A new large-scale clinical trial suggests that esketamine nasal spray, used on its own, may offer meaningful relief for adults with treatment-resistant depression. Participants who received esketamine without any accompanying oral antidepressant experienced a rapid reduction in depressive symptoms—often within 24 hours—and these improvements tended to persist over the course of the four-week trial. The findings were published in JAMA Psychiatry.
Ketamine was originally developed as an anesthetic but has gained attention in recent years for its potential antidepressant properties, particularly among individuals who have not improved with conventional medications. Esketamine, a chemically related compound and a more targeted version of ketamine, is the active ingredient in SPRAVATO®, a nasal spray approved by the U.S. Food and Drug Administration.
SPRAVATO® was initially authorized for use in combination with oral antidepressants to treat adults with treatment-resistant depression. Until recently, however, it was unclear whether esketamine could be effective on its own, without the need for additional oral medications.
Roughly one in three individuals with major depressive disorder does not respond adequately to at least two oral antidepressants, placing them in the category of having treatment-resistant depression. For these individuals, the typical next step involves adding new medications to their current treatment plan. But oral antidepressants often produce side effects such as fatigue, weight gain, gastrointestinal problems, and sexual dysfunction—issues that can lead to poor adherence or discontinuation.
The researchers behind this new study set out to examine whether esketamine, administered as SPRAVATO®, could serve as a single-agent treatment for patients who either do not respond to or cannot tolerate standard antidepressant drugs.
“The size and scope of the global depression epidemic is staggering. There are more than 280 million people worldwide living with major depressive disorder (MDD), and significant unmet needs remain for these patient,” said Adam Janik, the medical director at Johnson & Johnson and lead author of the new study.
“When we started researching SPRAVATO®, there had been no new mechanism of action in the mental health space for more than 30 years, which left patients with few options. In fact, SPRAVATO® was granted breakthrough therapy designation by the U.S. FDA for its first two indications, highlighting the need for innovation in the space.”
“We’ve dedicated years to studying SPRAVATO® and bringing it to market – more than a decade of research, 31 global clinical trials and six years of real-world use – and we’re proud to continue our nearly 70-year legacy in psychiatry innovation.”
The trial was a phase 4, randomized, double-blind, placebo-controlled clinical study, carried out at 51 outpatient centers across the United States between late 2020 and early 2024. The participants were adults diagnosed with major depressive disorder, based on standard diagnostic criteria. To qualify, individuals had to demonstrate a history of poor response—defined as less than 25% symptom improvement—to at least two different oral antidepressants during their current episode.
After discontinuing any previous antidepressants, participants were randomly assigned to one of three groups. One group received a fixed dose of 56 milligrams of intranasal esketamine, another received 84 milligrams, and the third group received a placebo spray. The treatments were administered twice a week over the course of four weeks. The primary measure of treatment effectiveness was the change in scores on the Montgomery-Åsberg Depression Rating Scale, which assesses symptom severity.
The efficacy analysis included 378 participants, with an average age of 45 years. Around 61% of the sample were women. All participants met criteria for moderate to severe depression at baseline, with average depression scores near the upper limit of the scale.
The researchers used both clinician-administered interviews and self-report questionnaires to monitor changes in depressive symptoms. They also assessed safety outcomes such as side effects, blood pressure, and potential signs of suicidality using standardized tools. In addition to immediate outcomes after the first dose, participants’ symptoms were tracked over time to assess sustained response and remission rates.
The results suggest that esketamine alone significantly outperformed the placebo in reducing depressive symptoms by day 28, the end of the double-blind treatment phase. Those receiving the 56 mg dose had an average symptom score reduction that was 5.1 points greater than the placebo group. Participants receiving the 84 mg dose showed an even larger improvement, with a 6.8-point advantage over placebo.
Notably, these changes were already apparent within 24 hours of the first dose. Both esketamine groups showed significantly better scores compared to placebo at that early time point, suggesting that the drug may offer much faster relief than traditional antidepressants, which typically take weeks to show effects.
