Archives of General Psychiatry
August 1, 2006
Carlos A. Zarate, Jaskaran 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.
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.
Journal of Clinical Psychopharmacology
June 20, 2012
Lobna Ibrahim, Nancy Diazgranados, Libby Jolkovsky et al.
219 citations
A small pilot study tested the antidepressant efficacy and tolerability of an oral formulation of the selective NMDA NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. In a randomized, double-blind, placebo-controlled crossover design, five patients completed both periods of MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Significant antidepressant effects were seen as early as day 5 on the Hamilton Depression Rating Scale and Beck Depression Inventory, but not on the Montgomery-Asberg Depression Rating Scale, the primary measure. No serious or dissociative adverse effects occurred. The findings suggest MK-0657 may have antidepressant properties, but larger studies are needed.
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.
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 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
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.
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.
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.
Neuropsychiatric Disease and Treatment
October 1, 2018
Wallace C. Duncan, Elizabeth E. Slonena, Nadia S. Hejazi et al.
17 citations
Patients with major depressive disorder who had a brief antidepressant response to ketamine (lasting 24-48 hours) showed blunted 24-hour wrist activity amplitude from baseline through three days post-infusion and a phase advance of activity on day one that returned to baseline by day three. Those with a continued response (over 72 hours) had phase-advanced activity at baseline and day one, plus increased amplitude on days one and three. Nonresponders did not show these patterns. The time course of antidepressant response to ketamine appears linked to underlying biological differences in motor activity timekeeping, which may involve circadian system mechanisms.
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.