Lithium Augmentation in Treatment-Resistant Depression: A Qualitative Review of the Literature

Depression is the leading cause of disability worldwide, affecting people of all ages. Both pharmacological and non-pharmacological therapies are available for its treatment. However, some patients do not respond to first-line pharmacological interventions, referred to as treatment-resistant depression (TRD). Individuals with TRD face a significantly higher risk of mortality, including an increased risk of suicide. Additionally, TRD poses a substantial economic burden on health care systems. Various treatment options have been explored for TRD, including augmentation of an antidepressant through the use of an additional agent. Lithium salts have shown promising benefits in the TRD. Lithium requires close therapeutic monitoring due to its narrow therapeutic range, with well-defined thresholds for efficacy and toxicity, in addition to its pharmacokinetic characteristics. Furthermore, lithium has been associated with a reduced risk of mortality by lowering aggression, impulsivity, and suicide rates. Compared with other agents used in the management of TRD—such as atypical antidepressants, second-generation antipsychotics (SGAs), ketamine, and thyroid hormones—lithium is considered a cost-effective augmentation option, alongside other evidence-based strategies, and has a well-established efficacy profile. This literature review examines the role of lithium as an augmentation agent in TRD, with a focus on its pharmacological and clinical properties, as well as the current evidence supporting its use.