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.
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.
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.
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.
The Journal of Clinical Psychiatry
July 16, 2021
Ibrahim Turkoz, Ella Daly, Jaskaran Singh et al.
21 citations
For patients with treatment-resistant depression who did not show a response within the first week of treatment, a full four-week induction course of esketamine nasal spray plus an oral antidepressant may still provide benefit. In a pooled analysis of two phase 3 trials, among those not meeting early response criteria at day 2 or days 2 and 8, the odds of a response by day 28 were about 1.6 times higher with esketamine plus antidepressant compared to antidepressant plus placebo. The findings suggest that lack of early improvement does not preclude later benefit from the full induction course.
Drug Discovery Today
December 1, 2023
Taeho Greg Rhee, Pasha A. Davoudian, Gerard Sanacora et al.
20 citations
Psychiatric disorders are the leading cause of disability globally, and interest in psychedelic substances as potential treatments has recently revived. This review examines the therapeutic potential and safety concerns of psilocybin, DMT, LSD, and MDMA, including their possible interactions with psychotherapy. It covers active and recently completed clinical trials drawn from published literature, conference abstracts, clinical trial registries, and press releases. The review suggests that these compounds may offer new avenues for treating psychiatric disorders, though safety considerations remain important.
Psychiatry Research
March 15, 2023
Ibrahim Turkoz, J. Craig Nelson, Samuel T. Wilkinson et al.
19 citations
A post hoc analysis of two pooled 4-week phase 3 trials examined predictors of response and remission in patients with treatment-resistant depression receiving esketamine nasal spray plus a new oral antidepressant compared to a new oral antidepressant plus placebo nasal spray. Younger age, being employed, having fewer failed antidepressants in the current episode, and early reduction in Clinical Global Impression-Severity score at day 8 predicted better outcomes. Those on esketamine had 68% higher odds of response and 55% higher odds of remission. In the esketamine group, response was more likely in employed patients, those without baseline anxiety, and those with early symptom improvement.
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.
The Journal of Clinical Psychiatry
October 2, 2024
Mia C Santucci, Mina Ansari, Sina Nikayin et al.
12 citations
In a real-world clinical setting, 45 patients with treatment-resistant bipolar depression received intravenous ketamine or intranasal esketamine. Among 38 who completed an acute series (twice-weekly treatments for up to four weeks), 39% achieved a clinical response (at least 50% improvement on the Montgomery-Asberg Depression Rating Scale) and 13.2% achieved remission (score of 10 or lower). Mean depression scores dropped from 31.1 to 19.2, a 38.3% improvement. No manic or hypomanic episodes occurred during the acute phase. However, during maintenance treatment, 28.9% of patients experienced hypomanic or manic symptoms, with one severe event requiring hospitalization.
General Hospital Psychiatry
January 1, 2024
Mina Ansari, Brian Pittman, Daniel S Tylee et al.
6 citations
Blood pressure increases during ketamine infusion for depression, peaking at 40 minutes with average rises of 16.0 mmHg systolic and 11.0 mmHg diastolic. Severe hypertension occurred in 12.5% of patients and 0.98% of infusion sessions, most often during the first three treatments. Older age and a history of hypertension were associated with larger blood pressure surges, indicating that careful cardiovascular monitoring is needed, especially for these patients.
Psychiatry Research
May 1, 2025
Gerard Sanacora, Brian S. Barnett, Bo Hu et al.
2 citations
Patients with treatment-resistant depression who preferred ketamine over electroconvulsive therapy (ECT) were more likely to respond to treatment, regardless of which treatment they actually received. Matching patients to their preferred treatment improved response rates for ketamine but not for ECT, and reduced adverse events for ECT-treated patients. Ketamine was the more popular choice overall. The findings suggest that aligning treatment with patient preference can influence effectiveness, safety, and possibly adherence, but these effects vary by treatment modality and context.
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.
Fundamental & clinical pharmacology
July 1, 2026
Nina Abukahok, Steven Lawrence, Samrachana Adhikari et al.
In the New York metropolitan area, over a third of clinics advertising ketamine for psychiatric conditions offer it for at-home use, raising safety concerns. A 2025 systematic web search identified 233 clinics; 36.5% prescribed ketamine for at-home use, 51.5% listed a medical doctor, 42.9% advertised oral ketamine, and depression was the most common condition treated (94.0%). Clinics advertising oral ketamine were over four times more likely to offer at-home use, while those listing a medical doctor were about half as likely. The findings suggest a consumer-oriented advertising approach that may warrant monitoring and clearer guidance to mitigate safety risks.
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
May 4, 2026
Samuel T. Wilkinson, Brandon Kitay, Matthew Macaluso et al.
Adding cognitive behavioral therapy to esketamine treatment reduces suicidal ideation more than esketamine alone in people with major depression and suicidal thoughts. In a randomized trial of 93 patients, 72% completed the study, meeting feasibility goals. Those who received 16 weeks of CBT plus esketamine showed greater improvement on three measures of suicidal ideation than those receiving esketamine with usual care: a mean difference of -1.91 on the Beck Scale for Suicidal Ideation, -0.33 on the Clinician Global Improvement Scale for Suicide Severity, and -3.77 on the depression rating scale. No difference was found on the Columbia-Suicide Severity Rating Scale or in suicide-related events.