Rapid antidepressant effects of ketamine combined with selective serotonin reuptake inhibitors: Mechanisms and outlook.
Chunfeng Xiao, Xinpeng Xu, Wentao Yao, Yuancan Pan, Song Wan, Jing Wei, Lu Xu
Journal of Psychiatric Research October 21, 2026 DOI: 10.1016/j.jpsychires.2026.10.038 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | Ketamine SSRIs |
| Dose | single subanesthetic dose |
| Topics | Esketamine Ketamine Serotonin |
| Key points | Proposes the GLIMPSE model, which argues that ketamine-SSRI synergy in major depressive disorder is driven upstream by a dorsal raphe-prefrontal cortex 5-HT-glutamate/GABA circuit and converges downstream on metaplasticity and synaptic priming. The authors hypothesize the combination is synergistic rather than additive and outline a serotonin syndrome safety-monitoring protocol plus a research agenda. |
Abstract
Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness. Selective serotonin reuptake inhibitors (SSRIs), while the cornerstone of first-line pharmacotherapy, are limited by delayed therapeutic onset and high rates of nonresponse or partial response. Our previous work demonstrated that a single subanesthetic dose of ketamine or its enantiomers can accelerate SSRI response and enhance efficacy in patients with residual fluctuations after initial improvement. We hypothesize that this combination is synergistic rather than merely additive, although the precise mechanisms remain to be fully characterized. Synthesizing these observations with a comprehensive literature review, we propose the GLIMPSE model (Glu-GABA Long-circuit Integrative Metaplasticity for Psychopathology and Synaptic Efficacy), an integrative framework positing that the dorsal raphe-prefrontal cortex 5-HT-glutamate/GABA circuit functions as an upstream driver, whereas metaplasticity and synaptic priming serve as the key downstream convergence points for ketamine-SSRI synergy. Building on this framework, we further outline a practical safety-monitoring protocol for serotonin syndrome associated with this combination, alongside a future-oriented research agenda grounded in the GLIMPSE model to guide subsequent mechanistic and clinical investigations.
Comparable studies
Other theoretical and historical papers on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics as Medicines: An Emerging New Paradigm General population | 2016 | Theoretical or philosophical paper | |
| Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate | 2018 | Theoretical or philosophical paper | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Dreams, Hallucinogenic Drug States, and Schizophrenia: A Psychological and Biological Comparison | 1983 | Theoretical or philosophical paper | |
| Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cites 22
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
and 17 more in the library