Adding Lithium Might Enable Ketamine's Antidepressant Activity in Ketamine-Resistant Patients, Study Suggests

Lithium may boost ketamine's antidepressant effects in treatment-resistant depression cases where patients do not respond to ketamine alone. Rodent experiments modeled ketamine resistance using ACTH for 14 days. In ketamine-resistant rats, lithium alone produced no antidepressant activity, but the combination of lithium plus ketamine produced robust antidepressant responses on standard rodent behavioral tests. Mechanistically, the combination was associated with elevated biochemical markers, including higher plasma insulin and increased insulin signaling. This fits a proposed pathway where ketamine-related neural plasticity mechanisms overlap with lithium, including AMPA receptor activity and BDNF-linked signaling, while insulin signaling may be a critical modulator missing in ketamine-resistant states. The findings help explain why a prior clinical trial that added lithium to ketamine did not improve outcomes in unipolar depression, suggesting future trials may need a precision medicine approach focused on patients' underlying biology and molecular signaling deficits rather than simply adding lithium universally.