American Journal of Psychiatry
October 3, 2017
S. Wilkinson, Elizabeth D. Ballard, M. Bloch et al.
680 citations
A single dose of ketamine rapidly reduces suicidal thoughts within one day and for up to one week in depressed patients with suicidal ideation. The effect is moderate to large and partially independent of changes in depressive symptoms. The analysis combined data from 167 participants across 10 studies comparing ketamine to a placebo (saline or midazolam). Ketamine significantly improved clinician-rated and self-reported suicidal ideation, though not on one self-report measure (the Beck Depression Inventory). The authors call for further research on long-term safety and suicide risk reduction before clinical use.
Molecular Psychiatry
February 27, 2018
A. Nugent, Elizabeth D. Ballard, T. Gould et al.
254 citations
In a double-blind, placebo-controlled, randomized cross-over trial with 35 unmedicated people with major depressive disorder (MDD) and 25 healthy controls, ketamine (0.5 mg/kg) improved depressive symptoms in MDD subjects but caused modest, temporary increases in depressive symptoms in healthy controls. Both groups showed increased resting gamma power measured by magnetoencephalography. Among MDD subjects, gamma power did not directly predict the size of the antidepressant effect. However, baseline gamma power moderated the link between post-ketamine gamma and response: higher post-ketamine gamma was tied to better response in those with low baseline gamma, but the opposite pattern appeared in those with high baseline gamma. This suggests biological subtypes based on homeostatic dysregulation and cautions against inferring ketamine's mechanism solely from studies of healthy controls.
Therapeutic Advances in Chronic Disease
April 13, 2015
Nicolas D. Iadarola, Mark J. Niciu, Erica M. Richards et al.
202 citations
A single subanesthetic dose infusion of the noncompetitive NMDA receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression, unlike current monoaminergic antidepressants which have a delayed onset and limited efficacy. Preclinical studies inspired by ketamine's clinical effects reveal enhanced synaptic plasticity and synaptogenesis through mechanisms including release of local translational inhibition of brain-derived neurotrophic factor, mammalian target of rapamycin activation, and glycogen synthase kinase-3 inhibition. Current efforts aim to extend ketamine's efficacy, uncover neurobiological mechanisms in biologically enriched subgroups, and identify biomarkers for personalized treatment. Other NMDA receptor antagonists show modest antidepressant effects but potentially fewer dissociative or psychotomimetic effects, prompting development of novel glutamatergic antidepressants with greater target specificity and fewer adverse effects.
Journal of Affective Disorders
February 17, 2018
M. Niciu, Bridget J. Shovestul, Brittany A. Jaso et al.
134 citations
Depersonalization—a feeling of detachment from one's own body or thoughts—was the dissociative symptom most strongly linked to ketamine's antidepressant effect in patients with treatment-resistant depression. Analyzing data from 126 patients with major depressive or bipolar disorder who received a single ketamine infusion, researchers found that higher scores on the depersonalization subscale of the Clinician-Administered Dissociative States Scale consistently predicted greater improvement in depression ratings across multiple time points. Derealization (feeling the world is unreal) showed a weaker and less consistent association, while amnesia was unrelated to antidepressant response. The finding suggests that depersonalization and antidepressant response may share neurobiological mechanisms, though off-target effects cannot be ruled out.
Current Neuropharmacology
March 25, 2016
Brittany A. Jaso, Mark J. Niciu, Nicolas D. Iadarola et al.
97 citations
Current antidepressants for major depressive disorder work through monoaminergic mechanisms and have a delayed onset and limited efficacy. Glutamate, the main excitatory neurotransmitter, is involved in depression's pathophysiology. Since ketamine, an NMDA receptor antagonist, showed rapid antidepressant effects in 2000, other NMDA receptor antagonists have been studied but with more modest effects. Some have advantages like oral administration and fewer side effects. This article reviews clinical evidence for glutamate receptor modulators: non-competitive NMDA antagonists (ketamine, memantine, dextromethorphan, AZD6765), NR2B-subunit antagonists (traxoprodil, MK-0657), glycine-site partial agonists (D-cycloserine, GLYX-13), and metabotropic glutamate receptor modulators (AZD2066, basimglurant). Preclinical targets like AMPA agonists and mGluR2/3 negative allosteric modulators are also discussed.
The International Journal of Neuropsychopharmacology
December 19, 2014
Mark J. Niciu, David A. Luckenbaugh, Dawn F. Ionescu et al.
55 citations
A single low-dose infusion of the anesthetic ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder. In this trial, depressed individuals with a family history of alcohol use disorder showed a longer-lasting antidepressant response to ketamine compared to those without such a family history. Adding the drug riluzole did not extend or enhance ketamine's antidepressant durability. The findings suggest that family history of alcohol use disorder may predict a more durable ketamine response, which should be accounted for in future ketamine depression studies.
Nat Commun
December 22, 2020
Elizabeth D. Ballard, Carlos A. Zarate
10 citations
Ketamine produces immediate antidepressant effects and also short-term dissociative effects, where individuals experience altered consciousness and perceptions. Whether these dissociative side effects are necessary for the antidepressant effects remains unclear. This perspective examines the relationship between dissociation and both acute and longer-lasting antidepressant responses to ketamine and other NMDA receptor antagonists. The current literature does not support the conclusion that dissociation is necessary for antidepressant response to ketamine, but further work is needed to explore this relationship at molecular, biomarker, and psychological levels.
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.