Johnson & Johnson (J&J) is intensifying its marketing efforts for Spravato (esketamine) by spotlighting compelling remission rate data for treatment-resistant depression (TRD). The pharmaceutical giant recently presented an overview of esketamine’s efficacy across six pivotal clinical trials at Psych Congress Elevate, aiming to solidify its position as a transformative treatment for millions of patients struggling with persistent depressive symptoms. This strategic move comes as Spravato continues its trajectory as a blockbuster drug, with sales reaching approximately $1.7 billion last year and Wall Street analysts projecting an increase to $2.3 billion in 2026.
The Evolution of Ketamine into Modern Psychiatry
The journey of esketamine into the psychiatric pharmacopoeia is a remarkable chapter in drug discovery, tracing its roots back more than six decades. In the 1960s, chemist Calvin Stevens at Parke-Davis synthesized ketamine while in pursuit of a safer anesthetic agent. Over the subsequent decades, ketamine’s unique properties, particularly its rapid antidepressant effects, began to attract significant attention within the scientific community, ultimately leading to its "migration" into psychiatry. Esketamine, specifically the S-enantiomer of the original ketamine compound, represents a more potent formulation developed to harness these therapeutic benefits.
Its official entry into the treatment landscape for depression began in March 2019, when the U.S. Food and Drug Administration (FDA) granted approval for esketamine nasal spray as an add-on therapy for adults with TRD, to be used in conjunction with a conventional oral antidepressant. This initial approval marked a significant milestone, offering a novel mechanism of action for patients who had exhausted other treatment options. Building on this success, January 2025 saw a further expansion of its label, with regulators clearing esketamine as the first and only monotherapy specifically for treatment-resistant depression. This broadened indication underscores the growing confidence in esketamine’s standalone efficacy and its potential to revolutionize care for this challenging patient population.
The Pervasive Challenge of Treatment-Resistant Depression
The market for effective TRD treatments is substantial and growing, reflecting a profound unmet medical need. According to the National Institute of Mental Health (NIMH), an estimated 21 million U.S. adults experienced at least one major depressive episode in 2021, accounting for 8.3% of the adult population. While many respond to initial antidepressant therapies, a significant proportion do not. Of the approximately 8.9 million U.S. adults receiving medication for major depression, roughly one-third—around 2.8 million individuals—fail to achieve an adequate response to standard oral antidepressants. This persistent lack of response, often defined after trials of two or more different antidepressant medications, is the threshold that characterizes treatment-resistant depression.
Dr. Rakesh Jain, MD, MPH, a clinical professor of psychiatry at Texas Tech University School of Medicine, Permian Basin, and the lead author of the recent analysis, emphasizes the sheer scale of this challenge. "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," Dr. Jain stated, highlighting the personal toll of TRD and the critical need for more effective interventions. The economic burden of TRD is also substantial, encompassing direct healthcare costs, lost productivity, and a diminished quality of life for affected individuals and their families.
Remission: The Elusive Goal in Depression Treatment
Dr. Jain frames remission as the central theme of the data presented at Psych Congress Elevate. Remission, defined as a near-complete absence of depressive symptoms, is the ultimate goal of depression treatment, distinguishing it from mere response (a reduction in symptoms). The analysis specifically reports remission rates using two distinct cutoffs on the Montgomery-Åsberg Depression Rating Scale (MADRS), a widely utilized clinician-rated instrument that assesses 10 core depressive symptoms, each scored from 0 to 6, yielding a total score ranging from 0 to 60. Conventionally, a MADRS score of 10 or below indicates remission, while scores of 7-19 suggest mild depression, 20-34 moderate, and 35 or above severe depression. Patients enrolled in these esketamine trials typically presented with baseline MADRS scores ranging from 29 to 38, placing them firmly in the moderate-to-severe depression category.
"We actually tightened the rules on SPRAVATO a little bit," Dr. Jain explained, referring to the analysis’s use of a more stringent MADRS score of 10 or below for remission, in addition to the 12 or below threshold. "We said, okay, 12 is fine, but can we go to 10? And it performed quite well, even at 10. That’s the key."
