The International Journal of Neuropsychopharmacology
November 14, 2018
Bashkim Kadriu, Laura Musazzi, Ioline D. Henter et al.
164 citations
Dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both major depressive disorder and bipolar depression. A single intravenous infusion of the glutamatergic modulator ketamine elicits fast-acting, robust, and relatively sustained antidepressant, antisuicidal, and antianhedonic effects in individuals with treatment-resistant depression. Ketamine's targets include noncompetitive N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput potentiation, and N-methyl-D-aspartate receptor targets on gamma-aminobutyric acid-ergic interneurons. This review describes ketamine and other novel glutamate-based treatments for treatment-resistant depression, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators, along with their putative mechanisms and clinically relevant studies.
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.
Advances in pharmacology (San Diego, Calif.)
January 1, 2020
Bashkim Kadriu, Elizabeth D Ballard, Ioline D Henter et al.
35 citations
Psychiatry is moving toward early identification and intervention to reduce the burden and duration of severe mental illnesses. The rapid-acting antidepressant ketamine has transformed understanding of antidepressant response and expanded treatment options for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response aim to identify biologically enriched subgroups more likely to benefit. This chapter reviews translational biomarkers from imaging, electrophysiology, sleep, circadian rhythms, HPA axis function, metabolism, immune, (epi)genetic, and neurotrophic systems. Ketamine's properties may model new rapid-acting treatments. However, most studies focus on acute effects, and no biomarkers are ready for clinical use.
Translational Psychiatry
May 2, 2022
Ruin Moaddel, Panos Zanos, Cristan Farmer et al.
32 citations
Subanesthetic-dose ketamine produces rapid antidepressant effects, but its mechanism remains unclear. A targeted metabolomic analysis of plasma and cerebrospinal fluid from nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg), along with parallel analysis in mice given ketamine, (2R,6R)-hydroxynorketamine (HNK), or saline, found that both ketamine and HNK affect multiple inflammatory pathways. Some changes were unique to humans or mice, suggesting species differences. Consistently implicated mechanisms across both species and sample types include LAT1, IDO1, NAD+, nitric oxide signaling, and the sphingolipid rheostat.
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.
Translational psychiatry
November 18, 2025
Jenessa N Johnston, Peixiong Yuan, Bashkim Kadriu et al.
2 citations
In neurons derived from induced pluripotent stem cells of five women with treatment-resistant depression (average age 40.2 years), both the glycoprotein reelin and the ketamine metabolite (2R,6R)-hydroxynorketamine increased expression of several synaptic proteins (GluA1, PSD-95, Dab1, Synapsin I, and p-ERK) within one hour, with effects declining by 24 hours. Gene expression changes were similar for both compounds, though only reelin upregulated mTORC1 signaling. The findings suggest that iPSC-derived neurons may serve as a useful in vitro model for studying treatment-resistant depression and testing potential therapeutics.
Research square
February 12, 2026
Jenessa Johnston, Greg Jones, Shiyong Peng et al.
Rapid-acting antidepressants such as ketamine and psychedelics share common downstream effects on gene expression in human cortical neurons, despite targeting different initial receptors. Using stem cells from people with treatment-resistant depression and healthy volunteers, neurons were treated with several compounds. After 6 and 24 hours, gene activity was highly correlated across all drugs, converging on pathways related to inflammation, mTORC1 signaling, and cell growth. One compound, HNK, increased gene activity in excitatory neurons and decreased it in inhibitory neurons. These gene changes matched protein changes in spinal fluid from people given ketamine, supporting the model's relevance for studying antidepressant mechanisms.