The American Journal of Psychiatry Looks at Six Years of FDA-Approved Spravato
Last reviewed and updated: August 17, 2026.
Key Takeaways
| The approvals | Spravato was approved in 2019 for treatment-resistant depression, in 2020 for depression with suicidal ideation, and in 2025 as a standalone monotherapy. |
| Six-year picture | Roughly six years of real-world use generally support its effectiveness and safety, with meaningful response and remission in treatment-resistant depression. |
| Safety | The main short-term effects are sedation and dissociation. No major new safety signals have emerged, and it is given under close monitoring. |
| How it is given | Spravato is given only in certified healthcare settings under a REMS program, with monitoring for at least two hours per session. |
| Coverage | Because it is FDA-approved, Spravato is more often covered by insurance than off-label IV ketamine, which is usually out of pocket. |
The coverage difference between Spravato and off-label ketamine is stark, and our clinic inquiry data shows why it matters.
Esketamine, a nasal spray derived from ketamine, was approved by the FDA in 2019 for treatment-resistant depression. This approval followed years of research suggesting ketamine’s potential to offer rapid relief for severe depression symptoms. However, six years after its introduction, many clinical challenges remain unresolved. The increased use of esketamine in mental health treatment has been accompanied by concerns about its efficacy, side effects, and potential abuse risks. The American Journal of Psychiatry took a deep dive into what the last six years of FDA-approved nasal ketamine has looked like.
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Detailed Takeaways From the Journal Review
| Takeaway | Description |
|---|---|
| Short-term Efficacy | Esketamine has shown rapid efficacy, with patients often reporting symptom relief within the first 24 to 48 hours of administration. However, while initial improvements are promising, the long-term benefits remain uncertain, with some studies indicating diminishing effects over time. |
| Limited Suicidality Impact | Esketamine has demonstrated potential in reducing severe depressive symptoms but has not shown a strong impact on suicidality in most clinical trials. This is a key area of concern, as rapid relief is critical for individuals at imminent risk. |
| Clinical Limitations | Esketamine’s trials have often faced challenges such as small effect sizes and significant placebo responses. The robustness of the findings has been questioned, particularly as clinical use grows beyond controlled environments. Nevertheless, it offers hope for treatment-resistant depression, where conventional antidepressants fail. |
| Abuse Potential | Despite its therapeutic applications, esketamine remains a Schedule III controlled substance due to concerns about its potential for abuse and misuse. The drug’s dissociative effects raise red flags, though its in-clinic administration mitigates these risks. Continued monitoring and regulatory oversight are essential to address these concerns. |
| Regulatory Concerns | Esketamine was approved by the FDA based on data from a single pivotal trial, leading to concerns about the completeness and quality of the evidence supporting its approval. However, its introduction into clinical practice has provided an alternative for patients who do not respond to traditional therapies. |
| Rapid Onset of Action | One of the most notable positive aspects of esketamine is its rapid onset. For individuals who have struggled with severe depression for years without relief, esketamine offers a potentially life-changing quick response, which is not commonly seen in other antidepressants. |
| Promising in Treatment-Resistant Depression | Esketamine has shown substantial promise in treating patients with treatment-resistant depression, providing an option for those who have not found relief through conventional antidepressants or psychotherapy. Its potential to break through therapeutic barriers makes it a valuable tool in psychiatric care. |
| Positive Patient Experience | Many patients who have used esketamine report positive experiences, particularly when conventional treatments have failed. Improved mood, increased energy, and a sense of clarity have been commonly noted, offering a glimmer of hope for those previously stuck in the cycle of depression. |
| Challenges in Long-Term Use | While esketamine offers rapid symptom relief, challenges persist with maintaining the benefits over time. The risk of relapse after discontinuation of treatment or prolonged use remains an open question, with some patients experiencing a return of depressive symptoms within weeks of finishing treatment. |
| Regulated Use and Monitoring | To ensure safety, esketamine is administered under medical supervision, with patients monitored for at least two hours post-administration. This regulated approach has been successful in minimizing adverse effects and controlling misuse, though access remains limited due to these strict guidelines. |
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Clinical Conundrums and Unanswered Questions
Since its approval, esketamine has sparked a shift in psychiatric care, particularly for patients resistant to traditional antidepressants. However, the drug’s clinical use is not without complexities. The nasal spray has been associated with dissociative effects, sedation, and, notably, its potential for abuse. This has led to the implementation of strict monitoring protocols, including in-clinic administration and a two-hour post-dose observation period. With increasing numbers of clinics offering esketamine and its popularity growing, the risks tied to unsupervised use, especially in online platforms, have become a significant concern.
