Acute and long-term effects of repeated ketamine infusions in treatment-resistant depression and associated metabolite changes.
Hitoshi Sakurai, Daiki Setoyama, Takahiro A Kato, Hisateru Tachimori, Masami Murao, Yasuyuki Matsumoto, Teruo Tada, Yayoi Imamura, Hiroyuki Seki, Takashi Tsuboi, Hiroyuki Uchida, Koichiro Watanabe
Psychiatry and Clinical Neurosciences July 15, 2025 DOI: 10.1111/pcn.13870 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label study Peer reviewed |
|---|---|
| Sample size | 30 |
| Population | Patients with treatment-resistant depression |
| Intervention | Ketamine |
| Dose | 0.5 mg/kg |
| Duration | 2-week intervention, 12-month follow-up |
| Topics | Depression Ketamine Esketamine |
| Keywords | 3‐hydroxybutyrate Metabolomics Treatment‐resistant depression Depression treatment Biomarkers Personalized medicine |
| Citations | 1 |
| Key points | Early increases in 3-hydroxybutyrate levels predicted antidepressant response to repeated ketamine infusions, but sustained remission was achieved in only a minority of patients. |
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).
Comparable studies
Other non-randomized and open-label trials on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder Subjects with DSM-IV-diagnosed treatment-resistant major depressive disorder | 2010 | Open-label trial | n = 33 |
| Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression Adults (≥ 18 years) with treatment-resistant depression | 2020 | Phase 3, open-label, multicenter, long-term study | n = 802 |
| Intravenous arketamine for treatment-resistant depression: open-label pilot study Humans with treatment-resistant depression | 2020 | Open-label pilot trial | n = 7 |
| A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide. Hospitalized patients with Major Depressive Disorder and acute suicidal ideation and... | 2024 | Open label study | n = 17 |
| Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression Participants with DSM-IV-defined major depressive disorder and treatment-resistant... | 2014 | Pooled analysis of three clinical trials | n = 97 |
Citations in the library
Cited by 3
- Effects of Repeated Ketamine Infusions on Suicidal Ideation in Treatment-Resistant Depression and Associated Changes in Selected Plasma Biomarkers Pharmacopsychiatry October 2, 2026
- Peripheral Biomarkers of Response to Ketamine and Esketamine Treatment in Unipolar Depressive Disorder—A Scoping Review Journal of Personalized Medicine September 23, 2026
- Multimodal predictors of response to intravenous ketamine in treatment-resistant depression: toward personalized treatment in major depressive and bipolar disorders. CNS Spectrums September 28, 2026
Cites 12
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
- Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine May 24, 2023
- Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. Journal of Affective Disorders 2019
- Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. Journal of Psychiatric Research May 1, 2022
- Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder International Journal of Environmental Research and Public Health April 17, 2018
and 7 more in the library