World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
American Journal of Psychiatry
April 16, 2018
Carla M. Canuso, Jaskaran B. Singh, Maggie Fedgchin et al.
666 citations
Adding intranasal esketamine to standard care rapidly reduced depression symptoms in people at imminent suicide risk. In a double-blind trial, 68 participants received either esketamine (84 mg) or placebo twice weekly for four weeks. Depression scores improved significantly more with esketamine at 4 hours and 24 hours after the first dose, but not at 25 days. Suicidal thoughts improved at 4 hours but not later. Clinician-rated suicide risk did not differ between groups at any time. Common side effects of esketamine included nausea, dizziness, dissociation, unpleasant taste, and headache. The findings suggest esketamine may offer rapid but temporary relief for severe depression with suicide risk.
JAMA Psychiatry
March 1, 2017
Gerard Sanacora, Mark A. Frye, William M. Mcdonald et al.
577 citations
Ketamine can produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. However, existing studies have relatively small sample sizes, lack longer-term data on efficacy, and provide limited data on safety. Despite these limitations, ketamine is increasingly used off-label for mood and other psychiatric disorders. This review and consensus statement provides an overview of the data, highlights limitations, and offers suggestions to facilitate evidence-based clinical decision-making and patient safety.
American Journal of Psychiatry
April 8, 2016
Jaskaran Singh, Maggie Fedgchin, Ella Daly et al.
530 citations
In adults with treatment-resistant depression, intravenous ketamine (0.5 mg/kg) given two or three times per week produced a substantial and similar reduction in depression scores over 15 days compared to placebo. The twice-weekly ketamine group showed an average 18.4-point drop on the Montgomery-Åsberg Depression Rating Scale, versus 5.7 points for placebo; the thrice-weekly group showed a 17.7-point drop, versus 3.1 points for placebo. Headache, anxiety, dissociation, nausea, and dizziness were common side effects, but dissociative symptoms were temporary and lessened with repeated doses.
JAMA
August 31, 2023
Charles L Raison, Gerard Sanacora, Joshua Woolley et al.
493 citations
A single 25-mg dose of synthetic psilocybin, administered with psychological support, produced a clinically significant and sustained reduction in depressive symptoms and functional disability over 43 days in adults with major depressive disorder. In a phase 2 trial of 104 participants, those receiving psilocybin showed a mean 12.3-point greater improvement on the Montgomery-Asberg Depression Rating Scale at day 43 compared with those receiving a niacin placebo. Psilocybin also improved daily functioning and led to more sustained response, though not remission. No serious adverse events occurred, but psilocybin was associated with more overall and severe adverse events.
Annual Review of Medicine
October 23, 2014
Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman et al.
420 citations
Ketamine, a glutamate-based antidepressant, can rapidly alleviate depression within hours of treatment. Replicated evidence shows its rapid and potent effects in treatment-resistant depression. Preclinical and biomarker studies have begun to explain the mechanism behind these rapid effects, offering new insights into depression's biology and identifying potential treatment targets. This article discusses ketamine's efficacy, safety, and tolerability, summarizes depression's neurobiology, reviews the mechanisms of ketamine's rapid antidepressant effects, and considers prospects for next-generation rapid-acting antidepressants.
The Journal of Clinical Psychiatry
May 11, 2020
Dong-Jing Fu, Dawn F. Ionescu, Xiang Li et al.
367 citations
In adults hospitalized for major depressive disorder with active suicidal thoughts, adding esketamine nasal spray to standard treatment (antidepressants and hospitalization) reduced depression symptoms more than placebo plus standard treatment within 24 hours, with benefits persisting over four weeks. The difference in suicidal ideation severity between groups was not statistically significant. Common side effects of esketamine included dizziness, dissociation, headache, nausea, and drowsiness.
The Journal of Clinical Psychiatry
April 20, 2020
Ewa Wajs, Leah Aluisio, Richard Holder et al.
288 citations
In a year-long open-label study of 802 adults with treatment-resistant depression, esketamine nasal spray combined with a new oral antidepressant showed a manageable safety profile and sustained improvement in depressive symptoms. Common side effects included dizziness, dissociation, nausea, and headache, mostly mild or moderate and resolving the same day. Two deaths occurred, neither linked to the drug. Cognitive performance remained stable or improved. Depression scores dropped during the first four weeks and stayed lower through the maintenance phase.