Achieving and, crucially, maintaining remission remains an elusive goal with many conventional antidepressant treatments. Dr. Jain points out that remission numbers are often not prominently reported in studies of other augmentation strategies, such as atypical antipsychotics, because "the numbers look abysmal, or they don’t separate from placebo." This highlights the significance of Spravato’s remission data.
A key benchmark for understanding the difficulty of achieving remission in TRD is the Sequenced Treatment Alternatives to Relieve Depression (STARD) study. Conducted by the National Institute of Mental Health, STARD was the largest real-world depression treatment trial ever undertaken, enrolling over 4,000 outpatients with nonpsychotic major depression and systematically sequencing them through up to four successive treatment steps. In the initial level-one analysis involving citalopram, only about 28% of the 2,876 evaluable patients achieved remission, as measured by the Hamilton Depression Rating Scale (HAM-D). Crucially, by the third treatment step, after two prior antidepressant treatments had failed—the very definition of treatment resistance—the remission rate plummeted to a mere 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%," Dr. Jain elaborated. "It’s a very sharp drop." This historical context underscores the challenge Spravato aims to address.
A Comprehensive Look at Spravato’s Clinical Evidence
The J&J poster presented at Psych Congress Elevate provides a comprehensive compilation of remission rates from six previously reported esketamine trials, offering a broad view of its performance across different clinical settings and durations. These trials include:
- Two four-week, placebo-controlled studies: TRD4005 (esketamine monotherapy) and TRANSFORM-2 (esketamine plus oral antidepressant).
- One active-controlled trial: ESCAPE-TRD (esketamine versus quetiapine extended-release).
- Three open-label extension studies: ESCAPE-LTE, SUSTAIN-2, and SUSTAIN-3, which followed patients for extended periods, some as long as 5.5 years.
The data presented highlights both rapid and durable remission potential. In the four-week placebo-controlled trials, Spravato demonstrated superior remission rates. For Spravato monotherapy, MADRS ≤10 remission rates at week 4 were 13.9% and 21.5% compared to 6.5% for placebo. When used as an add-on to an oral antidepressant (TRANSFORM-2), Spravato achieved a 42.6% remission rate (MADRS ≤10) at week 4, significantly higher than the 24.0% seen with placebo plus oral antidepressant.
The open-label extension studies provided insights into longer-term outcomes for patients who continued treatment. These studies reported impressive remission rates: 49.3% at approximately one year, 78.2% at about two and a half years, and 43.2% at the longest follow-up of around 5.5 years. While these long-term figures from open-label studies are encouraging, it is important to note, as the poster itself labels, that the analysis is descriptive, lacking formal meta-analysis, pooled effect estimates, or statistical comparisons, and trial-design differences limit direct comparability. Nevertheless, Dr. Jain asserts, "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 added, "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."
Among the trials, ESCAPE-TRD stands out as the only active-controlled study, directly comparing esketamine against another established augmentation strategy. Published in the New England Journal of Medicine in 2023, this trial showed that esketamine plus an SSRI or SNRI produced a significantly higher remission rate (MADRS ≤10) than quetiapine extended-release on the same backbone therapy, at 27.1% versus 17.6% at week 8. Moreover, esketamine patients were less likely to discontinue treatment due to safety or tolerability issues compared to those on quetiapine. This head-to-head comparison offers robust evidence supporting esketamine’s efficacy relative to a common alternative.
Navigating Regulatory Scrutiny and Professional Debate
Despite the promising data, professional opinion and regulatory guidelines on esketamine are not uniformly enthusiastic, reflecting the ongoing complexities of introducing novel psychiatric treatments. Guideline bodies have adopted varying stances. The 2022 VA/DoD (U.S. Department of Veterans Affairs and Department of Defense) depression guideline, for instance, lists ketamine or esketamine as an augmentation option after several failed drug trials. However, it issues only a "weak for" recommendation, based on low-quality evidence, with explicit reservations concerning monitoring requirements and feasibility.
