American Journal of Psychiatry
September 10, 2025
Gerard Sanacora, Muhammad Ahmed, Brianne Brown et al.
24 citations
Over nearly five years of real-world use in the United States, esketamine's safety profile remains consistent with clinical trial findings and product labeling. Among 58,483 patients completing 1,486,213 outpatient sessions, sedation occurred in 34.7% of sessions, dissociation in 41.0%, and increased blood pressure in 0.9%. Serious adverse events were rare, reported in less than 0.1% of sessions in the REMS program and 0.18% in the US-GMS database. Suicide rates were lower than background rates, and 210 incidences of all-cause abuse or misuse were reported. No new safety signals were identified.
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.
FOCUS The Journal of Lifelong Learning in Psychiatry
July 1, 2018
Gerard Sanacora, Rachel Katz
16 citations
Ketamine, originally used as an anesthetic, shows promise as a rapid-acting treatment for severe depression, including treatment-refractory cases. A single dose provides short-lived relief, but multiple infusions may offer sustained effects. Its quick onset could help prevent hospital stays, treat acute suicidal ideation, and facilitate medication changes. Combining ketamine with psychotherapy may enhance response and duration. Despite growing use for various psychiatric disorders, there is inadequate data on true clinical efficacy, safety, and mechanisms of action. This article reviews ketamine's history as an antidepressant, current hypotheses on its mechanisms, and existing evidence on safety and efficacy for clinicians.
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 international journal of neuropsychopharmacology
November 1, 2024
Randall L Morrison, Jaskaran Singh, Ella Daly et al.
9 citations
In patients with treatment-resistant depression, adding esketamine nasal spray to a newly initiated oral antidepressant did not harm cognitive function over the short or long term. Across three short-term double-blind studies (747 patients aged 18–64 years) and one long-term maintenance study (137 patients aged 65 or older), cognitive performance on tests of psychomotor function, attention, and memory either remained stable or slightly improved from baseline to the end of treatment. At the start, patients showed mild-to-moderate cognitive impairment. The correlation between depression severity and cognitive performance was weak. The analysis found no evidence that esketamine worsens cognition in treatment-resistant depression.
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.
JAMA Psychiatry
February 12, 2025
Brian S. Barnett, Roger D. Weiss, Gerard Sanacora
7 citations
Ketamine's use in psychiatry presents safety challenges, including risks of misuse, adverse effects, and lack of standardized protocols. Recommendations to optimize patient safety include careful patient selection, monitoring during and after administration, and establishing guidelines for appropriate use in clinical settings.
The international journal of neuropsychopharmacology
December 1, 2024
Craig Chepke, Richard Shelton, Gerard Sanacora et al.
7 citations
Esketamine nasal spray, approved for treatment-resistant depression and major depressive disorder with suicidal thoughts, rarely causes respiratory depression after marketing. Analysis of 47 months of postapproval safety data found 50 cases of respiratory depression among patients, with 8 strongly linked to the drug. The estimated incidence is 1 case per 20,000 treatment sessions. Symptoms are manageable and resolve with minor support. Monitoring, including pulse oximetry, is recommended during postdose observation.
CNS Spectrums
July 29, 2022
Ibrahim Turkoz, Oliver Lopena, Giacomo Salvadore et al.
6 citations
In adults with major depressive disorder and active suicidal ideation with intent who did not show early improvement, adding esketamine nasal spray to standard care increased the likelihood of achieving a response (63.9% vs 48.0%) and remission (35.1% vs 24.4%) after four weeks compared to placebo plus standard care. The odds of response were nearly double with esketamine. Similar benefits appeared for those who had not responded after one week. The findings suggest that continuing esketamine treatment for the full four weeks can be beneficial even when early response is absent.
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
June 17, 2025
Clio E Franklin, Murat Altinay, Kala Bailey et al.
2 citations
For treatment-resistant mood disorders, intensive interventions such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine, and esketamine are commonly used, but how genetics influences response to these therapies remains unclear. A review of the current literature finds that most studies have examined single variants in candidate genes, particularly COMT and BDNF, yet none have been consistently reproducible. Genome-wide association studies are few and mostly underpowered, with only one exceeding 1000 participants, yielding few statistically significant single nucleotide polymorphisms outside COMT and BDNF. Large-scale data collection is needed to establish genetic predictors and differentiate responses among treatments, a goal being pursued by the worldwide Gen-ECT-ic consortium.
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.
Focus (American Psychiatric Publishing)
April 1, 2025
Sophie I Elliott, Rachel B Katz, Robert B Ostroff et al.
2 citations
For severe treatment-resistant depression, both electroconvulsive therapy (ECT) and ketamine are effective, but it remains unclear which is superior. Two noninferiority trials and three meta-analyses show efficacy for both treatments yet report contradictory findings about which works better. Discrepancies may stem from differences in patient selection, outcome measures, treatment delivery, and site experience. Each treatment has unique risks and benefits that should be weighed for individual patients. The authors aim to help clinicians choose the optimal treatment by evaluating the latest evidence and patient-specific factors.
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.
Neurologic clinics
February 1, 2026
Mina Ansari, Sophie I Elliott, Sophie E Holmes et al.
1 citation
Placebo effects in depression treatment trials are substantial and can obscure the true efficacy of new drugs, especially for psychedelic-like compounds. Expectancy, the therapeutic setting, and trial design all interact to shape patient outcomes. This review examines these factors and discusses emerging methods to mitigate, measure, or harness placebo effects in future research on rapid-acting antidepressants and psychedelic therapies.
The Journal of clinical psychiatry
May 4, 2026
Samuel T Wilkinson, Brandon M 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.
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.
JAMA Psychiatry
September 1, 2023
Luana Colloca, Sina Nikayin, Gerard Sanacora
Expectations—what patients believe will happen—can powerfully shape the outcomes of psychedelic drug therapy. The article discusses how these beliefs interact with the pharmacological effects of psychedelics, potentially amplifying or diminishing therapeutic benefits. It suggests that managing expectations through preparation and the therapeutic setting may be as important as the drug itself. The authors argue that understanding this interplay is crucial for designing effective treatments and for interpreting clinical trial results.
Journal of affective disorders
June 1, 2023
Gustavo C Leal, Breno Souza-Marques, Rodrigo P Mello et al.
In a small pilot trial, the antidepressant arketamine was compared with placebo for treatment-resistant depression. Ten participants received both arketamine (0.5 mg/kg) and saline one week apart in a randomized, double-blind, crossover design. Depression improved over time, but there was no significant difference between arketamine and placebo. Dissociation and other adverse events were minimal. The study was underpowered, and the authors conclude that arketamine was not superior to placebo but was extremely safe, recommending larger trials with different dosing strategies.