247. DOES EXCITATORY/INHIBITORY BALANCE PREDICT KETAMINE RESPONSE IN TREATMENT-RESISTANT DEPRESSION? A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL WITH 1H-MRS

Abstract Background Only 18-45% of individuals with treatment-resistant depression (TRD) respond to intravenous ketamine therapy. Although some neurobiological predictors of response to ketamine have been reported, none have been consistently replicated across multiple studies. The imbalance between glutamatergic excitatory and GABAergic inhibitory neurotransmissions is implicated in the mechanism of action of ketamine treatment in TRD. However, existing evidence on the association between neurometabolite levels and response to ketamine in TRD remains inconsistent. One of the major limitations of previous studies was that they focused on glutamate, glutamine, or GABA, separately, and did not investigate the ratio of glutamate and glutamine (Glx) to GABA (i.e., Glx/GABA ratio) as an indicator of excitatory/inhibitory (E/I) balance. Aims & Objectives This study aimed to assess whether the baseline Glx/GABA ratio in the dorsal anterior cingulate cortex (dACC) could predict ketamine response in individuals with TRD. Method This exploratory study analyzed data from a double-blind, randomized controlled trial with an open-label extension (jRCTs031210124) conducted between August 2021 and October 2023. 31 individuals with TRD aged 20-59 years were included. 15 individuals in the ketamine group and 15 of 16 individuals in the placebo group received a total of four ketamine infusions (0.5 mg/kg) during the double-blind and open-label extension periods, respectively. Proton magnetic resonance spectroscopy (1H-MRS) was used to measure Glx and GABA levels in the dACC before and after treatment during the double-blind period. The 17-item Hamilton Depression Rating Scale (HDRS-17) was used to measure depressive symptoms. We used general linear models to examine the relationship between baseline Glx/GABA ratio and HDRS-17 score changes. Moreover, we fit separate simple linear regression models to assess the correlations between percent changes in the Glx/GABA ratio and HDRS-17 score changes in the ketamine and placebo treatment groups. Results The mean age of the entire sample was 42.1 (±9.4) years, with 8 (26.7%) individuals being females, and all individuals were Japanese. Changes in HDRS-17 scores following ketamine treatment were -4.9 (±6.5) in the double-blind group and -4.9 (±5.2) in the open-label extension group. Baseline demographic and clinical characteristics did not differ significantly between the groups. A higher baseline dACC Glx/GABA ratio was correlated with a greater improvement in HDRS-17 total score (β = -0.40, p = 0.046). In the ketamine group, a reduction in the dACC Glx/GABA ratio was correlated with a greater HDRS-17 score improvement (β = 0.74, p = 0.010), whereas no such association was observed in the placebo group. Discussion & Conclusions This study demonstrated that a higher baseline Glx/GABA ratio in the dACC predicted a better treatment outcome, and that a reduction in the Glx/GABA ratio was linked to the antidepressant effects of ketamine in individuals with TRD. These results suggest that the dACC Glx/GABA ratio could serve as a potential biomarker for predicting the antidepressant effects of ketamine in individuals with TRD. Further investigations with larger sample sizes are warranted to validate the role of E/I balance in relation to the ketamine treatment in this population.