Transient effects of multi‐infusion ketamine augmentation on treatment‐resistant depressive symptoms in patients with treatment‐resistant bipolar depression – An open‐label three‐week pilot study

INTRODUCTION: While the psychiatric benefits of ketamine have been verified through clinical trials, there is limited information about ketamine augmentation in patients with treatment‐resistant bipolar depression (TRBPD). Hence, in the present study, we investigate the therapeutic efficacy and functional brain alterations associated with multi‐infusion ketamine augmentation in patients with TRBPD. METHODS: The present three‐week study included 38 patients with TRBPD, all of whom received a series of nine ketamine injections over the study period. The Hamilton Depression Rating Scale (HAMD) was used to assess the effects of multi‐infusion ketamine combined with mood stabilizers. Brain function was evaluated by global functional connectivity density (gFCD). RESULTS: Adjunctive treatment with multiple infusions of ketamine, when combined with a mood stabilizer, could effectively alleviate depressive symptoms for one week, yet the symptoms began to relapse during the second week. Functional brain alterations were detected via gFCD. Specifically, gFCD reductions were mainly found in the bilateral insula, right caudate nucleus, and bilateral inferior frontal gyrus, while increased gFCD was mainly located in the bilateral postcentral gyrus, subgenual anterior cingulate cortex, bilateral thalamus, and cerebellum. Although gFCD alterations were sustained for up to three weeks after the first ketamine infusion, the antidepressant effects of ketamine augmentation sharply declined from the end of the second week of treatment. CONCLUSIONS: Multi‐infusion ketamine augmentation can rapidly alleviate depressive symptoms in patients with TRBPD. The clinical effects were primarily visible in the first week after treatment and partially sustained for two weeks; however, the therapeutic effects and related functional brain alterations sharply decreased from the end of the second week. Based on these findings, we demonstrated that the clinical efficacy and functional brain alterations induced by ketamine augmentation are transient.