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.
Frontiers in Pharmacology
September 2, 2020
Jenessa N Johnston, Jonathan S. Thacker, Charissa Desjardins et al.
25 citations
In adult male rats exposed to repeated corticosterone (a model of depression), ketamine restored the expression of reelin, a protein implicated in depression, and both reelin and ketamine rescued synaptic levels of mTOR and its activated form p-mTOR in the hippocampus and cerebellum, which had been reduced by corticosterone. Reelin, but not ketamine, also normalized serotonin transporter clustering on peripheral lymphocytes. These results suggest ketamine modulates reelin expression and support exploring reelin itself as a potential fast-acting antidepressant.
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.
European Archives of Psychiatry and Clinical Neuroscience
July 13, 2024
Jenessa N Johnston, Carlos A. Zarate, Mark D Kvarta
18 citations
Esketamine, the (S)-enantiomer of racemic ketamine, is an FDA-approved rapid-acting antidepressant for treatment-resistant depression (TRD) that outperforms traditional oral antidepressants. Research on biomarkers predicting response to esketamine remains limited and mostly extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest inflammation and mitochondrial function may contribute to its effects, but these findings require verification. Neuroimaging consistently implicates the prefrontal cortex, striatum, and anterior cingulate cortex. In perioperative settings, esketamine reduces depression and anxiety, correlating with increased brain-derived neurotrophic factor and serotonin. Better-designed biomarker-focused clinical trials are needed to clarify mechanisms and identify patients most likely to benefit.
Progress in neuro-psychopharmacology & biological psychiatry
June 8, 2024
Kaylene K A Scheil, Carla L Sánchez-Lafuente, Brady S Reive et al.
5 citations
Chronic stress reduces reelin, a brain protein, in the hippocampus and causes depression-like behavior. A single dose of reelin or ketamine each reversed these behavioral and molecular effects within one hour, and the benefit lasted at least one week. When given together, reelin and ketamine showed additive effects after one week. The findings suggest that reelin-based treatments could become a new class of rapid-acting antidepressants.
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.
Journal of Neuroendocrinology
January 1, 2026
Hiroe Hu, Yoojin Lee, Alaina N Tillman et al.
1 citation
People with both major depression and post-traumatic stress disorder (PTSD) have lower baseline levels of copeptin, a stable marker of vasopressin secretion, and a blunted reduction in copeptin after a single low-dose ketamine infusion compared to those with depression alone. Copeptin levels were unrelated to depression diagnosis or symptom severity of depression, anxiety, PTSD, anhedonia, suicidal ideation, or childhood trauma, but higher copeptin was linked to verbal aggression, an association weakened by PTSD. These findings point to a possible biological subtype of reduced vasopressin activity in co-occurring depression and PTSD, suggesting copeptin may serve as a peripheral biomarker for central vasopressin-driven circuits in neuropsychiatric disorders.
Research Square
February 12, 2026
Jenessa N 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.