The International Journal of Neuropsychopharmacology
November 16, 2020
Bashkim Kadriu, Maximillian Greenwald, Ioline D. Henter et al.
98 citations
Both the anesthetic ketamine and classic serotonergic psychedelics such as psilocybin may produce rapid and sustained antidepressant effects after a transient psychoactive period. Evidence suggests a potentially shared mechanism wherein both types of drugs engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. They appear to produce acute alterations in cortical network activity that may initially cause psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. Rapid-acting antidepressants currently under investigation may share downstream pharmacological effects, suggesting related mechanisms of action.
Neuropharmacology
January 13, 2023
Jenessa N Johnston, Bashkim Kadriu, Josh Allen et al.
64 citations
Ketamine and serotonergic psychedelics both show promise as rapid-acting antidepressants, though through different primary mechanisms: ketamine modulates glutamate, while serotonergic psychedelics increase serotonin signaling. However, downstream effects like mTORC1 signaling and GABAA receptor activity appear similar, which may explain their shared antidepressant properties. Research on serotonergic psychedelics remains less advanced than on ketamine, and both face regulatory and methodological challenges, including difficulties with placebo controls in trials and the need for long-term observation.
The International Journal of Neuropsychopharmacology
April 10, 2018
Jessica R. Gilbert, Julia S. Yarrington, Kathleen E. Wills et al.
58 citations
Ketamine, a drug that modulates glutamate signaling, produces rapid antidepressant effects. In a double-blind, crossover, placebo-controlled study, 18 people with major depressive disorder and 18 healthy controls each received a single intravenous infusion of ketamine (0.5 mg/kg) and a saline placebo. Magnetoencephalography measured brain activity during tactile stimulation 6 to 9 hours after each infusion. Dynamic causal modeling revealed that ketamine altered NMDA receptor-mediated connectivity differently in the two groups: backward connections were enhanced in depressed subjects, while forward connections were enhanced in controls. Among depressed subjects, improved mood correlated with reduced NMDA and AMPA connectivity in the somatosensory network. The findings indicate that AMPA- and NMDA-mediated glutamatergic signaling is central to ketamine's antidepressant action.
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.
Bipolar Disorders
April 2, 2025
Adam Fijtman, Mani Yavi, Abigail Vogeley et al.
2 citations
Ketamine rapidly reduces depressive symptoms in treatment-resistant depression but does not improve working memory, attention, or concentration. In a crossover trial, 21 individuals with treatment-resistant depression (14 with bipolar disorder, 7 with major depressive disorder) received ketamine or placebo infusions. Brain activity measured by magnetoencephalography during a working memory task showed increased gamma power in the parieto-occipital junction and decreased gamma power in the posterior superior temporal sulcus and inferior frontal gyrus after ketamine compared to placebo. These distinct gamma power changes in brain regions linked to attention and working memory suggest that ketamine alters neural activity without improving cognitive performance, highlighting the need for further research into its neurobiological mechanisms.
medRxiv Preprint Server
February 22, 2021
Jessica R. Gilbert, Christina S. Galiano, Allison C. Nugent et al.
preprint
A single intravenous infusion of ketamine rapidly reduces depressive symptoms in people with treatment-resistant major depressive disorder. In a double-blind, crossover, placebo-controlled study with 19 depressed individuals and 15 healthy volunteers, magnetoencephalographic recordings were taken before and six to nine hours after drug or placebo infusion while participants performed an emotional face attention task. Dynamic causal modeling revealed that ketamine accelerated GABA and NMDA transmission in the early visual cortex, sped NMDA transmission in the fusiform cortex, and slowed NMDA transmission in the amygdala.
arXiv Preprint Archive
February 4, 2021
Erik D. Fagerholm, Robert Leech, Steven C. R. Williams et al.
Ketamine rapidly reduces depressive symptoms in treatment-resistant major depressive disorder. Using brain imaging and dynamic causal modeling, researchers analyzed neural excitation/inhibition interactions in the primary somatosensory cortex of 18 unmedicated patients and 18 healthy controls during a somatosensory task. Patients were scanned at baseline, 6-9 hours after ketamine infusion, and 6-9 hours after placebo. A shift in neural dynamics toward a stable region of the Poincaré diagram—requiring increased excitatory and inhibitory coupling—predicted symptom improvement specifically after ketamine, not placebo. This drug-specific neural shift may serve as a biomarker for treatment response.