More than six decades after Calvin Stevens first synthesized ketamine at Parke-Davis while searching for a safer anesthetic, the molecule has completed its remarkable migration into psychiatry, where its enantiomer, esketamine, has become a significant therapeutic option for treatment-resistant depression (TRD). This journey from an anesthetic agent to a blockbuster psychiatric medication underscores a paradigm shift in the understanding and treatment of severe depressive disorders. Esketamine, specifically the more potent S-enantiomer of the original compound, achieved its initial U.S. Food and Drug Administration (FDA) approval as a nasal spray in March 2019 for TRD, specifically as an add-on therapy to a conventional oral antidepressant. A pivotal regulatory milestone followed in January 2025, when the FDA cleared esketamine as the first and only monotherapy for adults with treatment-resistant depression, broadening its potential application significantly. Following a somewhat quiet initial launch, the compound, marketed by Johnson & Johnson as Spravato, has demonstrated robust commercial success, generating approximately $1.7 billion in sales last year, with Wall Street analysts projecting an increase to nearly $2.3 billion in 2026. This financial trajectory highlights the substantial unmet medical need and the market’s responsiveness to novel treatments for TRD.
Johnson & Johnson is actively working to further accelerate Spravato’s sales trajectory by strategically disseminating key clinical data. A recent poster presentation at Psych Congress Elevate, a prominent forum for mental health professionals, showcased a comprehensive overview of remission rates observed with esketamine nasal spray across a portfolio of six clinical trials in TRD. The rationale behind this concerted effort is clear: the potential market for TRD treatments is not only vast but also continually expanding. Statistics from the National Institute of Mental Health (NIMH) reveal that an estimated 21 million U.S. adults experienced at least one major depressive episode in 2021, accounting for 8.3% of the adult population. Within this considerable cohort, a significant subgroup struggles with TRD. Of the estimated 8.9 million U.S. adults receiving medication for major depression, approximately one-third—a staggering 2.8 million individuals—do not respond adequately to standard oral antidepressants. This failure to achieve a satisfactory response after at least two adequate trials of different antidepressant medications is the clinical definition of treatment-resistant depression, a condition that poses immense challenges for patients and clinicians alike.
Dr. Rakesh Jain, MD, MPH, a distinguished clinical professor of psychiatry at Texas Tech University School of Medicine, Permian Basin, and the lead author of the analysis presented at Psych Congress Elevate, eloquently articulated the profound clinical burden. “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, underscoring the pervasive nature of this unmet need. His comments highlight the critical distinction between merely reducing symptoms (response) and achieving a state of near-complete absence of depressive symptoms (remission), which is often the ultimate goal of treatment and is associated with significantly improved quality of life and functional outcomes.
The Evolution of Ketamine and Esketamine: A Brief Timeline
The journey of ketamine from a surgical anesthetic to a groundbreaking psychiatric intervention is a testament to persistent scientific inquiry and serendipitous discovery.
- 1962: Calvin Stevens, a chemist at Parke-Davis, synthesizes ketamine while searching for a safer dissociative anesthetic with fewer hallucinogenic side effects than phencyclidine (PCP).
- 1970: Ketamine receives FDA approval as an injectable anesthetic for surgical procedures. Its rapid action and unique properties quickly establish it in medical practice.
- Late 1990s – Early 2000s: Researchers begin exploring ketamine’s off-label antidepressant effects, particularly its rapid onset of action in patients with severe depression, including those with suicidal ideation. This period marks the nascent stages of its psychiatric migration.
- 2019 (March): Esketamine (Spravato), the S-enantiomer of ketamine, receives FDA approval as a nasal spray for treatment-resistant depression in adults, to be used in conjunction with an oral antidepressant. This marks the first ketamine-based drug specifically approved for depression. The approval is granted under a Risk Evaluation and Mitigation Strategy (REMS) program due to potential risks.
- 2020 (August): Esketamine receives an additional FDA approval for the rapid reduction of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior, again in conjunction with an oral antidepressant. This approval further solidifies its role in acute psychiatric emergencies.
