More than six decades after chemist Calvin Stevens first synthesized ketamine in the laboratories of Parke-Davis—an endeavor originally aimed at developing a safer anesthetic—the molecule has completed a remarkable transformation. It has migrated from the surgical suite to the forefront of psychiatric medicine, where its potent S-enantiomer, esketamine, has become a commercial and clinical powerhouse. Marketed by Johnson & Johnson (J&J) as Spravato, the drug is now at the heart of a strategic push to redefine the standard of care for the millions of Americans suffering from treatment-resistant depression (TRD).
Following a January 2025 regulatory milestone—when the FDA granted approval for Spravato as the first and only monotherapy for TRD—Johnson & Johnson is looking to capitalize on its momentum. The company recently presented a comprehensive analysis of remission data at Psych Congress Elevate, a move designed to address lingering skepticism among clinicians and to reinforce the drug’s position in an increasingly competitive landscape. With global sales reaching roughly $1.7 billion last year and analysts projecting a surge toward $2.3 billion in 2026, the stakes for J&J—and for the patients it serves—have never been higher.
A Chronology of a Psychiatric Breakthrough
The journey of esketamine from a laboratory curiosity to a blockbuster therapeutic is a testament to the evolving understanding of neurobiology in mental health.
- 1960s: Calvin Stevens synthesizes ketamine, establishing the foundation for what would eventually become the world’s most widely used anesthetic.
- March 2019: The FDA approves esketamine nasal spray (Spravato) as an add-on treatment to conventional oral antidepressants for adults with TRD.
- 2020–2024: Spravato gradually gains clinical traction, despite a complex REMS (Risk Evaluation and Mitigation Strategy) program that requires supervised administration.
- January 2025: A pivotal regulatory shift occurs when the FDA approves Spravato as a standalone monotherapy, removing the requirement for it to be paired with other antidepressants.
- June 2026: J&J presents a multi-study data compilation at Psych Congress Elevate, aimed at synthesizing long-term remission outcomes to move the needle on clinical adoption.
This evolution mirrors a broader shift in psychiatry. For decades, clinicians relied on monoamine-based antidepressants that often required weeks or months to show efficacy. Spravato, acting primarily on the glutamate system, offered the promise of rapid action, fundamentally changing the expectations for what "recovery" looks like in the context of refractory depression.
The Magnitude of the Unmet Need
The impetus for J&J’s current marketing and education campaign is the sheer scale of the patient population. Data from the National Institute of Mental Health (NIMH) indicates that in 2021, an estimated 21 million U.S. adults—roughly 8.3% of the population—experienced at least one major depressive episode. Of those treated with medication, approximately one-third, or 2.8 million individuals, fail to respond to standard therapies.
"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," notes Dr. Rakesh Jain, MD, MPH, a clinical professor of psychiatry at Texas Tech University School of Medicine and lead author of the recent data analysis.
The threshold for "treatment-resistant depression" is typically defined as a failure to respond to two or more trials of antidepressant medication. As Dr. Jain points out, the clinical outcomes for these patients are historically bleak. He frequently cites the STAR*D trial, the largest real-world depression study to date, which demonstrated that while initial treatment may yield moderate success, the likelihood of achieving remission drops precipitously with each subsequent failure. By the time a patient enters the "third-step" of treatment, remission rates plummet to approximately 13.7%. For these patients, the "standard of care" is a cycle of diminishing returns.
Supporting Data: The Case for Remission
The Psych Congress Elevate poster is a deliberate effort to shift the clinical conversation from mere "response" (a reduction in symptoms) to "remission" (the near-complete resolution of symptoms). The analysis compiled data from six clinical trials, covering both short-term placebo-controlled studies and long-term open-label extensions.
Benchmarking Against the MADRS
The analysis utilizes the Montgomery-Åsberg Depression Rating Scale (MADRS), a 10-item clinician-rated instrument. Remission is traditionally defined as a score of 10 or below. In the TRANSFORM-2 trial, for example, Spravato plus an antidepressant showed a remission rate of 42.6% compared to 24.0% for the placebo-plus-antidepressant group at week four. Even more striking, the monotherapy data from the TRD4005 trial showed 21.5% remission at week four, significantly outpacing the 6.5% seen in the placebo arm.
