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.
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.
Expert Opinion on Drug Safety
April 13, 2022
Sina Nikayin, Eva Murphy, John H. Krystal et al.
114 citations
Ketamine and its derivative esketamine (Spravato) can rapidly relieve depression, but their long-term safety is reviewed here. Common side effects are temporary and mild, including dissociation, nausea, headache, and changes in heart rate and blood pressure. Esketamine may increase lower urinary tract symptoms, but severe bladder problems have not occurred at prescribed depression doses. High-dose ketamine can impair cognition long-term, but esketamine trials show cognition remains stable or improves, indicating no increased cognitive risk with appropriate use.
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.
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.
JAMA Psychiatry
April 16, 2025
Samuel T. Wilkinson, Gerard Sanacora
14 citations
The US Food and Drug Administration rejected MDMA as a treatment for posttraumatic stress disorder, citing concerns about lack of blinding and integrity issues in the clinical trials that had been conducted. This viewpoint examines the potential justifications for that decision.
American Journal of Psychiatry
September 10, 2025
Songze Li, Kristina T. Kumpf, Julian Urrutia et al.
13 citations
Repeated or high-dose subanesthetic ketamine causes excitotoxic neuronal damage and lasting cognitive deficits in animals, especially perinates. Infrequent low-to-moderate doses (<1 mg/kg human intravenous equivalent) do not produce overt brain damage in rats and nonhuman primates. In humans, frequent high-dose (>1 g/day) recreational users show memory and executive function impairments. However, a large clinical trial found that intranasal esketamine at up to 84 mg weekly or every other week for several years is associated with maintained or slightly improved cognition in adults with major depression, though some elderly patients showed potential worsening in attention and processing speed. Direct comparisons of esketamine and off-label racemic ketamine at higher doses are lacking.
Contemp Clin Trials
March 2, 2026
Samuel T. Wilkinson, Sandhya Prashad, Rachel Dalthorp et al.
1 citation
The EQUIVALENCE trial protocol describes a non-inferiority, comparative effectiveness study designed to test whether intranasal esketamine is no less effective than intravenous ketamine for treating treatment-resistant depression. The study will compare the two treatments head-to-head in patients who have not responded to prior antidepressant therapies. The protocol outlines the trial's design, including randomization, dosing regimens, outcome measures, and statistical analysis plan. By directly comparing these two forms of ketamine, the trial aims to provide evidence on whether the more convenient intranasal route can match the efficacy of the intravenous formulation, potentially offering a more accessible treatment option.
FOCUS The Journal of Lifelong Learning in Psychiatry
July 1, 2026
Morgan S. Hardy, S. William Li, Samuel T. Wilkinson
Ketamine, a rapid-acting antidepressant for treatment-resistant depression, works by blocking NMDA glutamate receptors and inducing a temporary state of enhanced neuroplasticity and metaplasticity—the brain's increased capacity for future plastic changes. This creates a posttreatment window of heightened cognitive flexibility, making patients more responsive to other interventions. Combining ketamine with cognitive-behavioral therapy (CBT) may leverage these neurobiological changes to produce a more durable antidepressant effect and reduce relapse. This differs from ketamine-assisted psychotherapy, which emphasizes the drug's consciousness-altering experience. Early studies show promise, but evidence is limited and optimal timing and structure remain undefined. The review summarizes the theoretical rationale and emerging evidence for integrating ketamine or esketamine with cognitive therapies, evaluates recent clinical trials, and proposes a framework for interventional psychiatrists.
The Journal of Clinical Psychiatry
September 3, 2025
Kristina T. Kumpf, Samuel T. Wilkinson, Bo Hu et al.
In a multisite randomized trial comparing cognitive effects of intravenous ketamine and electroconvulsive therapy (ECT) in patients with treatment-resistant depression, those receiving six ketamine treatments showed superior cognitive functioning after a three-week treatment course compared with those receiving nine ECT sessions. No significant differences in cognitive task performance were associated with response to either treatment. Among responders followed for up to six months, no group differences emerged. Subjective memory measures were mixed: both groups improved on the Squire Memory Complaint Questionnaire, with ketamine recipients reporting greater functional gains, while ketamine-treated patients reported improvements on a global self-evaluation of memory but ECT-treated patients reported a decline. Within the ketamine group, improvements in executive functioning and cognitive flexibility survived adjustment for changes in depression, suggesting partial independence of cognitive and mood effects.