Molecular Psychiatry
October 15, 2013
Gerard Sanacora, Mark A. Smith, Sanjeev Pathak et al.
234 citations
NMDA channel blockers can produce antidepressant effects without the psychotomimetic and dissociative side effects seen with ketamine. Using quantitative electroencephalography to align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to ketamine, the antidepressant response was maintained with repeated and intermittent drug administration in placebo-controlled data. This provides a path for developing glutamatergic-based treatments for treatment-refractory mood disorders.
Depression and Anxiety
April 6, 2016
Chadi G. Abdallah, Thomas G. Adams, Benjamin Kelmendi et al.
204 citations
Major depressive disorder is a common psychiatric condition that often responds poorly to traditional antidepressants, which can take weeks to work. Over the past two decades, the NMDA receptor antagonist ketamine has attracted attention because a single low dose produces rapid antidepressant effects in people with treatment-resistant depression. Evidence from animal and human studies suggests that ketamine triggers a surge of glutamate, initiating a cascade that promotes synaptogenesis and reverses stress-related damage, especially in the prefrontal cortex. This review covers the neurobiology of stress-related depression, the safety and efficacy of ketamine, its mechanism of action, and predictors of treatment response, along with research limitations and future directions.
Neuropsychopharmacology
May 12, 2023
Naim Zaki, Li Chen, Rosanne Lane et al.
122 citations
Adults with treatment-resistant depression who continued esketamine nasal spray plus an oral antidepressant in a long-term extension study (SUSTAIN-3) showed sustained improvement in depression ratings over up to 4.5 years. Among 1148 participants, common side effects included headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Depression scores dropped during the initial four-week induction phase and remained low during maintenance; about 46% of participants were in remission at the maintenance phase endpoint. No new safety concerns emerged with long-term, intermittent dosing.
Psychotherapy and Psychosomatics
January 1, 2017
Samuel T. Wilkinson, Dashaun Wright, Madonna K. Fasula et al.
120 citations
Ketamine provides rapid but short-lived antidepressant effects. In an open-label trial, patients with treatment-resistant depression received a 2-week course of intravenous ketamine alongside a 10-week course of cognitive behavioral therapy (CBT). Of 16 participants, 8 responded to ketamine and 7 achieved remission in the first 2 weeks. Among responders, 25% relapsed by the end of CBT, and the median time to relapse was 12 weeks after ketamine. Among remitters, 2 of 7 maintained remission through 8 weeks after ketamine. Ketamine nonresponders did not benefit from CBT. The combination may help sustain ketamine's effects, but randomized controlled trials are needed.
Psychotherapy and Psychosomatics
January 1, 2021
Samuel t. Wilkinson, Taeho greg Rhee, Jutta Joormann et al.
102 citations
Cognitive behavioral therapy (CBT) may help sustain the antidepressant effects of ketamine in people with treatment-resistant depression. In a trial, 42 patients with treatment-resistant depression received six intravenous ketamine infusions over three weeks. The 28 who responded were then randomized to CBT or treatment as usual for 14 weeks. On one depression scale, the CBT group showed significantly greater sustained improvement, with a moderate-to-large effect size. A smaller subset of ketamine responders also improved in emotional cognitive accuracy, while nonresponders did not. The findings are preliminary and need confirmation in larger trials.
The Journal of Clinical Psychiatry
July 23, 2018
Samuel T. Wilkinson, Rachel B. Katz, Mesut Toprak et al.
88 citations
In a clinical setting, ketamine infusions for severe, treatment-resistant mood disorders showed lower response and remission rates than those in research protocols. Of 44 patients starting a four-infusion protocol, 45.5% responded and 27.3% remitted by the fourth infusion. A small long-term subsample (n=14) received 12 to 45 total treatments over 14 to 126 weeks with no observed cognitive decline, increased delusions, or cystitis symptoms. The treatment was generally well tolerated, but the small maintenance group limits conclusions about long-term safety.
Proceedings of the National Academy of Sciences of the United States of America
November 27, 2023
J. Krystal, Alfred P. Kaye, S. Jefferson et al.
66 citations
Ketamine represents a new type of antidepressant that works quickly, helps people whose depression has not responded to other treatments, and reduces the chance of relapse. Its development came from a new understanding of depression's biology, and studying how ketamine works has deepened knowledge of depression and related conditions. Twenty-five years after the first findings on ketamine for depression were presented, this review examines what has been learned and suggests future ways to improve rapid-acting antidepressant therapy.
