Targeting the immune system in the treatment of bipolar disorder

Rationale Immune dysfunction has been strongly implicated in the pathophysiology of bipolar disorder (BD). As such, numerous clinical trials have investigated the effects of anti-inflammatory agents in the treatment of BD. Objectives Review clinical studies evaluating the effects of anti-inflammatory agents in the treatment of BD during all illness phases (e.g., depression, mania, and euthymia). Methods Relevant databases were searched from inception to August 27, 2018 for clinical studies evaluating the effects of anti-inflammatory agents in BD. Results The majority of identified clinical trials evaluated adjunctive anti-inflammatory agents in the acute treatment of bipolar depression, demonstrating antidepressant effects with N-acetylcysteine (NAC), pioglitazone, minocycline, and coenzyme Q10, along with mixed evidence for omega-3s, and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-manic effects of adjunctive anti-inflammatory agents have been minimally studied, with some promising preliminary results supporting potential anti-manic effects of adjunctive celecoxib and NAC. Maintenance studies are also limited, with inadequate evidence to support mood stabilizing effects of anti-inflammatories while euthymic. Regardless of illness phase, early results suggest that anti-inflammatory agents are likely most beneficial in the subgroup of BD with immune dysregulation. Conclusions Several proof-of-concept clinical trials have shown promising results for anti-inflammatory agents in the treatment of bipolar depression with moderate effect sizes and good tolerability. The effects of anti-inflammatory agents during manic and euthymic periods remains uncertain. Future larger studies, using stratified samples, enriched for participants with immune dysfunction, are required to determine the role of immune modulating agents in the treatment of BD.