- 2025 (January): Esketamine receives FDA approval as the first and only monotherapy for adults with treatment-resistant depression, signifying a major expansion of its clinical utility and offering a new standalone treatment option. This latest approval is a critical development, moving beyond the initial requirement for co-administration with an oral antidepressant.
Understanding Remission: A Critical Metric for Treatment Success
Dr. Jain framed remission as the central theme of the Psych Congress Elevate analysis. The poster explicitly reported remission rates against two specific cutoffs on the Montgomery-Åsberg Depression Rating Scale (MADRS), a widely accepted clinician-rated instrument. The MADRS assesses 10 core depression symptoms, each scored from 0 to 6, yielding a total score ranging from 0 to 60. Clinically, a score of 7 to 19 typically indicates mild depression, 20 to 34 moderate, and 35 or above severe. Conventionally, remission on the MADRS is defined as a score of 10 or below. The patients enrolled in these esketamine trials typically presented with baseline MADRS scores ranging from approximately 29 to 38, placing them firmly within the moderate-to-severe depression categories. Dr. Jain noted, “We actually tightened the rules on SPRAVATO a little bit. We said, okay, 12 is fine, but can we go to 10? And it performed quite well, even at 10. That’s the key.” This stringent approach to defining remission highlights the robustness of the data presented.
The pursuit of remission in depression treatment is an often-elusive goal. Dr. Jain explained that remission numbers are frequently not reported in clinical trials, particularly those involving atypical antipsychotic augmentation. “With many atypical antipsychotic augmentation trials, the reason you haven’t read remission numbers is that they’re not typically put out there,” he observed, adding, “The numbers look abysmal, or they don’t separate from placebo.” This observation underscores the difficulty in achieving true remission with many existing treatment modalities and highlights the significance of any data demonstrating meaningful remission rates.
A crucial benchmark for understanding the challenges of achieving remission is the Sequenced Treatment Alternatives to Relieve Depression (STARD) study. Conducted by the National Institute of Mental Health, STARD remains the largest real-world depression treatment trial ever undertaken, enrolling over 4,000 outpatients with nonpsychotic major depression. The study meticulously sequenced patients through up to four successive treatment steps to simulate real-world clinical practice. In the initial level-one analysis involving 2,876 evaluable patients treated with citalopram, approximately 28% achieved remission as measured by the Hamilton Depression Rating Scale (HAM-D). However, by the third step of treatment, after two prior antidepressant trials had failed—the very threshold that defines treatment resistance—the remission rate plummeted to a mere 13.7%. Dr. Jain emphasized this stark reality: “The problem is that the moment you go to a second antidepressant, the remission rate drops sharply, to as little as 14 or 15%. It’s a very sharp drop.” This dramatic decline in remission rates with successive treatment failures underscores the profound unmet need for more effective interventions in TRD.
Rapid and Durable Remission: The Promise of Esketamine
Dr. Jain’s interest in esketamine extends beyond merely achieving remission; he emphasizes its potential to support both rapid and durable remission. “The profound move is not just to achieve remission but to hold on to it year upon year upon year,” he asserted. This focus on sustained therapeutic benefit is critical for patients with chronic and relapsing depressive disorders. “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.”
The analysis presented at Psych Congress Elevate aimed to provide clinicians with a comprehensive and clear understanding of esketamine’s performance across various clinical settings. Dr. Jain highlighted the breadth of the data, stating, “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 further emphasized the non-selective nature of the data compilation: “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.” This transparent approach is intended to build confidence among clinicians who need to make informed decisions in complex real-world scenarios.
The J&J poster reported specific MADRS ≤ 10 remission rates. At week 4, remission rates were 13.9% and 21.5% for Spravato monotherapy doses, compared to 6.5% for placebo. In the TRANSFORM-2 study, which combined Spravato with an oral antidepressant, remission reached 42.6% versus 24.0% for placebo plus an oral antidepressant. Furthermore, data from the open-label extension studies, which followed patients who continued on the drug, showed encouraging long-term 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. It is important to note, as acknowledged by the poster itself, that this analysis is descriptive. It does not involve formal meta-analysis, pooled effect estimates, or statistical comparisons, and inherent trial-design differences limit direct comparability across studies.