FOCUS The Journal of Lifelong Learning in Psychiatry
April 1, 2022
Jennifer B. Dwyer, Angeli Landeros‐Weisenberger, Jessica A. Johnson et al.
51 citations
A single intravenous infusion of ketamine (0.5 mg/kg over 40 minutes) significantly reduced depressive symptoms in adolescents with major depressive disorder 24 hours later compared with the active placebo midazolam. The treatment effects appeared to persist for 14 days on one depression scale but not another. A greater proportion of participants responded to ketamine during the first three days after infusion (76%) compared with midazolam (35%). Ketamine caused transient dissociative symptoms but no serious adverse events.
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.
JAMA Psychiatry
May 11, 2022
Sina Nikayin, Taeho Greg Rhee, Maria Elena Cunningham et al.
43 citations
In a clinical setting, patients treated with intravenous ketamine or intranasal esketamine showed similar trajectories of depression severity over time, suggesting both treatments are comparably effective for depression.
JAMA Psychiatry
January 3, 2024
Samuel T. Wilkinson, Joseph J. Palamar, Gerard Sanacora
41 citations
Ketamine's use is expanding both as a medical therapeutic and as a recreational substance, raising concerns about potential risks. The authors discuss the need for increased research and surveillance to better understand and manage these dual trends.
Depression and Anxiety
April 15, 2016
Samuel T. Wilkinson, Gerard Sanacora
38 citations
Ketamine appears to rapidly but transiently reduce suicidal ideation, according to a review of open-label and randomized controlled trials. Some studies showed mixed results at different time points or with different assessments. The existing evidence is very preliminary due to small sample sizes, exclusion of patients with significant suicidal ideation at baseline, and potential functional unblinding when saline is used as a placebo. Ketamine is a promising therapeutic option for patients at imminent risk of suicide, but further controlled trials are needed before meaningful clinical recommendations can be made.
JAMA
August 14, 2017
Samuel T. Wilkinson, Gerard Sanacora
36 citations
Ketamine shows promise for treating psychiatric disorders, but important issues remain regarding its clinical use. A consensus statement addresses these concerns and offers suggestions for managing them, highlighting the need for careful consideration of ketamine's risks and benefits in psychiatric practice.
Harvard Review of Psychiatry
March 1, 2022
Igor D. Bandeira, Daniel H. Lins-Silva, Vitor Breseghello Cavenaghi et al.
35 citations
Ketamine shows potential for fast onset of action and good tolerability in treating obsessive-compulsive disorder (OCD), but results have been erratic. The systematic review included nine articles: three randomized controlled trials, three case reports, two open-label trials, and one retrospective chart review. Most studies used only single-session racemic ketamine administered intravenously. No evidence demonstrates whether racemic ketamine, S-ketamine, or R-ketamine has the best efficacy, and only sparse evidence suggests combining ketamine with psychotherapy could benefit patients. Future randomized, double-blind, placebo-controlled trials with larger samples, multiple sessions, and appropriate washout periods are needed.
The international journal of neuropsychopharmacology
June 6, 2025
Naim Zaki, Li Nancy Chen, Rosanne Lane et al.
32 citations
In a long-term extension study (SUSTAIN-3) involving 1,148 adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant was evaluated for safety and efficacy over up to 79 months (median 45.8 months). Common adverse events included headache (36.9%), dizziness (33.9%), and nausea (33.6%). Nine participants died, with causes including COVID-19 and suicide. Depressive symptoms, measured by the MADRS, improved during the initial induction phase (average reduction of 12.8 points) and this improvement was maintained during the optimization/maintenance phase. At the end of maintenance, 49.6% of participants were in remission. No new safety concerns emerged, and depression improvement generally persisted for those continuing treatment.
JAMA network open
June 3, 2024
Manish Kumar Jha, Samuel T Wilkinson, Kamini Krishnan et al.
29 citations
In people with treatment-resistant depression who do not have psychosis, intravenous ketamine works as well as electroconvulsive therapy (ECT) overall. Among outpatients with moderately severe or severe depression, ketamine produced greater improvement in depressive symptoms than ECT. In contrast, inpatients with very severe depression improved more with ECT early in treatment, though by the end of the three-week course both treatments were similarly effective. Higher premorbid intelligence and a diagnosis of posttraumatic stress disorder were linked to greater improvement with ECT, but not with ketamine. These findings may help patients and clinicians decide between the two treatments.