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.
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.
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.
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.
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.
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 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.