The lancet. Psychiatry
October 1, 2023
Gustavo C Medeiros, Malcolm Matheson, Isabella Demo et al.
38 citations
A systematic review of 69 neuroimaging studies (1751 participants) found no well-replicated biomarker for ketamine's antidepressant response, but identified several promising candidates. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions, increased functional connectivity within the prefrontal cortex, and increased functional activation of the striatum. The review highlights substantial methodological heterogeneity across studies and calls for further investigation of these biomarkers.
Clinical pharmacology and therapeutics
November 1, 2024
Shruti M Raja, Jeffrey T Guptill, Michelle Mack et al.
34 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (RR-HNK), was tested in a Phase 1 study in healthy volunteers for safety and tolerability. RR-HNK lacks anesthetic and dissociative effects but retains antidepressant and analgesic activity in preclinical models. In single doses from 0.1 to 4 mg/kg and multiple doses of 1 and 2 mg/kg given intravenously over 40 minutes, RR-HNK showed minimal adverse events and no serious adverse events. It did not cause dissociation or sedation. Drug levels in the body increased proportionally with dose, and cerebrospinal fluid analysis confirmed it reached the central nervous system. Some participants showed increases in gamma brain wave activity at lower to mid doses. These results support moving to Phase 2 trials.
Translational psychiatry
November 29, 2024
Gustavo C Medeiros, Isabella Demo, Fernando S Goes et al.
32 citations
Treatment-resistant depression accounts for a large share of the burden of major depressive disorder. Intravenous ketamine and intranasal esketamine are rapid-acting antidepressants that can effectively treat this condition, but response varies. Reliable predictors of response are urgently needed. Clinical predictors of a robust response to ketamine include a family history of alcohol use disorder and a history of childhood trauma. A promising brain-based biomarker is an increase in gamma power in frontoparietal regions measured by EEG. Blood-based biomarkers have shown limited usefulness, with small-effect increases in BDNF being the most consistent indicator. Dissociative symptoms during treatment are not typically associated with response. Most predictors have modest effect sizes, so multivariate models will be needed.
Journal of affective disorders
March 15, 2025
Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros et al.
24 citations
Baseline levels of stress-related hormones (CRF, ACTH, and cortisol) did not significantly influence how well ketamine worked as an antidepressant in people with treatment-resistant depression. However, higher levels of ACTH and CRF were associated with longer overall duration of depressive episodes, suggesting these hormones might serve as biomarkers for chronic depression. Additionally, people who developed depression at a younger age tended to have more severe depressive symptoms, indicating that earlier onset may lead to greater cumulative stress on the brain and body. The study involved 42 participants in a randomized, placebo-controlled, crossover trial.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Kyle A Brown, Musa I Ajibola, Todd D Gould
13 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), maintains antidepressant-like effects in mice without adverse effects. Using brain slices from mice, researchers developed a model to study how HNK produces rapid versus sustained synaptic changes. HNK rapidly strengthened connections between neurons in the hippocampus, an effect that did not require NMDA receptor activity. However, maintaining a primed state that enhanced later long-term potentiation (a form of synaptic plasticity) did require NMDA receptors. HNK's rapid effects depended on adenylyl cyclase 1 and protein kinase A activity. The findings suggest that targeting such priming mechanisms could be a strategy for developing antidepressants.
The American journal of psychiatry
September 1, 2024
Evan M Hess, Dede K Greenstein, Olivia L Hutchinson et al.
12 citations
Ketamine increases pleasure from social situations in people with treatment-resistant depression and promotes helping behavior in rats. In a randomized, double-blind, placebo-controlled study, participants who received a single intravenous dose of ketamine (0.5 mg/kg) reported greater pleasure from being with family or close friends, seeing smiling faces, helping others, and receiving praise for up to one week after treatment, compared to those given placebo. In a rodent experiment, ketamine-treated rats were more willing to forgo obtaining sucrose to protect a cage mate from electric shock, maintaining lower response rates for six days and delivering fewer shocks overall. These findings indicate that ketamine has prosocial, entactogen effects.
Neuron
November 19, 2025
Kyle A Brown, Musa I Ajibola, Gustavo C Medeiros et al.
