Frontiers in Psychiatry
September 2, 2025
Mina Kheirkhah, Nastasia McDonald, Julia Aepfelbacher et al.
1 citation
Adding mindfulness, music, and a light-occluding eye mask during ketamine infusion for depression did not improve antidepressant effects compared to ketamine alone, but it enriched the subjective experience. Participants in the combined sensory intervention group reported deeper engagement, a stronger sense of connection to reality, increased focus, moments of relief from sadness, and feelings of awe and spiritual insight. However, four individuals in that group reported discomfort. The findings suggest that while the sensory interventions make the experience more meaningful for many, they may cause discomfort for a few, and making them optional could avoid this.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 16, 2026
Nadia S. Hejazi, Mina Kheirkhah, Brady A. Riedner et al.
Slow-wave activity (SWA) during early non-rapid eye movement sleep is lower in people with treatment-resistant depression (TRD) than in healthy volunteers. Ketamine, but not placebo, increases SWA in TRD patients, especially those who respond to treatment, while having no effect on SWA in healthy volunteers. Ketamine also improves overall sleep in TRD patients by increasing total sleep time and sleep efficiency and reducing sleep latency. The increase in SWA after ketamine lessens with age. The findings suggest that ketamine's antidepressant effects are closely tied to its modulation of early sleep SWA and its ability to improve sleep architecture in TRD.
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.
Pharmacological reports : PR
January 22, 2026
Taichi Goto, Joy D Kreskow, Alexander L R Ross et al.
A small pilot trial tested whether a single low dose of ketamine (0.5 mg/kg) can reduce fatigue in people with chronic illnesses such as cancer, fibromyalgia, chronic fatigue syndrome, or lupus. Ten participants received both ketamine and the active placebo midazolam in random order, with a washout period between treatments. Because fatigue levels differed between the two study periods, results were analyzed separately. In the first period, fatigue scores dropped 21.0% after ketamine and 17.7% after midazolam; in the second period, the drops were 10.9% and 12.6%, respectively. The differences were not statistically significant, but the ketamine group showed a peak 38.7% reduction one day after infusion. The authors suggest future studies avoid crossover designs and find a better active placebo.
Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition
September 16, 2025
Jen Evans, Carlos A. Zarate
Ketamine, a rapid-acting antidepressant, changes functional connectivity in the brain in ways that correlate with the density of receptors known to be involved in depression. In a double-blind placebo-controlled trial, participants received an infusion of ketamine or placebo while undergoing resting-state fMRI. The resulting connectivity changes matched several receptor types linked to depression. This method may help evaluate how new drugs affect the brain.
medRxiv
August 28, 2025
Franziska Stadler, Johan Saelens, Ioline D. Henter et al.
preprint
An international online study of 759 people examined how psychedelic drug use affects cognitive performance and mental health in the short and long term. Participants completed tasks measuring working memory, selective attention, and visual/spatial perception, plus questionnaires on mental health and quality of life. Recent users showed significantly lower accuracy on all cognitive tasks and reported more depressive and dissociative symptoms. Lifetime users had the highest task accuracy without slower reaction times, and their use was not linked to long-term cognitive decline. However, lifetime users scored lower on psychological and social quality of life domains, suggesting possible long-term psychosocial effects.
Journal of Affective Disorders
December 15, 2024
Rodrigo Machado‐Vieira, Gregory H Jones, Alan C. Courtes et al.
Fatigue, a multidimensional condition that often overlaps with depression, responds only modestly to standard antidepressants and mood stabilizers but has shown positive response to intravenous ketamine, which is limited by cost and access. This study evaluated a single 50 mg dose of intranasal ketamine in 28 individuals with major depressive disorder or bipolar depression, about 60% of whom also had alcohol use disorder. The group by time interaction for the NIH-Brief Fatigue Inventory score was significant, favoring intranasal ketamine over placebo at 4, 24, and 48 hours post-treatment. Intranasal ketamine was well-tolerated with minimal adverse effects. The findings suggest intranasal ketamine induces rapid anti-fatigue effects and may serve as an alternative rapid-acting option for fatigue across different medical conditions.
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.
CNS Drugs
May 1, 2021
Ioline D. Henter, Lawrence T. Park, Carlos A. Zarate
Many patients with mood disorders such as major depressive disorder and bipolar depression do not respond well to standard antidepressants, creating a need for new treatments. Dysfunction in the brain's glutamate system is thought to play a role in these disorders. Subanesthetic doses of racemic (R,S)-ketamine, a glutamatergic modulator, have been observed to produce rapid reductions in depressive symptoms. This has led to investigation of other glutamate-modulating agents, including broad modulators, glycine site modulators, NMDA receptor antagonists, metabotropic glutamate receptor modulators, and mTORC1 activators. Most are in early development and have shown modest effects compared to (R,S)-ketamine and esketamine, though some have more favorable characteristics. The most promising agents appear to be those targeting ionotropic glutamate receptors.
Drugs
March 1, 2017
Marc S. Lener, Bashkim Kadriu, Carlos A. Zarate
Dysfunction of the glutamatergic system is implicated in mood disorders like major depressive disorder and bipolar depression. Subanesthetic-dose ketamine, which modulates glutamatergic signaling, produces rapid reductions in depressive symptoms in clinical studies. This finding has prompted the repurposing and development of other glutamatergic modulators for antidepressant efficacy, either as monotherapy or adjunct to conventional antidepressants. The review highlights evidence for the antidepressant effects of subanesthetic-dose ketamine and other modulators including D-cycloserine, riluzole, CP-101,606, CERC-301, basimglurant, JNJ-40411813, dextromethorphan, nitrous oxide, GLYX-13, and esketamine.