Metabolomic correlates of intravenous racemic ketamine in treatment-resistant major depressive disorder: the Bio-K/NNDC multicenter trial
Balwinder Singh, Siamak MahmoudianDehkordi, Jennifer L. Vande Voort, Sagar V Parikh, Eric D Achtyes, Fernando S Goes, William V Bobo, John F Greden, Giselli Scaini, Susannah J. Tye, Mark A Frye, Rima Kaddurah‐Daouk
The World Journal of Biological Psychiatry September 6, 2026 DOI: 10.1080/15622975.2026.2724510 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label trial Peer reviewed |
|---|---|
| Sample size | 69 |
| Population | Adults with treatment-resistant depression and major depressive disorder |
| Intervention | Intravenous racemic ketamine |
| Dose | 0.5 mg/kg |
| Duration | Three infusions, with assessments pre-dose, post-infusion 1, and post-infusion 3; remission assessed at 24 h post-third infusion |
| Measures | MADRS |
| Topics | Depression Esketamine Ketamine |
| Registration | NCT03156504 |
| Key findings | Ketamine infusions produced broad metabolic alterations, including increased acylcarnitines, cortisol, amino acids, and biogenic amines after the first infusion, with persistent elevations in C16, serotonin, and GABA after the third. Remitters showed greater GABA synthesis increases, but no metabolite change correlated with MADRS improvement after multiple-testing correction. |
Abstract
Objective: Ketamine is a rapid-acting antidepressant with an incompletely understood mechanism of action. Pharmacometabolomics can identify pathways underlying its effects and response variability. Using data from the Bio-K trial (NCT03156504), a multisite open-label study, we characterised metabolomic signatures of intravenous (IV) racemic ketamine in adults with treatment-resistant depression (TRD).
Methods: Sixty-nine adults with TRD and major depressive disorder received three ketamine infusions (0.5 mg/kg). Remission was defined as MADRS ≤9 at 24 h post-third infusion. Metabolomic profiling used the Biocrates MxP® Q500 kit (>600 metabolites). Mixed-effects models assessed changes across time points (pre-dose, post-infusion 1, post-infusion 3), adjusting for age, sex, infusion length (first), and body mass index, with false discovery rate correction.
Results: < 0.001); 54% achieved remission. Post-infusion 1, ketamine was associated with increased acylcarnitines, cortisol, amino acids (glutamine, glycine, BCAAs), and biogenic amines (GABA, putrescine), with reduced medium-chain acylcarnitines and glutamate. Post-infusion 3, C16, serotonin, and GABA elevations persisted while cortisol normalised. Remitters showed greater GABA synthesis increases, however, no metabolite change correlated with MADRS improvement after correction for multiple testing.
Conclusions: Ketamine exposure was correlated with broad metabolic alterations spanning mitochondrial activation, neurotransmitter modulation, and neuroendocrine signalling. These findings represent metabolic correlates of ketamine exposure and remission, rather than validated predictors or established mechanistic drivers of antidepressant response.
Trial Registration: ClinicalTrials.gov: NCT03156504.
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 |