spravato_annual_worldwide_sales_2019_2026
More than six decades after Calvin Stevens first synthesized ketamine at Parke-Davis while searching for a safer anesthetic, the molecule has completed its migration into psychiatry, where it has become a blockbuster. Esketamine, the more potent S-enantiomer of that original compound, won FDA approval for treatment-resistant depression as a nasal spray in March 2019, then only as an add-on to a conventional antidepressant. In January 2025, regulators cleared it as the only monotherapy for treatment-resistant depression. After a quiet start following its launch, the compound, which Johnson & Johnson markets as Spravato, brought in roughly $1.7 billion last year. Wall Street expects closer to $2.3 billion in 2026.
Johnson & Johnson is hoping one item that will further stoke sales is data recently presented at Psych Congress Elevate, an overview of remission rates with esketamine nasal spray across six clinical trials in treatment-resistant depression (TRD). The potential market is large and growing. An estimated 21 million U.S. adults had at least one major depressive episode in 2021, representing 8.3% of U.S. adults.
Rakesh Jain, MD, MPH
Of the estimated 8.9 million U.S. adults treated with medication for major depression, roughly a third, some 2.8 million people, fail to respond adequately to standard oral antidepressants, the threshold that defines treatment-resistant depression (TRD). “There are millions upon millions of patients, some of them your friends and mine, some of them your family members, who are being treated for depression and are simply not in remission,” said Rakesh Jain, MD, MPH, a clinical professor of psychiatry at Texas Tech University School of Medicine, Permian Basin, and the lead author of the analysis.
Why remission is so rarely reported
Jain frames remission as the central theme of the analysis. The poster reports it against two cutoffs on the Montgomery-Åsberg Depression Rating Scale (MADRS), a clinician-rated instrument that scores 10 core depression symptoms from 0 to 6 each for a total of 0 to 60. A score of 7 to 19 indicates mild depression, 20 to 34 moderate, and 35 or above severe, and remission is conventionally set at 10 or below. The patients entering these trials had baseline scores running from roughly 29 to 38, putting them in the moderate-to-severe range. “We actually tightened the rules on SPRAVATO a little bit,” Jain said. “We said, okay, 12 is fine, but can we go to 10? And it performed quite well, even at 10. That’s the key.”
In any event, remission is an elusive goal. “With many atypical antipsychotic augmentation trials, the reason you haven’t read remission numbers is that they’re not typically put out there,” Jain said. “The numbers look abysmal, or they don’t separate from placebo.” The benchmark he returns to is STAR*D, the largest real-world depression treatment trial ever conducted, a National Institute of Mental Health study that enrolled more than 4,000 outpatients with nonpsychotic major depression and sequenced them through up to four successive treatment steps. In the level-one citalopram analysis of 2,876 evaluable patients, about 28% remitted on the HAM-D. By the third step, after two prior treatments had failed, the threshold that defines treatment resistance, remission fell to 13.7%. “The problem is that the moment you go to a second antidepressant, the remission rate drops sharply, to as little as 14 or 15%,” Jain said. “It’s a very sharp drop.”
Reaching remission, and holding it
Jain said his interest in esketamine is both its potential to support rapid remission and durable remission. “The profound move is not just to achieve remission but to hold on to it year upon year upon year,” he said. “That’s why this poster became such an important poster at this year’s meeting. It demonstrated to clinicians of all stripes that this is not just depression, this is TRD, and we’re able to help people get to remission in numbers that are unusual.”
Jain points to the analysis providing clarity given the data scope. “How does it behave in double-blind settings, in open-label, and in comparative analyses? … Because to a clinician, a double-blind study matters, but it’s of academic interest. In real life, what you want to know is all of the above,” he said. “I think this data is not cherry-picking. We’re showing short-term, we’re showing long-term, we’re showing a head-to-head comparison, and we’re not taking the easy route.”
The J&J poster reports MADRS ≤10 remission at week 4 of 13.9% and 21.5% for Spravato monotherapy doses versus 6.5% for placebo, and 42.6% for Spravato plus oral antidepressant versus 24.0% for placebo plus oral antidepressant in TRANSFORM-2. From the open-label extension studies, which followed only patients who stayed on the drug, it reports remission of 49.3% at roughly one year, 78.2% at about two and a half years, and 43.2% at the longest follow-up of around 5.5 years. The same poster, though, labels the analysis as descriptive: no formal meta-analysis, no pooled effect estimates, no statistical comparisons, and trial-design differences that limit direct comparability.
