Reconsidering the gamma–delta shift as a biomarker of antidepressant effects of ketamine enantiomers

We read with interest the article entitled ‘Differential effects of ketamine enantiomers on electroencephalogram (EEG) parameters including the gamma-delta shift phenomenon’ (Koncz et al., 2026). The authors provide valuable electrophysiological data showing that esketamine produced stronger wake-promoting and non-rapid eye movement (NREM) sleep-suppressing effects than arketamine in rats and that only esketamine induced the gamma–delta shift. These findings are of interest in ongoing efforts to identify EEG-based biomarkers of rapid-acting antidepressants. However, we believe that several aspects of the authors' interpretation warrant caution. First, the study was conducted in naïve control rats without depression-like phenotypes (Chang & Hashimoto, 2024). This is an important limitation when proposing the gamma–delta shift as a biomarker of antidepressant efficacy. Ketamine exerts robust antidepressant effects in patients with treatment-resistant depression (TRD), whereas its effects in healthy subjects are qualitatively different and may include aversive or depressive-like symptoms, including anhedonia (Nugent et al., 2019). Therefore, EEG changes observed in healthy animals cannot be assumed to reflect mechanisms underlying antidepressant response in disease-relevant states. Validation of the gamma–delta shift as a biomarker of antidepressant action will require demonstration of its association with behavioural improvement in established rodent models of depression or stress susceptibility, and ideally in patients with major depressive disorder or TRD. Second, the conclusion that the absence of a gamma–delta shift after arketamine is consistent with a lack of antidepressant efficacy in TRD appears premature. Although recent placebo-controlled trials of arketamine did not meet their primary endpoints, these studies were limited by very small sample sizes and substantial placebo effects. Accordingly, the currently available clinical data do not definitively exclude antidepressant efficacy of arketamine under alternative dosing regimens, patient stratification strategies or trial designs. Thus, the present EEG findings in healthy rats should not be used to support strong translational claims regarding the clinical inefficacy of arketamine. In our view, the current study demonstrates that esketamine and arketamine produce distinct EEG signatures in normal rats, but it does not establish that the gamma–delta shift is a specific biomarker of antidepressant efficacy. Rather, the findings suggest that esketamine-induced NMDA receptor inhibition may contribute to the observed EEG changes, including the gamma–delta shift (Koncz et al., 2026). Importantly, dissociative symptoms related to NMDA receptor inhibition are not necessarily associated with antidepressant efficacy (Hashimoto, 2025a, 2025b). From this perspective, the EEG changes observed after esketamine administration may reflect neurophysiological effects associated with NMDA receptor-mediated behavioural changes, including dissociative symptoms and other adverse effects, rather than a specific biomarker of antidepressant response. Future clinical studies should therefore examine EEG changes after esketamine administration in patients with depression and determine whether these alterations are associated with antidepressant response or dissociative symptoms. Overall, further studies using depression-relevant animal models and clinically relevant patient populations will be essential before the gamma–delta shift can be considered a translational biomarker of the antidepressant effects of ketamine enantiomers. Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2025/26 (Alexander et al., 2025). Kenji Hashimoto: Conceptualization; writing—original draft; writing—review and editing. ChatGPT (OpenAI) was used to enhance the readability of the text. Dr. Hashimoto is the inventor on patent applications on ‘The use of R-ketamine in the treatment of psychiatric diseases’, ‘(S)-norketamine and salt thereof as pharmaceutical’, ‘R-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder’, ‘Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases’, ‘R-ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder’ and ‘TGF-β1 in the treatment of depression’ assigned to Chiba University (Chiba, Japan). Dr. Hashimoto has also received research support from Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). No new data were generated.