Journal of psychiatric researchOct 30, 2026

Fast antidepressant effects of ketamine combined with common antidepressants: How they work and future possibilities

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Nov 2, 2026

Abstract

A single subanesthetic dose of ketamine may accelerate the response to SSRIs in patients with major depressive disorder.

Selective serotonin reuptake inhibitors (SSRIs) often result in delayed effects and high rates of nonresponse in treating major depressive disorder (MDD).
Previous findings indicated that ketamine or its enantiomers can enhance the efficacy of SSRIs in patients experiencing residual symptoms.
The proposed GLIMPSE model suggests that a specific brain circuit plays a crucial role in the interaction between ketamine and SSRIs.
Metaplasticity and synaptic priming are identified as important factors in the synergy between ketamine and SSRIs.
A safety-monitoring protocol for serotonin syndrome associated with the combined use of ketamine and SSRIs is outlined.

Simplified

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.

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Fast antidepressant effects of ketamine combined with common antidepressants: How they work and future possibilities

Abstract

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