Expert Opinion on Drug Safety
March 9, 2022
Anees Bahji, Carlos A. Zarate, Gustavo H. Vazquez
71 citations
Ketamine and esketamine are effective, safe, and acceptable treatments for depression. A meta-analysis of 36 randomized controlled trials (2,903 participants, 57% female, average age 45 years) found that treatment with either form of ketamine improved response (2.14 times more likely), remission (1.64 times more likely), and depression severity compared to placebo. There was no difference in treatment retention, dropouts due to adverse events, or overall number of adverse events between ketamine and placebo.
Bipolar Disorders
September 14, 2012
David A. Luckenbaugh, Lobna Ibrahim, Nancy E. Brutsché et al.
69 citations
In people with bipolar depression, those who have a first-degree relative with alcohol dependence show a greater and more sustained antidepressant response to a single low dose of ketamine than those without such a family history. The study also found that individuals with a positive family history experienced fewer psychosis-like and dissociative side effects after ketamine infusion. These findings suggest that family history of alcohol dependence may help predict who benefits most from ketamine treatment and should be considered when developing new glutamatergic therapies for depression.
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.
World Psychiatry
September 25, 2015
Carlos A. Zarate, Mark J. Niciu
63 citations
Ketamine, an NMDA receptor antagonist, produces rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression. Sub-anesthetic dose infusions (0.5 mg/kg for 40 minutes) show efficacy within 24 hours, with relapse often within one week. Ketamine also rapidly reduces suicidal thinking. The drug's mechanism involves blocking NMDA receptors on inhibitory interneurons, leading to increased glutamate release and activation of AMPA receptors, which triggers intracellular signaling cascades that stimulate synaptic plasticity. Challenges include lack of FDA approval, need for standardized dosing and administration, and risks of abuse and long-term side effects with repeated use. Future research requires better control conditions, identification of enriched subgroups, and development of glutamate biomarkers.
The International Journal of Neuropsychopharmacology
April 10, 2018
Jessica R. Gilbert, Julia S. Yarrington, Kathleen E. Wills et al.
58 citations
Ketamine, a drug that modulates glutamate signaling, produces rapid antidepressant effects. In a double-blind, crossover, placebo-controlled study, 18 people with major depressive disorder and 18 healthy controls each received a single intravenous infusion of ketamine (0.5 mg/kg) and a saline placebo. Magnetoencephalography measured brain activity during tactile stimulation 6 to 9 hours after each infusion. Dynamic causal modeling revealed that ketamine altered NMDA receptor-mediated connectivity differently in the two groups: backward connections were enhanced in depressed subjects, while forward connections were enhanced in controls. Among depressed subjects, improved mood correlated with reduced NMDA and AMPA connectivity in the somatosensory network. The findings indicate that AMPA- and NMDA-mediated glutamatergic signaling is central to ketamine's antidepressant action.
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.
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.
Translational Psychiatry
December 3, 2023
Laith Alexander, Peter C. T. Hawkins, Jennifer W. Evans et al.
26 citations
Ketamine's antidepressant effects involve changes in brain connectivity that depend on which part of the anterior cingulate cortex (ACC) is examined. In a double-blind, placebo-controlled crossover trial, patients with treatment-resistant depression and healthy volunteers received intravenous ketamine or placebo. Two days later, resting-state functional connectivity between ACC subregions and other brain areas differed between groups. Changes in perigenual ACC connectivity to the insula correlated with improved depression scores. Subgenual ACC connectivity was most altered by ketamine compared to placebo, and changes in its connectivity to other ACC subregions and the ventral striatum correlated with reduced anhedonia. Accurate ACC segmentation is needed to understand ketamine's effects.
Frontiers in Neuroimaging
June 27, 2023
Vasileia Kotoula, Jennifer W. Evans, Claire Punturieri et al.
26 citations
Functional magnetic resonance imaging (fMRI) can identify brain areas linked to depression symptoms and potential treatment targets. A review of fMRI studies on selective serotonin reuptake inhibitors (SSRIs) and ketamine found that both conventional and fast-acting antidepressants normalize amygdala hyperactivity in response to negative emotional stimuli, suggesting a common pathway for antidepressant action. Ketamine's rapid effects on brain activity and connectivity also trend toward normalizing depression-related abnormalities. While fMRI shows promise for identifying treatment targets, improved methodology and study design are needed before its findings can be used as primary clinical trial outcomes.
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.
bioRxiv Preprint Server
June 8, 2023
Federica Lucantonio, Shuwen Li, Jaden Lu et al.
2 citations
preprint
Ketamine rapidly alleviates anhedonia, a core symptom of depression involving loss of pleasure, but the underlying brain mechanisms were unclear. In mice subjected to chronic stress, a single dose of ketamine restored stress-induced weakening of excitatory synapses on specific neurons in the nucleus accumbens (NAc), a reward center. These neurons, called D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), showed increased synaptic strength after ketamine. Artificially mimicking this change produced the same behavioral improvement, confirming its causal role. Ketamine acted on inputs from the medial prefrontal cortex and ventral hippocampus to NAc D1-MSNs, and blocking plasticity at these inputs prevented the behavioral effect. The findings demonstrate that ketamine rescues anhedonia through cell-type-specific and input-specific synaptic adaptations in the reward circuitry.
General Hospital Psychiatry
February 25, 2026
Alan C. Courtes, Blake Myers, Noah Daly et al.
1 citation
Psychological stress worsens cancer outcomes by activating adrenergic signaling between nerves and tumors, a process called tumor-neuron crosstalk. Preclinical models show stress triggers sympathetic pathways that promote cancer progression and treatment resistance. Conventional antidepressants are often less effective for cancer patients, but psilocybin has achieved 60-80% long-term remission of cancer-related depression and anxiety in limited samples, while ketamine provides rapid but short-lived symptom control. These agents may normalize HPA axis function and upregulate neurotrophic factors, reducing sustained adrenergic tone and interrupting stress-driven tumor-neuron signaling. Integrating these drugs into oncology could improve survival, and hospital-based psychiatrists are positioned to lead interdisciplinary research with biomarker-rich trials.
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.
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.
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.