Acute and long-term effects of repeated ketamine infusions in treatment-resistant depression and associated metabolite changes.

In an open-label study of 30 patients with treatment-resistant depression, four intravenous ketamine infusions (0.5 mg/kg) over two weeks rapidly reduced depression severity: the average Montgomery-Åsberg Depression Rating Scale score fell from 30.6 to 20.3 after the fourth infusion, and 26.7% of participants achieved remission. However, only 13.3% remained in remission at 12 months. Early changes in the metabolite 3-hydroxybutyrate predicted the degree of improvement both after the fourth infusion and at 12 months, suggesting it could serve as a biomarker for treatment response. The findings point toward more individualized use of ketamine infusions.

Study at a glance

Abstract

This study aims to investigate the acute and sustained antidepressant effects of repeated ketamine infusions in patients with treatment-resistant depression (TRD), and to identify early metabolomic changes predictive of treatment outcomes using metabolome analyses. This open-label study investigated the effects of four intravenous ketamine infusions (0.5 mg/kg) administered over 2 weeks in 30 patients with TRD. Clinical outcomes, including the Montgomery-Åsberg Depression Rating Scale (MADRS), were evaluated at baseline, 1-2 h after each infusion, and monthly during a 12-month follow-up. Plasma levels of 11 depression-associated metabolites were measured at baseline and 1.5-2 h after the first infusion. A general linear model was employed to analyze the association between metabolite changes after the first infusion and the MADRS score percent improvements after the fourth infusion and at 12 months. Remission was defined as a MADRS score of ≤10. All participants completed the four infusions. The MADRS score decreased from 30.6 ± 6.1 at baseline to 20.3 ± 11.5 after the fourth infusion, with a remission rate of 26.7%. At 12 months, 13.3% of participants remained in remission. Changes in 3-hydroxybutyrate levels after the first infusion predicted the MADRS score percent improvements after the fourth infusion (β = 1.35, 95% CI: 0.41-2.30, P = 0.005) and at 12 months (β = 1.38, 95% CI: 0.37-2.39, P = 0.007). While repeated ketamine infusions demonstrated rapid antidepressant effects, sustained remission was achieved in a minority of patients with TRD. 3-Hydroxybutyrate may serve as a biomarker for predicting treatment response. These findings underscore the potential for individualized strategies using ketamine infusions. jRCTs031210648 (Japan Registry of Clinical Trials).