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

Bipolar Disorder Clinical Trial

Official title:

A Pilot, Open-label, 8-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Minocycline for the Treatment of Bipolar Depression

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01403662
• Other study ID #: 3420337
• Status: Completed
• Phase: Phase 3
• First received: July 18, 2011
• Last updated: December 15, 2016
• Start date: July 2011
• Est. completion date: December 2014

Study information

• Verified date: December 2016
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical 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. 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: December 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 ß-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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bipolar Depression
• Bipolar Disorder
• Bipolar I Depression
• Bipolar II Depression
• Depression
• Depressive Disorder

Intervention

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.

Locations

Country	Name	City	State
Canada	University Health Network	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
University Health Network, Toronto

Country where clinical trial is conducted

Canada, 

References & Publications (2)

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. — View Citation

Molina-Hernández M, Tellez-Alcántara NP, Pérez-García 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline to week 8 on the Montgomery Asberg Depression Rating Scale (MADRS)	The MADRS assesses depressive symptoms	Baseline, Week 1, 2, 4, 6, 8	No
Secondary	Change from baseline to week 8 on the Hamilton Depression Rating Scale 17-item (HAMD-17)	The HAMD-17 assesses depressive symptoms	Baseline, Week 1, 2, 4, 6, 8	No
Secondary	Change from baseline to week 8 on the Somatic Symptom Inventory (SSI)		Baseline, Week 8	No
Secondary	Change from baseline to week 8 on the Clinical Global Impression (CGI) Rating Scale		Baseline, Week 1, 2, 4, 6, 8	No
Secondary	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	Baseline, Week 8	No
Secondary	Monitoring of Side-effects from baseline to week 8 with the Toronto Side Effect Scale (TSES)		Week 1, 2, 4, 6, 8	Yes
Secondary	Monitoring of suicide severity from baseline to week 8 with the Columbia Suicide Severity Rating Scale (C-SSRS).		Baseline, Week 1, 2, 4, 6, 8	Yes
Secondary	Change from baseline to week 8 in concentrations of pro-and anti-inflammatory cytokines (e.g. TNFa, IL-1ß, IL-2, IL-6, IL8, IFN?, IL-4, IL-5, IL-10)		Baseline, Week 8	No