhibited a significant improvement in negative symptoms as well as global improvement as measured with the Clinical Global Impression (CGI). Significant improvement was also noted on measures of executive function, including executive function composite score, spatial recognition memory, cognitive planning, and intradimensional/extradimensional set shifting.

A total of 40 individuals between the ages of 18 and 65 meeting DSM-IV-TR criteria for a current major depressive episode as part of bipolar I or II disorder will be enrolled into an 8-week, open-label study with adjunctive minocycline (100 mg every 12 hours).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Open-label, 8-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Minocycline for the Treatment of Bipolar Depression
Study Start Date : July 2011
Actual Primary Completion Date : February 2014
Actual Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bipolar Disorder

Arm Intervention/treatment
Experimental: Minocycline Drug: Minocycline
Minocycline (100 mg bid) will be administered as an adjunctive agent to conventional Health Canada-approved, or first-line CANMAT bipolar guideline-recommended, agents for bipolar disorder.
Other Name: Minocin

Primary Outcome Measures :
  1. Change from baseline to week 8 on the Montgomery Asberg Depression Rating Scale (MADRS) [ Time Frame: Baseline, Week 1, 2, 4, 6, 8 ]
    The MADRS assesses depressive symptoms

Secondary Outcome Measures :
  1. Change from baseline to week 8 on the Hamilton Depression Rating Scale 17-item (HAMD-17) [ Time Frame: Baseline, Week 1, 2, 4, 6, 8 ]
    The HAMD-17 assesses depressive symptoms

  2. Change from baseline to week 8 on the Somatic Symptom Inventory (SSI) [ Time Frame: Baseline, Week 8 ]
  3. Change from baseline to week 8 on the Clinical Global Impression (CGI) Rating Scale [ Time Frame: Baseline, Week 1, 2, 4, 6, 8 ]
  4. Change from baseline to week 8 in the in neurocognitive function [ Time Frame: Baseline, Week 8 ]
    California Verbal Learning Test- second edition (CVLT-II), Process Dissociation Task, Trail Making Test A and B, Verbal Fluency- Delis-Kaplan Executive Function System (D-KEFS,) Digit Symbol Substitution, Cognitive Failures Questionnaire

  5. Monitoring of Side-effects from baseline to week 8 with the Toronto Side Effect Scale (TSES) [ Time Frame: Week 1, 2, 4, 6, 8 ]
  6. Monitoring of suicide severity from baseline to week 8 with the Columbia Suicide Severity Rating Scale (C-SSRS). [ Time Frame: Baseline, Week 1, 2, 4, 6, 8 ]
  7. Change from baseline to week 8 in concentrations of pro-and anti-inflammatory cytokines (e.g. TNFα, IL-1β, IL-2, IL-6, IL8, IFNγ, IL-4, IL-5, IL-10) [ Time Frame: Baseline, Week 8 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Diagnosis of bipolar I or II disorder
  • Meets criteria for a current major depressive episode
  • A score of >= 20 on the HAMD-17 at the time of enrollment and at baseline
  • Episode duration will be greater than 4 weeks but not longer than 12 months.

Exclusion Criteria:

  • Insufficiently responding to >2 treatment strategies FDA/Health Canada-approved/guideline recommended for bipolar depression
  • Acute manic or mixed episode
  • An Axis I psychiatric disorder requiring primary clinical attention
  • Clinically significant medical illness
  • Treatment with minocycline or β-lactam antibiotics in the preceding 6 months
  • Hypersensitivity to minocycline or any other tetracycline
  • Physical injury requiring medical treatment or surgery in the last 6 months
  • Pregnant or breast-feeding
  • Inability to provide written informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01403662

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Canada, Ontario
University Health Network
Toronto, Ontario, Canada, M5T 2S8
Sponsors and Collaborators
University Health Network, Toronto
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Principal Investigator: Roger S McIntyre, MD, FRCPC University Health Network, Toronto
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Responsible Party: Roger McIntyre, Principal Investigator, University Health Network, Toronto Identifier: NCT01403662    
Other Study ID Numbers: 3420337
First Posted: July 27, 2011    Key Record Dates
Last Update Posted: December 19, 2016
Last Verified: December 2016
Keywords provided by Roger McIntyre, University Health Network, Toronto:
bipolar disorder
major depression
bipolar I depression
bipolar II depression
bipolar I disorder
bipolar II disorder
Additional relevant MeSH terms:
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Depressive Disorder
Bipolar Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Bipolar and Related Disorders
Anti-Bacterial Agents
Anti-Infective Agents