Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD

Nathan Wellington; Ana Bouças; Jim Lagopoulos; Bonnie Quigley; Anna Kuballa

doi:10.1007/s00213-025-06756-4

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Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD

Journal article

Open access

Peer reviewed

Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD

Nathan Wellington, Ana Bouças, Jim Lagopoulos, Bonnie Quigley and Anna Kuballa

Psychopharmacology, Vol.242, pp.1197-1243

2025

DOI: https://doi.org/10.1007/s00213-025-06756-4

PMCID: PMC12084251

PMID: 40097854

Appears in Thompson Institute Research Collection

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Abstract

Pharmacogenomics

Medical molecular engineering of nucleic acids and proteins

Molecular evolution

Expanding knowledge in psychology

Expanding knowledge in the biomedical and clinical sciences

post-traumatic stress disorder

ketamine

molecular biology

epigenetics

medical genetics

PTSD

BDNF

synaptic plasticity

NMDA

memory reconsolidation

gene expression

pharmocokinetics

pharocodynamics

Thompson Institute Special Collection

UniSC Diversity Area - Disability and Inclusion

Rationale Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine’s acute treatment effects on post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for the development of targeted interventions. Objectives This systematic review examines the pharmacokinetic and pharmacodynamic effects of ketamine on PTSD, differentiating between immediate and sustained molecular effects. Method A comprehensive search across databases (Web of Science, Scopus, Global Health, PubMed) and grey literature yielded 317 articles, where 29 studies met the inclusion criteria. These studies included preclinical models and clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, and neural pathways (PROSPERO ID: CRD42024582874). Results We found accumulating evidence that the immediate effects of ketamine, which involve changes in GABA, glutamate, and glutamine levels, trigger the re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95. Other molecular influences also include c-Fos, GSK-3, HDAC, HCN1, and the modulation of hormones like CHR and ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained effects arise from neurotransmitter remodulations and involve prolonged changes in gene expression. These include mTOR-mediated BDNF expression, alterations in GSK-3β, FkBP5, GFAP, ERK phosphorylation, and epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC). Conclusion These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine’s effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.

Details

Title: Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD
Authors: Nathan Wellington (Corresponding Author) - University of the Sunshine Coast, Queensland, Thompson Institute
Ana Bouças (Author) - University of the Sunshine Coast, Queensland, Thompson Institute
Jim Lagopoulos (Author) - Thompson Brain and Mind Healthcare (Australia)
Bonnie Quigley (Author) - University of the Sunshine Coast, Queensland, Thompson Institute
Anna Kuballa (Author) - University of the Sunshine Coast, Queensland, Centre for Bioinnovation
Publication details: Psychopharmacology, Vol.242, pp.1197-1243
Publisher: Springer
Date published: 2025
DOI: 10.1007/s00213-025-06756-4
ISSN: 1432-2072
PMID: 40097854; PMC12084251
Copyright note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Data Availability: All data analysed in this systematic review were obtained from previously published studies, which are publicly available. A full list of included studies and their sources is provided in the manuscript and supplementary material.
Organisation Unit: School of Health - Biomedicine; Thompson Institute; Centre for Bioinnovation
Language: English
Record Identifier: 991112352202621
Output Type: Journal article

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