6 citations
Ketamine, a rapid-acting antidepressant, relieves depression symptoms for days after the drug leaves the body, and repeated doses produce longer-lasting effects. This review proposes that ketamine and similar drugs act as synaptic primers, making synapses more responsive to subsequent doses, a process derived from metaplasticity. The indirect relationship between ketamine's pharmacokinetics and sustained pharmacodynamics defines a dosing model called primer pharmacology, which can optimize therapeutic outcomes. The plasticity mechanisms engaged by antidepressants overlap with those triggered by stress and psychotherapy, suggesting combined treatment strategies. Emerging primers like psilocybin also fit this framework, offering a model to guide clinical and translational psychiatry.
Neuropharmacology
November 1, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
3 citations
Ketamine produces rapid and lasting antidepressant effects in depressed patients. A metabolite called (2R,6R)-hydroxynorketamine (HNK) may contribute to these effects. In anxious male mice, blocking the liver enzyme cytochrome P450 with fluconazole before ketamine or HNK altered drug metabolism: it raised ketamine and norketamine levels in blood and brain but sharply reduced HNK levels. Fluconazole also prevented ketamine's sustained antidepressant-like actions in behavioral tests and its enhancement of cortical GABA levels 24 hours after injection. Giving (2R,6R)-HNK alone reversed fluconazole's blockade of ketamine's antidepressant-like activity. The findings suggest that HNK is essential for ketamine's sustained antidepressant effects and that drug interactions with cytochrome P450 inhibitors may affect ketamine treatment in patients.
Cell reports
May 21, 2025
Lace M Riggs, Sage Aronson, Ta-Chung M Mou et al.
2 citations
A single dose of (2R,6R)-hydroxynorketamine (HNK), a metabolite of ketamine, rapidly strengthens weakened synapses in a rat model of treatment-resistant depression. In plasticity-deficient Wistar Kyoto rats, (2R,6R)-HNK boosted glutamatergic transmission, restored long-term potentiation (LTP), and reversed deficits in hippocampal-dependent memory. The drug selectively increased activity of CA1 pyramidal neurons during novelty exploration and restored spatial recognition memory reliant on Schaffer collateral pathways. Prior spatial learning partially blocked LTP in control rats, a pattern mirrored in LTP-impaired rats where spatial learning deficits were reversed by (2R,6R)-HNK. The findings indicate that (2R,6R)-HNK promotes adaptive synaptic changes at impaired synapses, improving cognitive function.
Journal of psychopharmacology (Oxford, England)
July 13, 2026
Todd D Gould, Sanjay J Mathew, Maurizio Fava et al.
A new pharmacological model called event-driven pharmacology (EDP) is described, in which a plastogen—a drug that induces lasting neural plasticity—produces sustained effects after only transient binding, unlike traditional drugs that require continuous receptor occupancy. Plastogens such as ketamine and classical psychedelics can trigger metaplasticity, priming synapses to respond to later stimuli long after the drug has left the body. Dosing such drugs to maintain constant target occupancy may paradoxically reduce benefits and increase side effects. The EDP model calls for new drug development, dosing strategies, and biomarkers to harness the therapeutic potential of plastogens for depression and other synaptic disorders.
The Journal of neuroscience : the official journal of the Society for Neuroscience
February 3, 2026
Kyle A Brown, Patrick J Morris, Craig J Thomas et al.
The antidepressant effects of ketamine arise from its metabolite (2R,6R)-hydroxynorketamine (2R6R), not from ketamine itself. In mouse hippocampal slices, 2R6R rapidly strengthens synapses and induces long-lasting metaplasticity—a form of plasticity that primes synapses for future change—whereas ketamine alone does not. This rapid and sustained plasticity requires mTOR signaling and can be mimicked by activating mTOR. The sustained phase also depends on IP3 receptors, L-type calcium channels, and delayed BDNF/TrkB signaling, but not on new protein synthesis. The findings outline a sequence of molecular events underlying 2R6R's synaptic actions, with implications for developing rapid-acting antidepressants and understanding activity-dependent plasticity.
bioRxiv : the preprint server for biology
October 22, 2024
Kyle A Brown, Musa I Ajibola, Todd D Gould
preprint
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), rapidly potentiates synaptic transmission at the Schaffer collateral-CA1 synapse in mouse hippocampal slices, an effect that does not require N-methyl-D-aspartate receptor (NMDAR) activity. However, NMDAR activity is necessary to sustain a metaplastic state that lowers the threshold for long-term potentiation (LTP) hours after HNK exposure. The rapid potentiation depends on protein kinase A (PKA) and adenylyl cyclase 1 (AC1), but not AC5. These findings suggest that HNK's rapid synaptic actions initiate sustained priming mechanisms that favor antidepressant-relevant plasticity, offering a target for novel antidepressant strategies.