Moreover, while initial studies of esketamine suggested rapid relief from depression, newer data raises questions about its long-term effectiveness. Most trials show that the benefits of the drug may not extend beyond a few weeks, prompting experts to question its long-term viability as a treatment option.
Looking Ahead: A Complex Future
The future of esketamine in clinical practice hinges on ongoing research. Although some patients show meaningful improvements after multiple doses, the drug’s ultimate role remains unclear. More studies are needed to determine whether continuation treatment beyond the initial phase offers lasting benefits. Additionally, the risks associated with its use in unsupervised settings must be addressed, especially in light of the growing number of at-home ketamine treatment options.
As the landscape of mental health treatment continues to evolve, esketamine’s place in therapy will be shaped by both new evidence and regulatory oversight. For clinicians and patients alike, the challenge will be balancing its potential benefits with the risks and limitations that still linger.
Six Years of Spravato: What We Have Learned by 2026
Spravato, the brand name for esketamine, followed a steady path from a tightly restricted new drug to a mainstream option. The FDA approved it in 2019 for treatment-resistant depression in combination with an oral antidepressant. In 2020 the agency approved it for major depressive disorder with acute suicidal ideation. In January 2025 the FDA approved it as a standalone monotherapy for treatment-resistant depression. That six-year arc widened both the indications and the number of patients who qualify.
Roughly six years of use and study generally support Spravato’s effectiveness and safety. The American Journal of Psychiatry review examined this six-year record. Real-world data show meaningful response and remission rates in treatment-resistant depression. The safety profile has stayed manageable, with sedation and dissociation the main short-term effects. No major new safety signals have emerged over this period.
Spravato is given only in certified healthcare settings under a REMS program. Patients are monitored for at least two hours because of sedation, dissociation, and abuse potential. This delivery model shapes access in a real way. Patients cannot take Spravato at home and must visit a certified provider for every dose. That requirement limits convenience even as it protects safety.
Because it is FDA-approved, Spravato is more often covered by insurance than off-label IV ketamine. Patients usually pay for IV ketamine out of pocket. The 2025 monotherapy approval expanded who can use Spravato. Today it stands as an established, evidence-backed option for treatment-resistant depression. Its main tradeoffs are the in-clinic delivery requirement and the monitoring each session demands.
Frequently Asked Questions
- Is Spravato safe and effective after six years of use?
- Roughly six years of real-world use and study generally support Spravato’s effectiveness and safety for treatment-resistant depression. Real-world data show meaningful response and remission rates, and no major new safety signals have emerged. The main short-term effects are sedation and dissociation, which is why it is given under close monitoring in certified settings.
- What is Spravato approved for now?
- Spravato (esketamine) is approved for treatment-resistant depression and for major depressive disorder with acute suicidal ideation. Originally it had to be paired with an oral antidepressant, but in January 2025 the FDA approved it as a standalone monotherapy for treatment-resistant depression, expanding who can use it.
- How is Spravato given?
- Spravato is a nasal spray given only in certified healthcare settings under a REMS program. Patients self-administer it under supervision and are then monitored for at least two hours for sedation and dissociation. It cannot be taken at home, and patients should not drive on treatment days. These safeguards exist because of its side effects and abuse potential.
- Is Spravato covered by insurance?
- More often than off-label IV ketamine. Because Spravato is FDA-approved, it is more likely to be covered for treatment-resistant depression, though prior authorization is common. Off-label IV ketamine is usually paid out of pocket. Our data shows about 75 percent of patients inquiring about ketamine have no insurance pathway, so approval status strongly affects affordability.