Comprehensive Data Scope: A Deeper Dive into the Trials
The analysis compiled remission rates from six previously reported esketamine trials, offering a panoramic view of its efficacy:
- Short-Term, Placebo-Controlled Studies:
- TRD4005 Monotherapy Trial: A four-week, placebo-controlled study evaluating esketamine as a monotherapy.
- TRANSFORM-2: A four-week, placebo-controlled study where esketamine was paired with a conventional oral antidepressant.
- Active-Controlled Trial:
- ESCAPE-TRD: This phase 3 interventional trial compared flexible-dose esketamine nasal spray with quetiapine extended-release, both used with an SSRI/SNRI background therapy. Remission by MADRS at week 8 was the primary outcome. This head-to-head comparison offers valuable insights into esketamine’s performance against an established augmentation strategy.
- Open-Label Extension Studies (Long-Term Follow-up):
- ESCAPE-LTE (Long-Term Extension): Followed patients for extended periods.
- SUSTAIN-2: An open-label study designed to assess the long-term safety and efficacy of esketamine.
- SUSTAIN-3: Another open-label extension study, tracking patients for up to 5.5 years, providing crucial data on the durability of remission.
For each of these trials, the analysis reported remission against both MADRS ≤ 10 and MADRS ≤ 12 thresholds, providing a nuanced perspective on treatment outcomes. Dr. Jain underscored the strength of this diverse data set: “It’s such wide-ranging data: different studies, short-term, long-term, a comparative study.”
Navigating the Landscape of Professional Opinion and Regulatory Scrutiny
Despite the positive data presented, professional opinion regarding esketamine’s role in clinical practice spans a spectrum, with various guideline bodies arriving at different conclusions. This divergence reflects the complexity of evaluating novel treatments, balancing efficacy with safety, cost-effectiveness, and real-world applicability.
The 2022 VA/DoD depression guideline, for instance, lists ketamine or esketamine as an augmentation option only after several failed drug trials. However, it issues a “weak for” recommendation, resting on low-quality evidence, and explicitly notes reservations concerning patient monitoring and feasibility. These reservations often stem from the practical challenges of administering the drug within a structured healthcare system, including the need for specialized settings and prolonged observation periods.
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). NICE’s decision was based on the determination that the clinical and economic evidence presented could not reliably support a cost-effectiveness estimate that justified its widespread adoption. This decision, notably, predated the monotherapy approval, and healthcare systems often weigh the cost-benefit ratio heavily, especially for newer, more expensive treatments. Interestingly, Scotland’s medicines regulator had reached the opposite conclusion two years earlier, highlighting how different national healthcare priorities and economic evaluations can lead to varied policy outcomes regarding the same medication.
The strongest controlled evidence within the analysis, however, does favor esketamine. In the head-to-head ESCAPE-TRD trial, the only study in the set comparing esketamine against an active comparator, esketamine combined with an SSRI or SNRI demonstrated higher remission rates than quetiapine extended-release on the same antidepressant backbone. Specifically, remission rates at week 8 were 27.1% for esketamine versus 17.6% for quetiapine XR, a statistically significant result published in the prestigious New England Journal of Medicine (NEJM). Furthermore, esketamine-treated patients were less likely to discontinue treatment due to safety or tolerability issues compared to those receiving quetiapine, suggesting a potentially better tolerability profile.
However, even the magnitude of this advantage has been contested. NEJM correspondence related to the ESCAPE-TRD trial acknowledged that the observed 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 fell below what is generally considered the smallest clinically meaningful difference. This nuance suggests that while statistically significant, the clinical impact of the difference might be modest for some patients.
