The epigenetic mechanisms of ketamine in the treatment of depression: a systematic review

Aim: Ketamine antidepressant effects go beyond immediate receptor action, involving lasting transcriptional and epigenomic changes that support its rapid, long-lasting benefits. The present systematic review synthesized existing preclinical and clinical evidence on the epigenetic mechanisms of ketamine in the treatment of depression. Methods: A comprehensive search of three electronic databases was conducted through April 2025. Of 264 records screened, 18 studies met inclusion criteria most of which were preclinical. The study protocol was registered with PROSPERO (CRD420251063429). Results: Most preclinical studies (n = 7) consistently showed that ketamine may modulate histone acetylation and methylation, boosting transcription of neuroplasticity-related genes. Six studies implicated non-coding RNAs–particularly microRNAs–in sustaining antidepressant effects. Five studies reported that ketamine reversed promoter hypermethylation in genes linked to synaptic signaling and stress, including brain-derived neurotrophic factor, restoring their expression. These effects were strongest in brain areas key to emotional regulation, like the hippocampus, medial prefrontal cortex, and nucleus accumbens. Indirect epigenetic mechanisms have been implicated in the regulation of circadian clock and inflammatory genes. Conclusions: Ketamine may exert multilayered epigenetic modulation, leading to the reactivation of key neuroplasticity pathways. Although preclinical findings were strong, limited human data highlighted the need for translational studies to determine the clinical relevance of these mechanisms.