American Journal of Psychiatry
August 28, 2013
James W. Murrough, Dan V. Iosifescu, Lee C. Chang et al.
1,207 citations
A single intravenous infusion of ketamine produced greater improvement in depression severity 24 hours later than the active placebo midazolam in patients with treatment-resistant major depression. In a randomized controlled trial of 73 participants, the ketamine group scored 7.95 points lower on the Montgomery-Åsberg Depression Rating Scale than the midazolam group. Response rates were 64% for ketamine and 28% for midazolam, with an odds ratio of 2.18 favoring ketamine. The findings support NMDA receptor modulation as a mechanism for rapid improvement in severe, chronic depression, though more information on durability and safety is needed before clinical use.
JAMA Psychiatry
April 16, 2014
Adriana Feder, Michael K. Parides, James W. Murrough et al.
618 citations
A single intravenous dose of ketamine (0.5 mg/kg) rapidly reduced posttraumatic stress disorder (PTSD) symptom severity more than the active placebo midazolam in patients with chronic PTSD. Twenty-four hours after infusion, the ketamine group showed a mean reduction of 12.7 points on the Impact of Event Scale-Revised compared to midazolam. Ketamine also lessened comorbid depressive symptoms and improved overall clinical presentation. The treatment was generally well tolerated without persistent dissociative symptoms. These results suggest ketamine may offer a novel pharmacologic approach for chronic PTSD, though replication is needed.
Depression and Anxiety
March 25, 2014
Rebecca B Price, Dan V. Iosifescu, James W. Murrough et al.
342 citations
A single subanesthetic dose of intravenous ketamine reduced explicit suicidal thoughts and implicit associations between self and escape in adults with treatment-resistant major depression more than the active placebo midazolam. Twenty-four hours after infusion, 53% of ketamine-treated patients scored zero on all three explicit suicide measures, compared with 24% of the midazolam group. The reductions in explicit suicidal cognition were largest in those with higher baseline suicidal thoughts and were partly explained by decreases in other depressive symptoms. The findings suggest ketamine may offer rapid relief from suicidal cognition beyond what a psychoactive placebo provides.
Psychological Medicine
August 12, 2015
James W. Murrough, Laili Soleimani, Kaitlin E. DeWilde et al.
297 citations
A single infusion of ketamine, compared to midazolam as an active placebo, did not reduce suicidal ideation scores on the Beck Scale for Suicidal Ideation at 24 hours in patients with mood and anxiety disorders who were at elevated risk for suicidal behavior. A significant difference favoring ketamine emerged at 48 hours, but the effect was no longer significant by the end of 7 days. The intervention was well tolerated with no dropouts during the primary assessment period. The findings support the safety and tolerability of ketamine for suicidal ideation but larger studies are needed.
The International Journal of Neuropsychopharmacology
October 8, 2013
Colin N. Haile, James W. Murrough, Dan V. Iosifescu et al.
251 citations
In patients with treatment-resistant depression, ketamine increased blood levels of brain-derived neurotrophic factor (BDNF) in those who responded to the drug, compared to non-responders, 240 minutes after infusion. Higher BDNF levels were strongly linked to lower depression scores at multiple time points up to 72 hours. No such associations appeared in patients given the anesthetic midazolam. The findings support BDNF as a marker of ketamine's antidepressant effects.
The Journal of Clinical Psychiatry
September 2, 2014
Le-Ben Wan, Cara F. Levitch, Andrew M. Perez et al.
232 citations
Ketamine given intravenously at 0.5 mg/kg over 40 minutes was safe and well tolerated in a large group of patients with treatment-resistant depression. Across 205 infusions in 97 participants, the antidepressant response rate was 67%. Only about 2% of infusions were stopped due to adverse effects, and the overall dropout rate was 3%. Common temporary side effects in the first four hours included drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. About one third of participants had changes in blood pressure or heart rate. There were small but significant increases in psychotomimetic and dissociative symptoms, but no lasting psychotic effects, medical complications, or increased substance use among those followed long-term.
Translational Psychiatry
March 21, 2017
Drew D. Kiraly, Sarah R. Horn, Nicholas T. van Dam et al.
182 citations
Patients with treatment-resistant depression (TRD) show elevated levels of the pro-inflammatory cytokine interleukin-6 compared to healthy controls, supporting the immune hypothesis of depression. Analysis of 41 cytokines, chemokines, and growth factors in blood samples from 26 healthy controls and 33 unmedicated TRD patients revealed a unique pattern of increased inflammatory mediators, chemokines, and colony-stimulating factors. Following a single intravenous infusion of ketamine (0.5 mg/kg), several cytokines showed transient changes, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response, suggesting novel treatment targets for TRD patients with dysregulated immune functioning.
Translational Psychiatry
February 17, 2015
James W. Murrough, Katherine A. Collins, Jessica Fields et al.
