Bipolar DisorderPhase 3NCT01403662
Evaluating the Efficacy of Adjunctive Minocycline for the Treatment of Bipolar Depression
A Phase 3 study testing Minocycline in people with Bipolar Disorder and Bipolar Depression, run by University Health Network, Toronto at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Bipolar Disorder, Bipolar Depression, Bipolar I Depression
- What is being tested?
- Minocycline
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 29 participants
- Where
- 1 siteCanada
- Study dates
- Jul 2011to Dec 2014
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 9Show fewer
- Physical injury requiring medical treatment or surgery in the last 6 months
- Pregnant or breast-feeding
- Inability to provide written informed consent.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Pilot, Open-label, 8-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Minocycline for the Treatment of Bipolar Depression
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.
Read the 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).
- Being tested
- Minocycline
- Keywords
- bipolar disorder, depression, major depression, bipolar I depression, bipolar II depression, bipolar I disorder, bipolar II disorder, minocycline, minocin
- Medical subject headings
- Bipolar Disorder, Depression, Depressive Disorder, Major, cyclopia sequence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MinocyclineDrug
Also called Minocin
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.
| Study group | Role | What they receive |
|---|---|---|
| Minocycline | Experimental | Not described Receives: Drug: Minocycline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline to week 8 on the Montgomery Asberg Depression Rating Scale (MADRS)
The MADRS assesses depressive symptoms
Measured: Baseline, Week 1, 2, 4, 6, 8
Secondary outcomes (7)
Change from baseline to week 8 on the Hamilton Depression Rating Scale 17-item (HAMD-17)
The HAMD-17 assesses depressive symptoms
Measured: Baseline, Week 1, 2, 4, 6, 8
Change from baseline to week 8 on the Somatic Symptom Inventory (SSI)
Measured: Baseline, Week 8
Change from baseline to week 8 on the Clinical Global Impression (CGI) Rating Scale
Measured: Baseline, Week 1, 2, 4, 6, 8
Change from baseline to week 8 in the in neurocognitive function
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
Measured: Baseline, Week 8
Monitoring of Side-effects from baseline to week 8 with the Toronto Side Effect Scale (TSES)
Measured: Week 1, 2, 4, 6, 8
Monitoring of suicide severity from baseline to week 8 with the Columbia Suicide Severity Rating Scale (C-SSRS).
Measured: Baseline, Week 1, 2, 4, 6, 8
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)
Measured: Baseline, Week 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2011 (estimated)
- Study startJul 2011
- Primary completionFeb 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Roger McIntyre, University Health Network, Toronto
- Investigators
- Roger S McIntyre, MD, FRCPC, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01403662
- Sponsor's protocol ID
- 3420337
- Status last verified
- Dec 2016
- First submitted
- 18 Jul 2011
- Last updated
- 19 Dec 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49. doi: 10.4088/JCP.08m04666yel. Epub 2009 Nov 3.
PubMed 19895780Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, Olivera-Lopez JI, Jaramillo-Jaimes MT. Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):380-6. doi: 10.1016/j.pnpbp.2007.09.004. Epub 2007 Sep 14.
PubMed 17933448
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot, Open-label, 8-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Minocycline for the Treatment of Bipolar Depression
- ClinicalTrials.gov ID
- NCT01403662
- Acronym / sponsor ID
- 3420337
- Keywords
- bipolar disorder, depression, major depression, bipolar I depression, bipolar II depression, bipolar I disorder, bipolar II disorder, minocycline
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 29 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- Jul 2011
- Primary completion
- Feb 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 27 Jul 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Minocycline | Experimental | Drug: Minocycline |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MinocyclineAlso: MinocinMinocycline (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. | Drug | Minocycline |
Primary outcome
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
7 secondary outcomes
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
Change from baseline to week 8 on the Somatic Symptom Inventory (SSI)
Time frame: Baseline, Week 8
Change from baseline to week 8 on the Clinical Global Impression (CGI) Rating Scale
Time frame: Baseline, Week 1, 2, 4, 6, 8
Change from baseline to week 8 in the in neurocognitive function
Time frame: Baseline, Week 8
Monitoring of Side-effects from baseline to week 8 with the Toronto Side Effect Scale (TSES)
Time frame: Week 1, 2, 4, 6, 8
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2016.
- Background: PubMed 19895780Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49. doi: 10.4088/JCP.08m04666yel. Epub 2009 Nov 3.
- Background: PubMed 17933448Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, Olivera-Lopez JI, Jaramillo-Jaimes MT. Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):380-6. doi: 10.1016/j.pnpbp.2007.09.004. Epub 2007 Sep 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roger S McIntyre, MD, FRCPC principal investigator
University Health Network, Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Minocycline in people with Bipolar Disorder and Bipolar Depression, run by University Health Network, Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline to week 8 on the Montgomery Asberg Depression Rating Scale (MADRS) (time frame: Baseline, Week 1, 2, 4, 6, 8). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01403662, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2016.