The number needed to treat—an estimate of how many patients would need to be treated for one to benefit—was 6.5 to 7 for symptom response and slightly higher for remission, indicating a moderate effect size. These figures are comparable to or better than those typically seen with adjunctive use of esketamine.
Patients who continued into the optional 12-week open-label phase—where everyone received esketamine—also tended to show either sustained or further improvement in their depressive symptoms.
“SPRAVATO® as a monotherapy offers a safe and effective treatment option for people living with treatment-resistant depression, especially for those experiencing treatment-limiting tolerability concerns or nonresponse with oral antidepressants,” Janik told PsyPost.
As with previous esketamine studies, certain side effects were more common in the treatment group than among those given placebo. These included nausea, dizziness, headache, and dissociation—a temporary sense of detachment from one’s thoughts or surroundings. However, these side effects were generally short-lived and tended to occur during the dosing sessions themselves, resolving within a few hours.
“The safety profile of SPRAVATO® as a standalone treatment was consistent with the existing body of clinical and real-world data when used in conjunction with an oral antidepressant, and no new safety concerns were identified,” Janik said.
No deaths were reported during the study. Serious adverse events were rare and did not appear to be related to the treatment. Rates of suicidal thoughts or behaviors, a concern in some depression trials, were similar or slightly lower in the esketamine groups compared to placebo.
“The data confirms what our team hypothesized from the outset,” Janik said. “We followed the science, and the results reflect that SPRAVATO® is safe and effective, offering rapid and sustained relief for patients with treatment-resistant depression.”
Because esketamine has known psychoactive properties, the researchers took steps to minimize the risk of participants correctly guessing whether they had received the active drug or placebo. Still, many participants were able to tell, which is a common limitation in studies involving psychoactive treatments. Importantly, analyses showed that participants’ symptom improvements were not simply driven by whether they had experienced side effects such as dissociation, suggesting that the antidepressant effect was not merely due to expectancy.
“SPRAVATO® is approved for use in adults alone or in conjunction with an oral antidepressant with MDD who have had an inadequate response to at least two oral antidepressants and for adults in conjunction with an oral antidepressant for depressive symptoms with MDD with acute suicidal thoughts or actions,” Janik explained.
“Since its first approval in 2019, we’ve been focused on ensuring safe and appropriate use of this important medicine. All patients receiving SPRAVATO® are required to enroll in the SPRAVATO® REMS program and be monitored by a healthcare professional for at least two hours post-administration to ensure the medication is well-tolerated and monitor for any serious side effects. SPRAVATO® is never dispensed for at-home use.”
Although the trial provides strong evidence for the efficacy of esketamine as a standalone treatment, there are caveats to consider. The sample lacked racial and ethnic diversity, and participants with certain co-occurring psychiatric conditions were excluded. This could limit how broadly the results can be applied to more diverse or medically complex populations. In addition, the trial’s follow-up period was relatively short, meaning long-term safety and efficacy still require further study.
Future research may focus on better understanding the biological mechanisms through which esketamine works, especially given that its precise mode of action remains unclear. Additional studies may also explore how to identify which patients are most likely to benefit and whether the treatment can be safely and effectively integrated into broader mental health care settings.
“Our approach to MDD reflects the complexity of this condition,” Janik told PsyPost. “We’re advancing a pipeline of mechanistically distinct therapies aimed at addressing the biological drivers of MDD, including the residual symptoms that conventional treatments often leave unresolved.”
“We’re committed to exploring new mechanisms of actions to treat MDD, and we are investigating novel adjunctive treatments designed to improve outcomes for patients whose symptoms persist despite treatment with currently available antidepressant treatments.”
The study, “Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial,” was authored by Adam Janik, Xin Qiu, Rosanne Lane, Vanina Popova, Wayne Drevets, Carla Canuso, Matthew Macaluso, Gregory Mattingly, Richard Shelton, John Zajecka, and Dong-Jing Fu.
