Psychopharmacology
June 1, 2025
Nathan J Wellington, Ana P Boųcas, Jim Lagopoulos et al.
16 citations
Ketamine's immediate effects on PTSD involve changes in GABA, glutamate, and glutamine levels that trigger re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95, along with other molecular influences. Sustained therapeutic effects arise from neurotransmitter remodulations and prolonged changes in gene expression, including mTOR-mediated BDNF expression and epigenetic modifications. These molecular changes promote long-term synaptic stability and re-regulation in key brain regions. Understanding these sustained mechanisms is critical for developing safe and effective personalised treatments.
Clinical Case Reports
December 1, 2022
Adem T. Can, Daniel F. Hermens, Jim Lagopoulos
6 citations
A single patient with severe treatment-resistant depression received maintenance therapy with very low-dose subcutaneous ketamine, following initial improvement with intravenous ketamine. A retrospective chart review showed that this approach sustained the antidepressant response without significant side effects, suggesting a potential alternative maintenance strategy for patients who respond to intravenous ketamine but require ongoing treatment.
European archives of psychiatry and clinical neuroscience
May 21, 2024
Zack Y Shan, Adem T Can, Abdalla Z Mohamed et al.
3 citations
Ketamine treatment for chronic suicidality alters how brain networks synchronize and transition over time. In a 6-week open-label trial with 29 patients, those who received ketamine showed significantly more transitions among whole-brain connectivity states after treatment. At a 10-week follow-up, patients spent more time in and more frequently visited a highly synchronized brain state, and these changes correlated with reduced suicidal ideation scores. Patients who persistently responded to ketamine had a higher baseline fraction of a cognitive control network state with strong connections, suggesting that pre-treatment brain connectivity patterns may help predict who will benefit from ketamine therapy. These findings point to a biological mechanism for ketamine's suicide-prevention effects.
Australian & New Zealand Journal of Psychiatry
December 17, 2025
Megan Dutton, Paul Schwenn, Jules Mitchell et al.
1 citation
Australia reclassified psilocybin as a Schedule 8 substance for treatment-resistant depression, a major policy shift. Implementation faces challenges: limited prescriber access, no Australian Register of Therapeutic Goods-listed products, lack of standardized training, and high costs. Ethical issues include informed consent, cultural safety, and therapeutic fidelity in trauma-informed care. Recommendations include national training accreditation, fidelity monitoring, and research into neurobiologically informed stratification models for treatment. These steps aim to ensure safe, equitable, and evidence-based integration of psilocybin-assisted therapy into Australia's mental health system.
medRxiv
May 27, 2025
Nathan J Wellington, Ana Paula Bouças, Paul Schwenn et al.
1 citation
preprint
People with post-traumatic stress disorder who had a sustained clinical response to oral ketamine showed distinct baseline differences in DNA methylation and gene expression across 112 genes compared with non-responders. Key biomarkers included DENND5B, ZFY, PDGFRA, CPT1A, AHRR, and others involved in metabolism, cell signaling, neuronal development, immune response, and synaptic plasticity. Non-responders had persistent dysregulation in these pathways, suggesting biological barriers to treatment. Clinically, sustained responders had more severe PTSD at baseline and responded at lower ketamine doses. The findings point toward molecular profiling that could help personalize ketamine therapy for PTSD.
medRxiv Preprint Server
November 26, 2024
Bonnie L. Quigley, Adem T. Can, Megan Dutton et al.
1 citation
preprint
A weekly low-dose oral ketamine treatment for six weeks significantly reduced PTSD symptoms in adults with PTSD, many of whom also had depression. PTSD Checklist scores dropped from an average of 40 before treatment to 17 after treatment, and remained reduced at 21 one month later. 73% of participants showed at least a 50% reduction in symptoms after treatment, and 59% maintained that improvement at follow-up. The results suggest oral ketamine is a feasible and tolerable treatment option, comparable to intravenous ketamine, and may overcome limitations of IV administration.
medRxiv Preprint Server
May 26, 2025
Nathan J. Wellington, Bonnie L. Quigley, Ana P. Bouças et al.
preprint
A six-week course of oral ketamine produced substantial and persistent changes in gene expression in 23 people with PTSD. Short-term effects included suppression of inflammation and antimicrobial activity; long-term effects shifted toward sustained immune regulation, inflammation remodulation, and tissue repair. Over four weeks, the number of genes whose activity changed rose by 37%, the magnitude of expression changes increased 6.5-fold, and pathway activity strengthened 8.8-fold. Key immune and inflammatory pathways modulated included interferon alpha/beta signaling, IL-17 signaling, cytokine storm signaling, neutrophil degranulation, and antimicrobial peptide signaling. Central regulators such as IL-6, IL-1β, IFI27, IL-10, CXCL8, SOCS1/3, and CAMP were implicated. These molecular changes point to mechanisms underlying ketamine's long-term therapeutic effects and suggest avenues for personalized maintenance therapy to prevent relapse.
medRxiv Preprint Server
March 2, 2025
Bonnie L. Quigley, Emerald Orr, Sophie Kafka et al.
preprint
In a 6-week open-label trial of low-dose oral ketamine for PTSD, blood samples from 25 participants showed a small but significant decrease in both BDNF and VEGF-A levels after treatment, with a positive correlation between the two biomarkers. This suggests ketamine's effects may involve a reciprocal interaction between BDNF and VEGF-A, offering potential insight into a biological mechanism for PTSD symptom reduction. Novel relationships between FKBP51, serotonin, and clinical scales were also observed. No significant changes in immune cytokines were detected, possibly because half the participants had low-grade inflammation and half did not.
Brain and behavior
November 1, 2024
Jules S Mitchell, Toomas E Anijärv, Adem T Can et al.
Subanesthetic doses of ketamine show promise for treating suicidality, but predictive biomarkers are lacking. This study examined EEG-derived complexity measures—Lempel-Ziv complexity (LZC) and multiscale entropy (MSE)—in 31 participants receiving six weekly oral doses of racemic ketamine (0.5-3 mg/kg). Responders, defined by a ≥50% reduction in Beck Suicide Scale score or a score ≤6, showed elevated baseline eyes-open complexity compared to nonresponders, which decreased from baseline to post-treatment. Elevated baseline eyes-open LZC in responders was localized to the left frontal lobe. EEG complexity metrics may serve as sensitive biomarkers for predicting and evaluating oral ketamine treatment response.