The Long-Term Horizon
Perhaps the most compelling component of the J&J data is the open-label extension studies (ESCAPE-LTE, SUSTAIN-2, and SUSTAIN-3), which followed patients for up to 5.5 years. These studies reported remission rates of 49.3% at one year and an impressive 78.2% at 2.5 years. While these figures come from a cohort that persisted with the treatment—and thus may be subject to selection bias—they provide a narrative of durability that has been absent in the pharmacotherapy of depression for decades.
Dr. Jain defends the breadth of the data, arguing that it represents a "real-world" picture of how the drug functions across different clinical scenarios. "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," he asserts.
Official Responses and Clinical Skepticism
Despite the optimistic data, the medical community remains divided. The path to universal adoption is blocked by both logistical hurdles and legitimate scientific debate.
Professional guidelines reflect this caution. The 2022 VA/DoD clinical practice guidelines characterize the recommendation for ketamine or esketamine as "weak for," citing concerns over the quality of evidence and the practical burden of the mandatory two-hour monitoring period post-administration. Similarly, Britain’s NICE (National Institute for Health and Care Excellence) previously declined to recommend the drug for routine NHS use, citing uncertainty regarding long-term cost-effectiveness.
The scientific literature has also featured pointed critiques. In a 2025 editorial for the American Journal of Psychiatry, researchers Sanjay Mathew and Nicholas Murphy argued that the Phase 3 data failed to definitively prove that maintenance treatment beyond the initial weeks provides a sustained benefit. Furthermore, a systematic review by Fountoulakis et al. suggested that when looking at the effect sizes of add-on therapy, esketamine performed similarly to older, cheaper atypical antipsychotic augmentation strategies.
J&J’s response to these critiques has been to focus on the "total patient" experience. They emphasize that for a patient who has failed multiple oral medications, the incremental improvement—even if viewed as narrow by statistical purists—represents a life-altering difference.
The Psychological Barrier to Adoption
Perhaps the most significant obstacle to Spravato’s growth is the inertia of the psychiatric profession itself. As Dr. Jain notes, "Psychiatry is slow to change, it just is."
The current clinical environment requires a shift in how psychiatrists organize their practice. Because Spravato is dispensed via a restricted REMS program, clinics must have the infrastructure to provide a supervised, two-hour observation window after every dose. This limits the number of patients a clinic can treat and necessitates a logistical overhaul that many traditional practices are hesitant to undertake.
However, the feedback from the Psych Congress Elevate presentation suggests a change in sentiment. Clinicians who engaged with the data expressed a renewed willingness to reconsider the timing of Spravato initiation. Rather than treating it as a "last resort" for the most severe cases, the data is pushing a segment of the psychiatric community to view it as a viable second- or third-line intervention—one that should be considered earlier in the treatment algorithm.
Implications for the Future of Mental Health
The success of Spravato is signaling a paradigm shift. We are moving away from an era of "trial-and-error" prescribing—where patients cycle through months of SSRIs and SNRIs—toward an era of rapid, mechanism-based intervention.
For Johnson & Johnson, the strategy is clear: by providing clinicians with long-term remission data, they are attempting to build the "clinical confidence" necessary to overcome the logistical hurdles of the REMS program. If the company can prove that Spravato doesn’t just treat the "peaks" of a depressive episode but provides a sustained, long-term state of remission, the drug may well become the standard of care for refractory cases within the next five years.
Ultimately, the rise of esketamine is as much about the sociology of medicine as it is about chemistry. It requires clinicians to become comfortable with a drug that has a history of recreational stigma and a complex administration profile. As the data accumulates and more patients achieve lasting relief, the skepticism that once defined the conversation is beginning to yield to a more pragmatic, data-driven approach.
The journey that began in a 1960s laboratory has arrived at a critical juncture. For the 2.8 million Americans struggling with TRD, the "blockbuster" status of Spravato is secondary to the more fundamental question: is it finally possible to turn the tide on a disease that has long resisted traditional science? If the current trends continue, the answer may finally be yes.
About the Author
