Modest Antisuicidal Effects from Repeated Ketamine in TRD: No Biomarker Breakthrough

Repeated Ketamine Infusions Yield Modest Reductions in Suicidal Ideation

Repeated intravenous ketamine infusions produced modest but statistically significant reductions in suicidal ideation among patients with treatment-resistant depression (TRD), according to a secondary analysis published on October 2, 2026 (OpenAlex W7216096074). Participants received four ketamine infusions (0.5 mg/kg) over two weeks. Suicidal ideation was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS, item 10), Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR, item 12), and Columbia Suicide Severity Rating Scale (C-SSRS).

Mean MADRS item 10 scores decreased from 1.5±1.5 at baseline to 1.0±1.3 post-intervention (p=0.01), and QIDS-SR item 12 scores dropped from 1.3±0.9 to 0.8±0.9 (p=0.01). C-SSRS scores also declined (1.1±1.3 to 0.8±1.2), but this change did not reach statistical significance (p=0.17). These findings reinforce ketamine’s potential for rapid symptom relief in TRD, but the magnitude of effect was modest and did not eliminate suicidal ideation in most participants.

No Statistically Robust Plasma Biomarkers Identified

This study did not identify any plasma biomarkers that robustly correlated with clinical improvement in suicidal ideation after adjusting for multiple comparisons. Eleven targeted plasma biomarkers were measured using liquid chromatography–mass spectrometry. In unadjusted analyses, decreased suicidal ideation showed nominal associations with increased citric acid (r=−0.40, p=0.03) and kynurenic acid (ρ=−0.37, p=0.04) levels. However, these associations did not survive false discovery rate correction, a statistical adjustment to reduce the likelihood of false positives when testing multiple hypotheses.

The lack of definitive biomarkers limits immediate translational impact, as clinicians and researchers remain unable to predict which patients will benefit most from ketamine or to objectively track response. This negative result is particularly notable given the field’s ongoing search for reliable biological markers to guide personalized treatment strategies in depression and suicidality. The study’s rigorous correction for multiple comparisons sets a higher evidentiary bar than many earlier exploratory reports, providing a cautionary note against overinterpreting nominal biomarker findings in small samples.

Implications for Clinical Trials and Future Research

These findings underscore the need for larger, controlled trials to validate both the clinical efficacy and biomarker correlates of repeated ketamine infusions in TRD. The open-label design and modest sample size limit generalizability, as placebo effects and regression to the mean cannot be excluded. Importantly, the study demonstrates the feasibility of serial biomarker sampling in this population, which may inform future multicenter trials powered to detect smaller effect sizes and to apply more comprehensive -omics approaches.

For trial designers, the failure to identify robust plasma biomarkers in this cohort suggests that future studies should consider broader panels, alternative matrices (such as cerebrospinal fluid or neuroimaging), and more granular timepoints. The study also highlights the challenge of balancing exploratory biomarker discovery with the statistical rigor required to avoid false leads—a recurring issue in psychiatric biomarker research.

Risks, Limitations, and Unknowns

While repeated ketamine infusions were generally associated with modest improvements in suicidal ideation, the durability and clinical significance of these effects remain uncertain. The absence of a control group means that spontaneous improvement or expectancy effects cannot be ruled out. Additionally, the study did not report on adverse events or dissociative side effects, which are clinically relevant given ketamine’s known risk profile.

The lack of robust biomarkers also raises questions about the underlying mechanisms of ketamine’s antisuicidal action. The nominal associations with citric acid and kynurenic acid—both involved in neuroenergetics and glutamatergic signaling—are hypothesis-generating but not actionable. The field still lacks a clear mechanistic bridge between ketamine’s rapid clinical effects and measurable changes in peripheral biology.

Outlook: Guiding Future Discovery and Clinical Practice

Although this study did not deliver a biomarker breakthrough, it contributes to the evidence base informing future trial design and biomarker discovery in psychedelic and rapid-acting antidepressant research. The modest clinical effect observed supports continued investigation of ketamine in TRD, but also highlights the need for more precise patient selection and monitoring tools.

For policy-makers and clinicians, the findings reinforce the importance of cautious, evidence-based adoption of ketamine protocols, with an emphasis on safety monitoring and realistic expectations regarding efficacy. For researchers, the negative biomarker results serve as a reminder to prioritize adequately powered, controlled studies and to publish null findings, which are critical for refining hypotheses and avoiding publication bias.

How we research: This article was written by Dr. Alex M. Carter, PhD (Neuroscience), reviewed by Dr. Sarah L. Kim, MD (Psychiatry) on 2026-10-05. Primary data were sourced directly from the published study and linked trial registry.