The Journal of Clinical Psychiatry
July 13, 2010
Nancy Diazgranados, Lobna Ibrahim, Nancy E. Brutsché et al.
563 citations
A single infusion of ketamine (0.5 mg/kg) rapidly reduced suicidal thoughts in people with treatment-resistant major depression. Suicidal ideation scores dropped significantly within 40 minutes and remained lower for at least 4 hours. Among the 10 participants who had a score of 4 or higher on the Scale for Suicide Ideation at the start, all dropped below 4—9 within 40 minutes and 1 by 80 minutes. Depression, anxiety, and hopelessness also improved substantially at all measured time points. The findings suggest ketamine may offer a fast-acting intervention for suicidal ideation, a medical emergency with few pharmacologic options.
Harvard Review of Psychiatry
August 1, 2010
Carlos A. Zarate, Rodrigo Machado‐Vieira, Ioline D. Henter et al.
226 citations
Mood disorders like bipolar disorder and major depressive disorder are common, chronic, and recurrent, affecting millions worldwide. Existing antidepressants and mood stabilizers are insufficient for many, with low remission rates, delayed action, residual symptoms, and relapses. New therapeutic agents with faster and sustained effects are urgently needed. The glutamatergic system has been implicated in the pathophysiology of these disorders, with evidence confirming the role of modulators riluzole and ketamine as proof-of-concept agents. Trials with diverse glutamatergic modulators are underway, and this system holds promise for developing next-generation therapeutics.
The Annual Review of Pharmacology and Toxicology
January 6, 2014
Mark J. Niciu, Ioline D. Henter, David A. Luckenbaugh et al.
166 citations
The NMDA receptor antagonist ketamine produces rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression, contrasting with the modest effects of classic monoaminergic antidepressants that take weeks. Open-label and case studies support these properties. Preclinical research has identified three targets—mTOR, eEF2, and GSK-3—as key to its mechanism. Current efforts focus on prolonging ketamine's effects, developing selective NMDA receptor antagonists without its adverse effects, and identifying biomarkers of its antidepressant action.
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.
Discover Mental Health
April 15, 2022
Mani Yavi, Holim Lee, Ioline D. Henter et al.
150 citations
Ketamine and its enantiomer esketamine offer rapid antidepressant effects, often within one day, for treatment-resistant depression, with symptom improvement lasting three to seven days. Esketamine received FDA approval in 2019 as an adjunctive treatment for adults with treatment-resistant depression, administered under medical supervision due to a risk evaluation and mitigation strategy. Side effects such as dissociative symptoms, hypertension, and confusion or agitation are generally tolerable and limited to the time of treatment, though longer-term risks including abuse or dependence remain poorly understood. The drug has also been studied for suicidality, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder. Research on ketamine may also deepen understanding of mood disorder mechanisms and guide development of new treatments.
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.
Harvard Review of Psychiatry
February 21, 2018
Ioline D. Henter, Rafael Teixeira de Sousa, Carlos A. Zarate
94 citations
Glutamatergic system dysfunction is implicated in bipolar depression and major depressive disorder. Subanesthetic doses of ketamine produce rapid reductions in depressive symptoms, prompting the development of other glutamatergic modulators. This review highlights evidence for antidepressant effects of broad modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine, AVP-786, nitrous oxide, AZD6765), NR2B-specific NMDA receptor antagonists (traxoprodil, MK-0657), glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and metabotropic glutamate receptor modulators (AZD2066, basimglurant, JNJ40411813, RG1578).
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.
Acta Psychiatrica Scandinavica
July 17, 2020
Lawrence T. Park, David A. Luckenbaugh, Steven Pennybaker et al.
23 citations
A single intravenous dose of ketamine improved both typical/melancholic and atypical depressive symptoms in people with treatment-resistant major depressive disorder or bipolar depression. At one day after infusion, the effect was larger for typical/melancholic symptoms (Cohen's d = 0.61) than for atypical symptoms (Cohen's d = 0.41), and improvements persisted at day three. The findings suggest ketamine may have early preferential effects on typical/melancholic symptoms, though it benefits both symptom dimensions.
Neuropsychiatric Disease and Treatment
October 1, 2018
Wallace C. Duncan, Elizabeth E. Slonena, Nadia S. Hejazi et al.
17 citations
Patients with major depressive disorder who had a brief antidepressant response to ketamine (lasting 24-48 hours) showed blunted 24-hour wrist activity amplitude from baseline through three days post-infusion and a phase advance of activity on day one that returned to baseline by day three. Those with a continued response (over 72 hours) had phase-advanced activity at baseline and day one, plus increased amplitude on days one and three. Nonresponders did not show these patterns. The time course of antidepressant response to ketamine appears linked to underlying biological differences in motor activity timekeeping, which may involve circadian system mechanisms.
Neuroscience and Biobehavioral Reviews
July 1, 2024
Mina Kheirkhah, Allison C. Nugent, Alicia A Livinski et al.
13 citations
Music and ketamine each influence therapeutic outcomes, yet their combined use is rarely studied. This scoping review maps existing research on administering music alongside ketamine or esketamine in humans. Studies include healthy volunteers and patients of various ages, using different doses and treatment processes, with music played at varying times relative to drug administration. Research on music during ketamine anesthesia is included, as anesthesia drove early ketamine use. Recreational ketamine studies are excluded. The review is limited to English-language articles with no year restriction. It is the first comprehensive overview of music and ketamine/esketamine interplay, offering guidance for future study design.
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.
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.
Translational Psychiatry
April 21, 2026
Paul A Parcon, Amanda Bardhoshi, Amanda Olsen-Dufour et al.
Ketamine, a rapid-acting antidepressant, increases cyclic adenosine monophosphate (cAMP) activity in the brain within an hour of infusion, likely by affecting phosphodiesterase-4 (PDE4), an enzyme that normally terminates cAMP signaling. In rats given 10 mg/kg ketamine, binding of a radioligand to PDE4 increased by a mean of 24% (range 3%–42%); in rhesus macaques given 0.5 mg/kg, binding increased by a mean of 14% (range 12%–16%). A radioligand selective for the PDE4B subtype showed a mean increase of 28% (range 16%–37%) in monkeys. Control experiments ruled out blood-flow effects. The findings suggest that boosting cAMP activity through PDE4 inhibition, particularly the PDE4B subtype, may underlie ketamine's rapid antidepressant effects and point to a common pathway for antidepressant action.
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.
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.
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.