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.
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.
Journal of Traumatic Stress
January 1, 1998
J. Douglas Bremner, John H. Krystal, Frank W. Putnam et al.
826 citations
A new instrument, the Clinician Administered Dissociative States Scale (CADSS), was developed to measure present-state dissociative symptoms. Initial analyses showed good interrater reliability and construct validity. CADSS scores successfully discriminated patients with dissociative disorders from patients with other psychiatric disorders and from healthy subjects.
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.
Archives of General Psychiatry
March 1, 2000
Amit Anand, Dennis S. Charney, Dan A. Oren et al.
425 citations
A drug that inhibits glutamate release, lamotrigine, reduced several effects of ketamine in healthy adults. Lamotrigine given before ketamine decreased perceptual abnormalities, positive and negative schizophrenia-like symptoms, and learning and memory impairment. However, it increased the immediate mood-elevating effects of ketamine. These findings suggest that glutamate release plays a role in some effects of NMDA receptor blockade and that drugs reducing glutamate release might help treat conditions like schizophrenia, though more research 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
March 17, 2009
Sanjay J. Mathew, James W. Murrough, Marije Aan Het Rot et al.
295 citations
A single intravenous dose of ketamine (0.5 mg/kg) produced rapid antidepressant effects in patients with treatment-resistant major depression, with 65% responding at 24 hours and 54% at 72 hours. Pretreatment with lamotrigine did not reduce ketamine's mild side effects or improve its antidepressant action. In a subsequent randomized trial, riluzole (100-200 mg/day) failed to prevent relapse over 32 days; 80% of riluzole-treated patients relapsed versus 50% on placebo, leading to early termination. Ketamine appears well-tolerated and rapidly effective, but better strategies to sustain its benefits 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.
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.
October 1, 1999
R. Andrew Chambers, J. Douglas Bremner, Bita Moghaddam et al.
140 citations
Dissociative symptoms during trauma and afterward in PTSD may be linked to stress-induced glutamate release in the brain. Animal studies show stress stimulates cortico-limbic glutamate release, affecting behavior and neural plasticity, and contributing to neural toxicity. NMDA receptor antagonists also trigger transient glutamate release and produce dissociative-like symptoms in animals and humans. A drug that reduces glutamate release lessens the perceptual effects of the NMDA antagonist ketamine in humans. Because hyperglutamatergic states may contribute to acute and long-term trauma effects, drugs that attenuate glutamate release warrant exploration for treating traumatized individuals with dissociative symptoms.
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.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
American Journal of Geriatric Psychiatry
February 24, 2026
Rachel Fremont, Amelia Karim, Tanya Peguero Estevez et al.
1 citation
In an open-label clinical trial, a single intravenous infusion of ketamine (0.5 mg/kg) was safe and well tolerated in 13 patients with mild cognitive impairment and major depressive disorder. No serious adverse events occurred. Depression severity, measured by the Montgomery-Asberg Depression Rating Scale, dropped from a mean of 27.4 before treatment to 5.7 at 24 hours after the infusion—a large-magnitude improvement. For 8 of the 13 patients, this improvement persisted for up to one month, with a mean score of 12.1 and at least a 50% reduction. These findings suggest ketamine may be effective for depression in this population, but larger randomized controlled trials are needed to confirm efficacy and assess cognitive effects.
medRxiv Preprint Server
April 10, 2021
Agnes Norbury, Sarah B. Rutter, Abigail B. Collins et al.
1 citation
preprint
In a small randomized clinical trial, repeated doses of ketamine improved PTSD symptoms more than midazolam. Brain scans showed that symptom improvement was linked to increased communication between the ventromedial prefrontal cortex and amygdala when viewing emotional faces, especially in those who received ketamine. Ketamine-related improvement was also predicted by decreased activity in the dorsal anterior cingulate during emotional conflict and increased resting-state connectivity between the ventromedial prefrontal cortex and anterior insula. Further analysis indicated that ketamine specifically strengthened the prefrontal cortex's ability to inhibit amygdala responses to threatening social cues, suggesting a normalization of brain circuits involved in fear regulation.
The Journal of Clinical Psychiatry
April 2, 2025
Adriana Feder, Oneysha Brown, Sarah B. Rutter et al.
Combining six ketamine infusions with a brief exposure-based psychotherapy, written exposure therapy (WET), produced large and durable reductions in PTSD symptoms for patients with chronic, severe PTSD. In an open-label trial, 13 of 14 patients completed treatment. PTSD symptom severity, measured by the CAPS-5, dropped from an average of 41.6 before treatment to 20.8 at 12 weeks, a large-magnitude improvement. Nine patients (69%) were treatment responders, and eight (61.5%) maintained improvement up to six months. The authors suggest the combined treatment may be effective but call for larger randomized controlled trials to confirm efficacy and synergy.
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.