AbstractBackgroundLithium is widely used as treatment of acute mania and as prophylactic therapy for bipolar disorder. International and national guidelines also consider lithium as a possible treatment of acute bipolar depression. Research on the use of lithium in bipolar depression, however, seems to be limited compared to the data available for its efficacy in the other phases of bipolar disorder.ObjectiveTo provide a systematic review of the evidence for lithium in the treatment of acute bipolar depression and provide directions for further research.MethodA systematic review of clinical studies investigating the use of lithium in bipolar depression was performed using preferred reporting items for systematic reviews and meta‐analyses guidelines in Pubmed, Embase and Psychinfo using the medical subjects headings and free text terms “lithium,” “bipolar depression,” “dosage,” “serum concentration” and “bipolar disorders.”ResultsThis review included 15 studies with a total of 1222 patients, between the age of 18 and 65, suffering from bipolar depression of which 464 were treated with lithium. There are currently only limited and low‐quality data on the efficacy of lithium as a treatment of bipolar depression. It appears that there have been no placebo controlled randomized controlled trials with lithium concentrations that are considered to be therapeutic. The older studies suffered from limitations such as small sample sizes, insufficient treatment lengths, and insufficient monitoring of serum concentrations.ConclusionIn contrast to data for the treatment of mania and prophylaxis, robust data on the efficacy of lithium in bipolar depression is currently lacking, making it impossible to make conclusions regarding efficacy or inefficacy, for which further research is needed.