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.
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.
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 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.
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.
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.
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.
The Journal of Clinical Psychiatry
April 24, 2024
Gregory H Jones, Courtney M Vecera, Ana C Ruiz et al.
13 citations
A single dose of intranasal ketamine (50 mg) produced rapid antidepressant effects compared to placebo in unmedicated inpatients with major depression and current suicidal ideation, but did not significantly reduce suicidal thoughts. Patients with comorbid alcohol use disorder showed a statistical trend toward greater improvement in suicidality, though the primary outcome was not met. The treatment was well tolerated. The antidepressant benefit was largely unaffected by the presence of alcohol use disorder or the type of mood disorder (unipolar or bipolar). Among those receiving ketamine, improvement in depression correlated with reduced suicidal ideation only in patients without alcohol use disorder.
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.
Journal of Affective Disorders
December 15, 2024
Rodrigo Machado‐Vieira, Gregory H Jones, Alan C. Courtes et al.
Fatigue, a multidimensional condition that often overlaps with depression, responds only modestly to standard antidepressants and mood stabilizers but has shown positive response to intravenous ketamine, which is limited by cost and access. This study evaluated a single 50 mg dose of intranasal ketamine in 28 individuals with major depressive disorder or bipolar depression, about 60% of whom also had alcohol use disorder. The group by time interaction for the NIH-Brief Fatigue Inventory score was significant, favoring intranasal ketamine over placebo at 4, 24, and 48 hours post-treatment. Intranasal ketamine was well-tolerated with minimal adverse effects. The findings suggest intranasal ketamine induces rapid anti-fatigue effects and may serve as an alternative rapid-acting option for fatigue across different medical conditions.
Pharmaceuticals (Basel, Switzerland)
November 7, 2023
Courtney M Vecera, Alan C. Courtes, Gregory Jones et al.
Treatment-resistant depression (TRD) lacks a consensus definition, with studies requiring between 1 and 4 failed antidepressant therapies. An imbalance between the neurotransmitters L-glutamate and GABA is emerging as key in TRD. Among glutamatergic targets, NMDA receptor antagonism, particularly with ketamine and esketamine (Spravato), has shown robust responses. NMDA-glycine site modulators D-cycloserine and apimostinel show promising safety and efficacy. Dextromethorphan-bupropion (Auvelity) demonstrates positive results, especially in subpopulations with cognitive dysfunction. The most promising GABA modulators are synthetic neurosteroid analogs like brexanolone. Three compounds are FDA-approved: esketamine for TRD, Auvelity for MDD, and brexanolone for postpartum depression, though concerns exist with esketamine and brexanolone.