Further critiques have appeared in the American Journal of Psychiatry. In a 2025 editorial, Baylor psychiatrists Sanjay Mathew and Nicholas Murphy argued that the phase 3 program for esketamine did not conclusively establish that patients should continue treatment significantly beyond the first week, even as prescriptions nearly doubled after early 2023. This raises questions about the optimal duration of therapy and long-term efficacy. Additionally, a systematic review by Fountoulakis, Saitis, and Schatzberg (AJP 2025) found esketamine’s add-on effect sizes at weeks 2 to 4 to be between 0.15 and 0.23, comparable to the atypical antipsychotic augmentation strategies that Dr. Jain had earlier suggested yield "abysmal" remission numbers. This review also found no significant antisuicidal benefit directly attributable to esketamine, further complicating its overall clinical assessment.
Clarifying the Suicidality Indication
Dr. Jain pointed to another FDA-approved use for esketamine—major depressive disorder with acute suicidal ideation or behavior—as further evidence of its broad clinical utility. “It’s also approved for what’s called MDD with suicidal ideation,” he stated, emphasizing, “That’s a formal indication from the FDA.” However, it is crucial to consult the prescribing information, which offers a more circumscribed understanding of this indication than the general label might suggest. The FDA approves esketamine, alongside an oral antidepressant, for the rapid reduction of depressive symptoms in these patients. Critically, the prescribing information directly 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. This distinction is paramount: the drug treats the depression of acutely suicidal patients, but the label makes no claim that esketamine itself reduces suicidality. Dr. Jain clarified that this specific poster’s focus was not on suicidality, but rather on remission rates in TRD.
Overcoming Inertia: The Psychology of Psychiatric Clinicians and Practical Roadblocks
The ultimate impact of the presented remission data, by Dr. Jain’s own admission, hinges as much on clinician psychology as it does on the scientific evidence. “Psychiatry is slow to change, it just is,” he observed, acknowledging a professional conservatism. “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 posits that the primary obstacles are inertia and a lack of comprehensive information, gaps that the poster presentation at Psych Congress Elevate was specifically designed to address.
Beyond this psychological inertia, more concrete frictions exist. Spravato is dispensed solely through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. This stringent requirement is due to potential risks, including sedation, dissociation, respiratory depression, and abuse potential. The REMS program mandates that the drug be administered only in a certified healthcare setting, followed by a mandatory monitoring period of at least two hours after every dose. Patients are also prohibited from driving or operating machinery until the following day. These logistical demands impose significant practical burdens on clinics, requiring dedicated space, trained staff, and considerable patient time commitment, all of which contribute to the high cost and administrative complexity of treatment.
Dr. Jain believes that while multiple roadblocks exist, “one of the bigger ones is clinician hesitation and lack of knowledge, which is why I put this poster out.” He reported positive feedback from clinicians who viewed the poster, indicating that it prompted a re-evaluation of their treatment approaches. “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.” This suggests that despite the existing complexities and divergent opinions, the presentation of compelling remission data could incrementally shift clinical practice.
Broader Implications and Future Outlook
The strategic presentation of Spravato’s remission data at Psych Congress Elevate underscores Johnson & Johnson’s aggressive push to expand the drug’s market share and reinforce its position as a leading treatment for TRD. The significant sales figures and projected growth indicate a clear demand for rapid-acting, novel antidepressants, particularly in a landscape where conventional treatments often fall short.
For patients suffering from TRD, the availability of a treatment demonstrating significant remission rates, even with the accompanying logistical challenges, represents a beacon of hope. The prospect of achieving and sustaining remission—a state often elusive with traditional therapies—can dramatically improve quality of life, functional capacity, and overall well-being.
However, the ongoing debate among guideline bodies and academic critics highlights the need for continued research, particularly regarding long-term safety, cost-effectiveness in diverse real-world populations, and comparative effectiveness against other emerging rapid-acting treatments or neuromodulation therapies. As the understanding of depression neurobiology evolves, and as new therapeutic modalities emerge (including psychedelic-assisted therapies and other novel mechanisms), the landscape of TRD treatment will continue to change. Esketamine, with its unique mechanism of action and its journey from anesthetic to antidepressant, serves as a powerful example of innovation in mental health, even as its optimal integration into clinical practice remains a subject of ongoing discussion and refinement. J&J’s efforts aim to consolidate esketamine’s role, but the full picture of its long-term impact on patient care will continue to unfold as more real-world data accumulates and professional consensus evolves.