The analysis is a compilation of existing data, gathering remission rates from six previously reported esketamine trials: two four-week, placebo-controlled studies (the TRD4005 monotherapy trial and TRANSFORM-2, which paired esketamine with an oral antidepressant), one active-controlled trial pitting esketamine against quetiapine extended-release (ESCAPE-TRD), and three open-label studies that followed patients for as long as 5.5 years (ESCAPE-LTE, SUSTAIN-2 and SUSTAIN-3). For each, it reports remission against two MADRS thresholds, 10 or below and 12 or below.
Jain casts that range as the poster’s strength. “It’s such wide-ranging data: different studies, short-term, long-term, a comparative study,” he said.
Of the trials included is J&J’s ESCAPE-TRD record, which describes a Phase 3 interventional trial comparing flexible-dose esketamine nasal spray with quetiapine XR, both with SSRI/SNRI background therapy, with remission by MADRS at week 8 as the primary outcome.
While demand for Spravato continues to grow, professional opinion on the enantiomer runs along a spectrum, with guideline bodies landing at different points on the same axis. The 2022 VA/DoD depression guideline lists ketamine or esketamine as an augmentation option after several failed drug trials, but only as a “weak for” recommendation resting on low-quality evidence, with explicit reservations about monitoring and feasibility. (VA/DoD guideline synopsis, Annals of Internal Medicine) Britain’s NICE went further in 2022, declining to recommend esketamine for routine NHS use on the grounds that the clinical and economic evidence could not support a reliable cost-effectiveness estimate, a decision that predates the monotherapy approval. (NICE TA854) (Scotland’s medicines regulator had reached the opposite conclusion two years earlier.)
The strongest controlled evidence in the analysis does favor esketamine. In the head-to-head ESCAPE-TRD trial, the only one in the set pitting it against an active comparator, esketamine plus an SSRI or SNRI produced higher remission than quetiapine extended-release on the same backbone, 27.1% versus 17.6% at week 8, a result published in the New England Journal of Medicine. (Reif et al., NEJM 2023) Esketamine patients were also less likely to discontinue for safety or tolerability reasons than those on quetiapine.
Even there, the magnitude is contested. The same trial’s gap in depression scores was narrow, a 2.8-point advantage on the 60-point MADRS at week 8 and 2.2 points at week 32, both of which its NEJM correspondence acknowledged fell below the smallest clinically meaningful difference. (NEJM correspondence) Two critiques run in the American Journal of Psychiatry. In a 2025 editorial, Baylor psychiatrists Sanjay Mathew and Nicholas Murphy argued that the phase 3 program never established that patients should continue much beyond the first week, even as prescriptions nearly doubled after early 2023. (Mathew & Murphy, AJP 2025) A systematic review by Fountoulakis, Saitis and Schatzberg put esketamine’s add-on effect sizes at weeks 2 to 4 at 0.15 to 0.23, comparable to the atypical antipsychotic augmentation Jain waves off, with no significant antisuicidal benefit. (Fountoulakis et al., AJP 2025)
Jain points to another FDA-approved use, for major depressive disorder with acute suicidal ideation or behavior, as evidence of its reach. “It’s also approved for what’s called MDD with suicidal ideation,” he said. “That’s a formal indication from the FDA.” The prescribing information he recommends consulting is more circumscribed than the label might suggest. It approves esketamine, alongside an oral antidepressant, for the rapid reduction of depressive symptoms in those patients, and states directly that its effectiveness in preventing suicide or reducing suicidal ideation has not been demonstrated, and that its use does not remove the need for hospitalization when clinically warranted. (FDA prescribing information, 2025) The indication treats the depression of acutely suicidal patients; the label makes no claim that the drug reduces the suicidality itself. “That wasn’t a specific focus [on suicidality in] this particular poster. We were much more focused on the remission rates.”
On the psychology of psychiatric clinicians
Whether the poster changes practice comes down, by Jain’s own account, as much to clinician psychology as to data. “Psychiatry is slow to change, it just is,” he said. “So there are many clinicians who have heard of Spravato but are hesitant, not for any particular reason, that’s just the nature of psychiatry.” He casts the main obstacle as inertia and missing information, the gap the poster is built to close. The frictions outside the clinician’s head are more concrete. Spravato is dispensed only through a restricted REMS program because of risks that include sedation, dissociation, respiratory depression, and abuse, which means a certified setting, a monitoring period of at least two hours after every dose, and no driving until the next day.
“While there are multiple roadblocks, I think one of the bigger ones is clinician hesitation and lack of knowledge, which is why I put this poster out,” he said. The clinicians who stopped at the poster, he added, told him they needed to start thinking about the drug earlier and more often.
Speaking of the feedback of the poster, Jain said the common reaction was to be impressed. “I didn’t get any pushback,” he said. “On the contrary, the reaction was, ‘I really do need to start thinking about Spravato earlier and more often. And I told them, you’re right, that’s what the data compels us to do.’”
Filed Under: Psychiatric/psychotropic drugs
