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).
