Evaluating the Efficacy of Adjunctive Minocycline for the Treatment of Bipolar Depression
Condition: Bipolar Disorder; Bipolar Depression; Bipolar I Depression; Bipolar II Depression
MeSH terms: Depression; Depressive Disorder; Bipolar Disorder
Study type: Interventional
Phase: Phase 3

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.
    

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).
    

Intervention name(s): Minocycline
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Minocin
Intervention MeSH terms: Minocycline
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: bipolar disorder; depression; major depression; bipolar I depression; bipolar II depression; bipolar I disorder; bipolar II disorder; minocycline; minocin