New Pharmacologic Approaches to the Treatment of Bipolar Depression

Depression is the most commonly experienced mood state over the life span in individuals with bipolar disorder (BD) and is the primary driver of functional impairment and suicidality in BD. Despite this, there are few effective treatments for BD depression, with only a handful of atypical anti-psychotics and inconsistent evidence for traditional mood stabilizing agents. There have been few major 'breakthroughs' in the treatment of BD depression, and until recently, few agents that work via novel mechanisms of action to exert therapeutic effects. Here, we review treatments for BD depression which are emergent or on the horizon. Included are new atypical anti-psychotics, glutamate modulators (ketamine and cycloserine/lurasidone), neurosteroid modulators (zuranolone), anti-inflammatories and mitochondrial modulators, cannabidiol (CBD) and psilocybin. New atypical anti-psychotics lumateperone and cariprazine have demonstrated efficacy in large-scale, placebo-controlled, double-blind randomized controlled trials (RCT) in treatment of BD depression. Non-racemic amisulpride showed potential therapeutic benefit in one RCT which requires replication. Three small RCTs examined the efficacy of intravenous ketamine in BD depression and showed rapid antidepressant and anti-suicidal effects after a single infusion. Anti-inflammatory and mitochondrial modulators show inconsistent evidence for efficacy. There are currently no adequately powered RCTs of zuranolone, psilocybin or CBD in BD depression to support their use. While there are potentially efficacious, mechanistically novel agents on the horizon, they require further study and validation. Further investigation on how these agents may impact specific subgroups of patients will also advance the field.