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

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. 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). Most preclinical studies (<i>n</i> = 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. 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. This study looked at how ketamine, a fast-acting antidepressant, may work by changing the way genes are turned on or off – not by altering DNA itself, but through epigenetic mechanisms. These changes can affect how brain cells function and recover from stress and depression. We reviewed 18 studies that explored how ketamine affects gene expression through epigenetics, including studies in animals and a few in humans. These studies focused on three types of gene control: histone changes, DNA methylation, and microRNAs – tiny molecules that can turn genes off. Ketamine can boost brain plasticity by loosening tight DNA structures (via histone acetylation); reactivate genes that were shut down by stress (by removing DNA methylation); alter microRNAs, which affect brain growth factors like BDNF, helping reverse symptoms of depression. Understanding how ketamine changes gene activity helps us figure out why it works so quickly – and why it may work when other antidepressants don’t. It also points to possible biomarkers (like specific microRNAs in the blood) that could help predict who will benefit from treatment. More research is needed in humans, especially to understand differences by sex, age, and cell type. This could lead to personalized treatments for depression and better use of ketamine in the clinic.