Archives of General Psychiatry
August 1, 2006
Carlos A. Zarate, Jaskaran B. Singh, Paul J. Carlson et al.
3,762 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate receptor antagonist, produced rapid and robust antidepressant effects in treatment-resistant major depression. Improvement was significant within 110 minutes and remained so for one week. The effect size was very large after 24 hours and moderate to large after one week. Among 17 subjects, 71% met response and 29% met remission criteria the day after infusion; 35% maintained response for at least one week. These findings suggest a role for glutamatergic modulation in achieving rapid relief from depression.
Archives of General Psychiatry
August 1, 2010
Nancy Diazgranados, Lobna Ibrahim, Nancy E. Brutsché et al.
969 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate-receptor antagonist, produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. Depressive symptoms improved within 40 minutes and remained significantly better than placebo through day 3. The largest drug effect occurred at day 2. Seventy-one percent of subjects responded to ketamine versus 6% to placebo. One subject in each group developed manic symptoms. Ketamine was generally well tolerated, with dissociative symptoms only at the 40-minute point.
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.
Translational Psychiatry
October 14, 2014
Níall Lally, Allison C. Nugent, David A. Luckenbaugh et al.
269 citations
A single infusion of ketamine rapidly reduced anhedonia in 36 patients with treatment-resistant bipolar depression, and this effect occurred independently from reductions in general depressive symptoms. The anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen, highlighting the role of the glutamatergic system in treating such symptoms.
The International Journal of Neuropsychopharmacology
June 7, 2012
Wallace C. Duncan, Simone Sarasso, Fabio Ferrarelli et al.
253 citations
A single infusion of the NMDA receptor antagonist ketamine rapidly reduces depressive symptoms in patients with treatment-resistant major depressive disorder. In 30 patients, ketamine increased electroencephalogram slow wave activity during early non-REM sleep and raised plasma levels of brain-derived neurotrophic factor. The occurrence of high amplitude slow waves and their slope also increased, indicating enhanced synaptic strength. Changes in BDNF levels correlated with changes in EEG parameters, but only in patients who responded to ketamine. This suggests that enhanced synaptic plasticity, reflected by increased slow wave activity and BDNF, is part of the mechanism behind ketamine's rapid antidepressant effects.
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.
Journal of Psychopharmacology
February 17, 2015
Níall Lally, Allison C. Nugent, David A. Luckenbaugh et al.
224 citations
Anhedonia, a core symptom of major depression that often resists standard treatment, rapidly decreased after a single infusion of the antidepressant ketamine in medication-free patients with treatment-refractory major depressive disorder, and the reduction lasted up to three days. Adding daily oral riluzole or placebo did not alter this effect. In a subgroup, reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex. The relationship remained significant in the dorsal anterior cingulate cortex and orbitofrontal cortex, and at trend level in the hippocampus, when controlling for total depression score. Results are tenuous due to the lack of a placebo control for ketamine.
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.
The Journal of Clinical Psychiatry
May 15, 2014
Mark J. Niciu, David A. Luckenbaugh, Dawn F. Ionescu et al.
167 citations
Higher body mass index and a family history of alcohol use disorder in a first-degree relative were associated with greater improvement in depression symptoms after a single ketamine infusion. Patients with no prior suicide attempts also showed greater improvement, but only at day 7. The analysis combined data from four studies of treatment-resistant inpatients with major depressive disorder or bipolar depression who received a single 0.5 mg/kg ketamine infusion over 40 minutes. The findings suggest that certain clinical characteristics may help predict who benefits most from ketamine's rapid antidepressant effects, though the analysis was post hoc and the models explained only 13% to 36% of the variation in symptom improvement.
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.
The Journal of Clinical Psychiatry
September 8, 2009
Rodrigo Machado‐Vieira, Peixiong Yuan, Nancy E. Brutsché et al.
154 citations
Ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder, but these effects are not linked to changes in brain-derived neurotrophic factor (BDNF) levels. In 23 adults aged 18 to 65, a single intravenous infusion of ketamine (0.5 mg/kg) significantly improved depression scores on the Montgomery-Asberg Depression Rating Scale within 230 minutes. However, BDNF levels measured at the same time points did not change from baseline, and no association appeared between antidepressant response and BDNF. The findings indicate that ketamine's initial antidepressant action operates through mechanisms other than BDNF.
Proceedings of the National Academy of Sciences
March 13, 2019
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart et al.
153 citations
A single subanesthetic dose of ketamine produces rapid (within hours) and sustained antidepressant effects, unlike standard antidepressants that take months and fail in about 30% of patients. The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with fewer adverse effects. Using behavioral, genetic, pharmacological approaches and EEG measurements, the study found that antidepressant-relevant actions of (2R,6R)-HNK involve metabotropic glutamate receptor subtype 2 (mGlu2) signaling and identified high-frequency EEG oscillations as a marker of rapid antidepressant responses. The findings suggest clinical trials combining subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK for depression treatment.
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.
British Journal of Clinical Pharmacology
February 1, 2012
Xiaochen Zhao, Swarajya Lakshmi Vattem Venkata, Ruin Moaddel et al.
136 citations
Ketamine is metabolized into several compounds, and this study shows that norketamine is not the main metabolite circulating in the blood after a single 40-minute infusion of 0.5 mg/kg ketamine in patients with treatment-resistant bipolar depression. Instead, dehydronorketamine was the major metabolite in four out of nine patients, norketamine in three, and hydroxynorketamine in two. Large inter-patient variation in metabolite levels was observed. The findings suggest that future research on ketamine's effects should measure these downstream metabolites.
