Proceedings of the National Academy of Sciences
September 25, 2012
Alan Anticevic, Mark G. Gancsos, John D. Murray et al.
260 citations
Glutamate signaling through NMDA receptors is essential for brain computations that support cognition, and its disruption may contribute to schizophrenia. Using ketamine, an NMDA receptor antagonist, the study found that the normal anticorrelation between the default-mode and task-positive brain systems was disrupted during a working memory task. The degree of this disruption predicted task performance and produced schizophrenia-like symptoms. A computational model suggests that cortical disinhibition underlies this effect, linking glutamate's role in large-scale brain organization to cognition and psychiatric symptoms.
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 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.
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.
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 Journal of Clinical Psychiatry
December 6, 2016
Jennifer L. Vande Voort, Elizabeth D. Ballard, David A. Luckenbaugh et al.
67 citations
People with depression who had a reduction in suicidal thoughts after a single ketamine infusion also showed less nighttime wakefulness, measured by EEG, the night after the infusion compared to those whose suicidal thoughts did not improve. The level of wakefulness in responders was similar to that of healthy controls. This suggests that ketamine's effect on suicidal ideation may involve changes in sleep-wake regulation.
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
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.
Neural Plasticity
January 1, 2015
Annie J. Xu, Mark J. Niciu, Nancy B. Lundin et al.
27 citations
Ketamine and lithium both inhibit an enzyme called glycogen synthase kinase 3, and in rodents they show synergistic antidepressant-like effects at low doses. In a randomized, double-blind, placebo-controlled crossover trial, 36 patients with treatment-resistant bipolar depression maintained on either lithium or valproate received a single 0.5 mg/kg ketamine infusion. Both groups showed significant improvement in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale, but there was no statistically significant difference between the mood stabilizer groups. Serum levels of lithium or valproate did not correlate with ketamine's antidepressant effects. The results suggest that lithium may not enhance ketamine's antidepressant efficacy in this population.
Journal of Psychopharmacology
October 17, 2017
Mark J. Niciu, Nicolas D. Iadarola, Dipavo Banerjee et al.
23 citations
In a sample of 55 unmedicated individuals with treatment-resistant major depressive disorder, baseline volumes of the hippocampus, amygdala, and thalamus measured with 3-Tesla MRI did not correlate with the antidepressant effect of a single 0.5 mg/kg ketamine infusion at any time point (230 minutes, 1 day, or 1 week). A secondary analysis by BDNF rs6265 genotype suggested that in val/val homozygotes, larger thalamic volume was positively associated with response at 230 minutes, while in met carriers, larger thalamic volume was negatively associated, though these correlations did not reach statistical significance. The authors conclude that baseline thalamic volume combined with BDNF genotype may serve as a rapid antidepressant response biomarker.
Pharmacopsychiatry
June 23, 2014
Nancy B. Lundin, Mark J. Niciu, David A. Luckenbaugh et al.
17 citations
In people with treatment-resistant major depressive disorder or bipolar depression who receive a single intravenous ketamine infusion, baseline blood levels of vitamin B12 and folate do not correlate with how much their depression scores improve at 230 minutes, 1 day, or 7 days afterward. The finding suggests that ketamine's antidepressant effect may work independently of these peripheral vitamin levels.
Journal of psychopharmacology (Oxford, England)
February 5, 2026
Benjamin R. Lewis, Matthew J Reid, Andrew M Novick et al.
Clinical trials of classical psychedelics like psilocybin for mental health conditions face unique challenges that may persist if these treatments enter clinical practice. Four categories of challenges with trial participants are identified: treatment nonresponse, expectancy effects and functional unblinding, post-session psychological difficulties, and contagion effects. Management strategies for study teams to mitigate these risks are described. The National Network of Depression Centers and similar organizations can guide best practices to responsibly advance this promising field.