Britain’s National Institute for Health and Care Excellence (NICE) went further in 2022, declining to recommend esketamine for routine use within the National Health Service (NHS). This decision, made prior to the monotherapy approval, was based on the assessment that the clinical and economic evidence presented could not reliably support a cost-effectiveness estimate. Interestingly, Scotland’s medicines regulator had reached the opposite conclusion two years earlier, highlighting the differing interpretations of available evidence across jurisdictions.
Even within the medical literature, the magnitude of esketamine’s benefit has been a subject of debate. While the ESCAPE-TRD trial favored esketamine in terms of remission, the difference in overall depression scores (MADRS) was narrower: a 2.8-point advantage at week 8 and 2.2 points at week 32. The NEJM correspondence accompanying the trial publication acknowledged that these differences fell below the smallest clinically meaningful threshold.
Further critiques have appeared in the American Journal of Psychiatry. In a 2025 editorial, Baylor psychiatrists Sanjay Mathew and Nicholas Murphy questioned whether the Phase 3 program definitively established the necessity for patients to continue treatment much beyond the first week, noting that prescriptions had nearly doubled after early 2023. Another systematic review by Fountoulakis, Saitis, and Schatzberg (AJP 2025) concluded that esketamine’s add-on effect sizes at weeks 2 to 4 were modest (0.15 to 0.23), comparable to those of atypical antipsychotic augmentation strategies that Dr. Jain often dismisses, and importantly, found no significant antisuicidal benefit.
Regarding the latter point, Dr. Jain clarifies another FDA-approved use for Spravato: major depressive disorder with acute suicidal ideation or behavior. "It’s also approved for what’s called MDD with suicidal ideation," he stated, referring to a formal FDA indication. However, it is crucial to consult the prescribing information, which stipulates that esketamine, used alongside an oral antidepressant, is approved for the rapid reduction of depressive symptoms in these patients. The label explicitly states that its effectiveness in preventing suicide or reducing suicidal ideation has not been demonstrated, and its use does not obviate the need for hospitalization when clinically warranted. The drug treats the underlying depression in acutely suicidal patients, but makes no direct claim about reducing suicidality itself. "That wasn’t a specific focus [on suicidality in] this particular poster. We were much more focused on the remission rates," Dr. Jain confirmed.
Clinician Adoption and Future Outlook for Spravato
Ultimately, the impact of this remission data on clinical practice hinges on factors beyond just the scientific evidence. As Dr. Jain candidly admits, "Psychiatry is slow to change, it just is." He identifies clinician hesitation and a lack of comprehensive information as significant obstacles to broader adoption, a gap he hopes the Psych Congress Elevate poster will bridge. The inertia inherent in medical practice often means that even compelling new data takes time to translate into widespread changes in prescribing patterns.
Beyond this "clinician psychology," more concrete frictions exist. Spravato is not a simple oral pill; it is administered only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. This program is in place due to potential risks including sedation, dissociation, respiratory depression, and abuse potential. Consequently, treatment requires administration in a certified healthcare setting, a mandatory monitoring period of at least two hours after every dose, and strict prohibitions on driving until the following day. These logistical requirements present practical challenges for both patients and healthcare providers, potentially limiting access and increasing the burden of treatment.
"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," Dr. Jain reiterated. He reported a positive reception at the congress, with clinicians expressing a need to consider Spravato earlier and more frequently in their treatment algorithms. "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."
J&J’s aggressive push with this comprehensive remission data aims to overcome these adoption barriers, leveraging the clear advantage esketamine appears to offer in achieving and sustaining remission for a patient population desperately in need of effective alternatives. The company’s strategy is to underscore Spravato’s unique profile in a challenging therapeutic area, hoping to translate strong clinical outcomes into sustained market growth and improved patient lives. As the mental health landscape continues to evolve, Spravato represents a significant, albeit debated, advancement in the quest to alleviate the burden of treatment-resistant depression.
