Journal of psychopharmacology (Oxford, England)
July 13, 2026
Todd D Gould, Sanjay J. Mathew, Maurizio Fava et al.
The occupancy-driven pharmacology model in psychopharmacology has guided drug discovery and development for decades, whereby the goal is stable receptor occupancy over an extended period with a direct relationship of drug exposure to pharmacodynamic and therapeutic response. Event-driven pharmacology (EDP) is a concept where the acute pharmacodynamic actions of a plastogen, a transient binding...
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.
(R,S)-ketamine (ketamine) induces rapid and sustained antidepressant-relevant neuroplastogenic effects in vivo. The metabolite (2R,6R)-hydroxynorketamine (2R6R) forms shortly after the administration of ketamine, and independently elicits rapid plasticity and sustained metaplasticity. Ketamine's therapeutic actions appear to result from distinct, time-sensitive plasticity phases, though the...
Neuron
November 19, 2025
Kyle A Brown, Musa I Ajibola, Gustavo C Medeiros et al.
6 citations
Recent antidepressant drug development focuses on a next generation of drugs to rapidly relieve symptoms. Yet, how ketamine, the prototype rapid-acting antidepressant, maintains symptom relief days after drug elimination, and how repeated doses sustain longer-lasting therapeutic effects, remains unclear. Derived from elements of metaplasticity (synaptic priming), this review discusses a...
Cell Reports
May 21, 2025
Lace M Riggs, Sage Aronson, Ta-Chung M Mou et al.
2 citations
An acute increase in excitatory synaptic transmission contributes to the rapid antidepressant actions of neuroplastogens, including ketamine and its bioactive metabolite, (2R,6R)-hydroxynorketamine (HNK). It is hypothesized that drug-induced metaplastic changes in synaptic strength account for therapeutically relevant behavioral adaptations in vivo. Using the plasticity-deficient Wistar Kyoto...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Kyle A Brown, Musa I Ajibola, Todd D Gould
13 citations
The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination....
Journal of Affective Disorders
March 15, 2025
Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros et al.
24 citations
Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a...
Translational Psychiatry
November 29, 2024
Gustavo C Medeiros, Isabella Demo, Fernando S Goes et al.
32 citations
A large and disproportionate portion of the burden associated with major depressive disorder (MDD) is due to treatment-resistant depression (TRD). Intravenous (R,S)-ketamine (ketamine) and intranasal (S)-ketamine (esketamine) are rapid-acting antidepressants that can effectively treat TRD. However, there is variability in response to ketamine/esketamine, and a personalized approach to their use...
Clinical pharmacology and therapeutics
November 1, 2024
Shruti M Raja, Jeffrey T Guptill, Michelle Mack et al.
34 citations
(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and...
Neuropharmacology
November 1, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
3 citations
(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated...
The American journal of psychiatry
September 1, 2024
Evan M. Hess, Dede Greenstein, Olivia L Hutchinson et al.
12 citations
The authors sought to assess the prosocial, entactogen effects of ketamine. Pleasure from social situations was assessed in a sample of participants with treatment-resistant depression from randomized, double-blind, placebo-controlled studies, using four items of the Snaith-Hamilton Pleasure Scale (SHAPS) at five time points over 1 week following treatment with ketamine (0.5 mg/kg...
Molecular Psychiatry
April 1, 2024
Kyle A Brown, Todd D Gould
45 citations
The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the...
The lancet. Psychiatry
October 1, 2023
Gustavo C Medeiros, Malcolm Matheson, Isabella Demo et al.
38 citations
Ketamine is an effective antidepressant, but there is substantial variability in patient response and the precise mechanism of action is unclear. Neuroimaging can provide predictive and mechanistic insights, but findings are limited by small sample sizes. This systematic review covers neuroimaging studies investigating baseline (pre-treatment) and longitudinal (post-treatment) biomarkers of...
Science (New York, N.Y.)
February 17, 2023
Evan M. Hess, Todd D Gould
9 citations
Psychedelics act on intracellular serotonin receptors that are not accessible by serotonin alone.
Journal of Neuroscience
January 3, 2023
Panos Zanos, Kyle A Brown, Polymnia Georgiou et al.
109 citations
Ketamine is a well-characterized NMDA receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a...
Translational Psychiatry
May 2, 2022
Ruin Moaddel, Panos Zanos, Cristan A Farmer et al.
32 citations
Abstract Subanesthetic-dose racemic ( R,S )-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical...
British Journal of Pharmacology
July 1, 2019
Panos Zanos, Jaclyn N. Highland, Xin Liu et al.
(R)-Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)-ketamine has lower potency than (R,S)-ketamine to inhibit NMDA receptors in vitro, the extent to which (R)-ketamine shares the NMDA receptor-mediated adverse effects of (R,S)-ketamine in vivo has not been fully characterised. Furthermore, (R)-ketamine is metabolised to (2R,6R)-hydroxynorketamine (HNK),...
Proceedings of the National Academy of Sciences
March 13, 2019
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart et al.
153 citations
Significance Despite available medications for depression, currently approved antidepressants take months to exert therapeutic effects, and ∼30% of patients remain treatment resistant. In contrast, a single subanesthetic dose of ketamine exerts rapid (within hours) and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite ( 2R , 6R )-hydroxynorketamine [(...
The Annual Review of Pharmacology and Toxicology
October 9, 2018
Todd D Gould, Carlos A. Zarate, Scott M. Thompson
132 citations
For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal...