Lithium is the standard long-term treatment for bipolar disorder, but only 30% of patients respond, and there is no way to predict who will benefit. Ketamine, a rapid antidepressant, may work better in patients whose symptoms typically predict poor lithium response. This scoping review of 19 preclinical and 23 clinical studies found that ketamine and lithium act on overlapping biological pathways (GSK-3β/mTOR and synaptic plasticity), but the clinical predictors of response diverge: ketamine response is linked to metabolic risk, anxiety, and mixed features—factors that predict poor lithium response. No study directly tested whether ketamine response predicts lithium response. The findings suggest mechanistic overlap but clinical divergence, though sampling bias may confound results.
Lithium is the first-choice long-term treatment for bipolar disorder, but only 30% of patients respond, and there is no reliable way to predict who will. Ketamine, a rapid antidepressant, may work better in patients whose clinical features typically predict poor lithium response. A scoping review of clinical and preclinical studies found that ketamine and lithium converge on the GSK-3β/mTOR pathways and enhance synaptic plasticity, and lithium limits ketamine-related oxidative stress and hyperlocomotion. However, clinical predictors diverge: ketamine response is linked to metabolic risk, anxiety, mixed features, and non-melancholic presentations—factors that generally predict poorer lithium response.