111 citations
A single low dose of ketamine increases brain activity in the right caudate when people with treatment-resistant depression view happy faces, reversing a baseline deficit compared with healthy volunteers. Twenty patients with treatment-resistant depression not taking other antidepressants underwent fMRI before and 24 hours after receiving intravenous ketamine (0.5 mg per kg of body weight). Twenty matched healthy controls were scanned once. Before ketamine, depressed patients showed reduced neural responses to happy faces in the right caudate. After ketamine, responses to happy faces increased in a similar region. Greater connectivity of the right caudate during positive emotion perception was linked to greater improvement in depression severity. No effects were seen for sad faces.
The Journal of Clinical Psychiatry
May 26, 2020
George I. Papakostas, Naji C. Salloum, Rebecca S. Hock et al.
107 citations
Adjunctive intranasal esketamine is more effective than placebo for treating major depressive disorder. Pooling five randomized, double-blind trials with 774 patients, esketamine outperformed placebo on depression rating scale score change, response, and remission. The effect was statistically significant across different study samples and baseline antidepressant regimens. Esketamine appears to be an effective treatment strategy for patients who are treatment-resistant or acutely suicidal.
Depression and Anxiety
December 30, 2018
Naji C. Salloum, Maurizio Fava, Marlene P. Freeman et al.
49 citations
In a double-blind trial, 99 people with treatment-resistant depression received either a single intravenous dose of ketamine (0.1, 0.2, 0.5, or 1.0 mg/kg) or midazolam (0.045 mg/kg). Among them, 45 had high baseline anxiety and 54 did not. No significant difference in depression improvement was found between the ketamine and midazolam groups for either anxious or nonanxious participants at 1 or 3 days after infusion. The results suggest that ketamine may work similarly for both anxious and nonanxious treatment-resistant depression, unlike some traditional antidepressants.
Journal of Clinical Psychopharmacology
April 25, 2020
Marlene P. Freeman, Rebecca S. Hock, George I. Papakostas et al.
45 citations
Higher body mass index (BMI) and obesity are linked to a stronger acute antidepressant effect from a single intravenous dose of ketamine in patients with treatment-resistant depression. In a randomized, double-blind, placebo-controlled trial, patients with obesity showed a significantly greater reduction in depression symptoms 24 hours after ketamine infusion compared to those with normal BMI. Overweight patients also showed a trend toward greater improvement. Similar but weaker effects were observed at 72 hours. The findings suggest that obesity may enhance the rapid antidepressant response to ketamine, which could have clinical relevance for the many patients with both major depressive disorder and obesity.
The Journal of Clinical Psychiatry
November 14, 2022
Anna Feeney, Bettina B. Hoeppner, Marlene P. Freeman et al.
9 citations
Among people with treatment-resistant depression, those taking oral benzodiazepines alongside a single intravenous infusion of ketamine showed less improvement in depression scores 24 hours later if they were on higher benzodiazepine doses. The same pattern was not seen in those who received a midazolam placebo. By day 3 after the infusion, benzodiazepine use no longer affected depression scores. The findings suggest that higher doses of benzodiazepines may temporarily weaken ketamine's rapid antidepressant effect.
Expert Review of Neurotherapeutics
March 1, 2023
Zamfira Parincu, Dan V. Iosifescu
Major depressive disorder (MDD) is a leading cause of disability, but many patients do not improve with standard monoamine-targeting drugs, and benefits typically take 4-6 weeks. Combinations of dextromethorphan, an oral NMDA receptor antagonist, may offer faster relief. A systematic search of US Clinical Trials, PubMed, press releases, and poster presentations identified two case reports and eight clinical trials on dextromethorphan for MDD or treatment-resistant depression (TRD), plus additional studies in bipolar disorder. Clinical studies show that dextromethorphan combined with quinidine or bupropion effectively reduces depressive symptoms in MDD. However, results in adults with TRD or bipolar depression were mixed. The dextromethorphan-bupropion combination appears well-tolerated, safe, and efficacious for MDD, but more studies on TRD and bipolar depression are needed.
Journal of Affective Disorders
August 15, 2017
James W. Murrough, Elizabeth Wade, Sehrish Sayed et al.
A combination of dextromethorphan and quinidine, given at up to 45/10 mg twice daily for 10 weeks, reduced depression scores in patients with treatment-resistant depression. Twenty patients with unipolar treatment-resistant depression enrolled; six discontinued early. Depression scores on the Montgomery-Asberg Depression Rating Scale dropped by an average of 13 points, and on the Quick Inventory of Depressive Symptomatology by nearly 6 points. Response and remission rates were 45% and 35%, respectively. No treatment-emergent suicidal thoughts, psychosis, or dissociation occurred. The open-label, proof-of-concept design limits conclusions, but results suggest the combination is tolerable and warrants larger placebo-controlled trials.