BackgroundResidual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects.AimsWe conducted a double-blind crossover study of a low dose (15 mg, ‘placebo’) and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine.MethodThirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning.ResultsThe active dose of methylene blue significantly improved symptoms of depression both on the Montgomery–Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects.ConclusionsMethylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.