The Annual Review of Pharmacology and Toxicology
October 9, 2018
Todd D. Gould, Carlos A. Zarate, Scott M. Thompson
132 citations
Depression has long been treated with drugs that target monoamine brain systems, but these take weeks to work. Low doses of ketamine can improve core depressive symptoms—including mood, anhedonia, and suicidal ideation—within hours after a single dose, with effects lasting up to a week. This discovery has shifted thinking about how depression might be treated more effectively. This review covers clinical data on ketamine and other rapid-acting antidepressants and what is known about their mechanisms. It also discusses brain circuits engaged by these drugs and future medication targets such as hydroxynorketamine, metabotropic glutamate receptor 2/3 antagonists, and modulators of NMDA, AMPA, and GABA receptors.
The Journal of Clinical Psychiatry
September 25, 2014
Dawn F. Ionescu, David A. Luckenbaugh, Mark J. Niciu et al.
111 citations
Patients with treatment-resistant major depressive disorder who also have high anxiety (anxious depression) responded better to a single infusion of ketamine than those without high anxiety, contrary to expectations based on traditional antidepressants. Over 28 days of follow-up, the anxious group showed significantly fewer depression symptoms at multiple time points and relapsed much later (median 19 days versus 1 day). No significant differences in side effects were observed. These results suggest that ketamine, an NMDA receptor antagonist, may be especially effective for the anxious depression subtype, which is typically difficult to treat with standard antidepressants.
Journal of Neuroscience
January 3, 2023
Panos Zanos, Kyle A. Brown, Polymnia Georgiou et al.
109 citations
Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects, but the role of NMDA receptor activation in these effects is unclear. In male mice, ketamine showed an inverted U-shaped dose-response in antidepressant-sensitive tests, indicating that excessive NMDA receptor inhibition can prevent its antidepressant actions. Pretreatment with other NMDA receptor antagonists blocked ketamine's behavioral effects, upregulation of AMPA receptor subunits, and metaplasticity. The antidepressant-like actions of other rapid-acting compounds were also blocked by NMDA receptor inhibition. Ketamine acted synergistically with an NMDA receptor positive allosteric modulator. The authors conclude that rapid-acting antidepressants share a common downstream NMDA receptor activation-dependent effector mechanism, and promoting NMDA receptor signaling may be an effective antidepressant strategy.
Bipolar Disorders
November 14, 2014
Dawn F. Ionescu, David A. Luckenbaugh, Mark J. Niciu et al.
109 citations
A single infusion of ketamine (0.5 mg/kg) reduced depression symptoms in both anxious and non-anxious patients with treatment-resistant bipolar depression. Thirty-six patients (21 anxious, 15 non-anxious) received the infusion over 40 minutes. Both groups showed significant antidepressant responses on the Montgomery-Åsberg Depression Rating Scale and Hamilton Depression Rating Scale through 14 days post-infusion. The anxious group did not show a disadvantage in antidepressant response compared to the non-anxious group, contrasting with typical poor treatment outcomes for anxious bipolar depression with traditional medications. The findings suggest ketamine may be effective for anxious bipolar depression, warranting further study.
The International Journal of Neuropsychopharmacology
November 1, 2011
Giacomo Salvadore, Jan Willem van der Veen, Yan Zhang et al.
105 citations
Pretreatment levels of certain amino-acid neurotransmitters in the prefrontal cortex predict how well patients with major depressive disorder respond to a single intravenous infusion of ketamine. In fourteen drug-free patients, a lower ratio of glutamine to glutamate in the dorsomedial/dorsal anterolateral prefrontal cortex was associated with greater improvement in depressive symptoms 230 minutes after ketamine administration. Higher glutamate levels in the ventromedial prefrontal cortex correlated with greater improvement in anxiety symptoms. The findings suggest that the presence of reduced glial cells, reflected by the lower glutamine-to-glutamate ratio, may indicate which patients are more likely to benefit from ketamine treatment.
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.
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.
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).
The International Journal of Neuropsychopharmacology
September 12, 2011
Oz Malkesman, Daniel Austin, Tyson Tragon et al.
91 citations
D-serine, a co-agonist at NMDA receptors, produces antidepressant-like effects in rodents. A single acute dose of D-serine reduced immobility in the forced swim test without affecting motor function, reversed sexual reward-seeking deficits caused by serotonin depletion, and reversed learned helplessness behavior. Mice lacking NMDA receptor NR1 subunits in forebrain excitatory neurons showed a depression-like phenotype and did not respond to D-serine. These findings suggest D-serine has antidepressant-like effects and support the idea of complex glutamatergic dysfunction in depression, though it remains unclear whether D-serine shares a convergent mechanism with NMDA antagonists like ketamine.
Bipolar Disorders
September 18, 2013
Allison C. Nugent, Nancy Diazgranados, Paul J. Carlson et al.
86 citations
In people with bipolar disorder who are depressed, a single ketamine infusion alters brain glucose metabolism in regions linked to mood disorders. Those who improved most showed the largest metabolic increase in the right ventral striatum. Ketamine also lowered metabolism in the left hippocampus compared with placebo. Higher baseline activity in the subgenual anterior cingulate cortex predicted a stronger antidepressant response to ketamine. These metabolic changes may help explain how ketamine works.