A new study led by Dr. Robert Meisner and colleagues at McLean Hospital has reignited the ongoing debate in psychiatry: which ketamine treatment is more effective for treatment-resistant depression (TRD)? The research compares the effectiveness of intravenous (IV) racemic ketamine with intranasal (IN) esketamine, under the brand name Spravato—two common options for patients unresponsive to standard antidepressants.
While the results indicate that IV ketamine may provide faster and more significant symptom relief, critics, including Dr. Samuel T. Wilkinson of Yale, warn that methodological limitations prevent definitive conclusions. Here’s what the study shows, why it matters, and how experts are responding.
The Study at a Glance
Published in: Journal of Clinical Psychiatry (September 2025)
Title: Comparative Effects of Repeated Ketamine Infusion Versus Intranasal Esketamine in Patients With Treatment-Resistant Depression
Authors: Meisner et al.
Study Design
- Type: Retrospective chart review
- Participants: 153 patients with severe TRD
- IV ketamine group: 111 patients
- IN esketamine group: 42 patients
- Assessment Tool: Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR16)
- Duration: 4–5 week induction phase (8 treatments)
Key Results
Patients receiving IV ketamine experienced a 49.2% reduction in depressive symptoms by the eighth treatment session. In contrast, those treated with intranasal esketamine showed a 39.6% reduction over the same period.
Additionally, significant symptom improvement was observed after just the first treatment in the IV ketamine group, while the esketamine group required two sessions before a statistically significant response was noted.
Both treatment methods significantly reduced depression severity, but IV ketamine achieved greater reductions more quickly. These findings support a growing clinical view that IV ketamine may be more potent, at least for short-term symptom relief.
Why This Matters
TRD remains a difficult diagnosis and prognosis, often marked by multiple unsuccessful medication trials, hospitalizations, and an increased risk of suicide. Traditional antidepressants can take weeks to show effects—if they work at all. Ketamine-based therapies, however, have demonstrated rapid antidepressant effects—sometimes within hours—providing a fast-acting, potentially life-saving option for individuals in crisis, particularly those experiencing suicidal ideation.
This study offers solid naturalistic data by comparing IV and IN formulations in a real-world clinical setting. If IV ketamine truly proves more effective, it could influence future treatment guidelines and insurance policies.
A Word of Caution: Criticism from Dr. Wilkinson
While the findings are promising, Dr. Samuel T. Wilkinson advises caution in interpretation. Writing in the same journal, Wilkinson emphasizes several key limitations of the Meisner study:
1. Lack of Randomization
Patients were not randomly assigned to treatments. This introduces the risk of selection bias and confounding variables—especially socioeconomic status, which often affects treatment decisions.
“All else being equal, the average patient receiving ketamine will be of higher socioeconomic status… which is generally linked with better health outcomes.” — Dr. Samuel T. Wilkinson
Since IV ketamine is rarely covered by insurance, patients paying out-of-pocket can vary greatly in education, income, or health literacy—factors known to influence clinical outcomes.
2. No Adverse Event Reporting
The study did not systematically report side effects or adverse events. This is important because long-term safety profiles differ between IV ketamine (off-label) and IN esketamine (FDA-approved with REMS restrictions).
3. Limited Generalizability
Retrospective studies rely on chart data and often lack the rigor of randomized controlled trials. Wilkinson references a previous randomized trial (n=63) that found no significant difference in efficacy between the two drugs, although that study only assessed short-term outcomes after a single dose.
Other Observational Studies
Meisner’s findings echo earlier observational research:
- Nikayin et al. (2022): Both treatments helped to reduce symptoms significantly, but IV ketamine showed slightly better results in how quickly symptoms improved. However, overall response and remission rates were similar for both groups. The researchers note that since this was not a controlled trial, the results should be viewed with caution, but IV ketamine may offer a slight advantage.
- Singh B et al (2023): Both treatments had similar outcomes with no major differences in response rate or number that reached remission. However, IV ketamine helped patients reach remission faster, requiring fewer treatments than nasal esketamine.
These consistent signals suggest a trend favoring IV ketamine, but none of the studies exclude potential confounders, and there are clear limitations.
Safety and Public Health Considerations
Dr. Wilkinson’s opinion is that intranasal esketamine has a safer public health profile compared to intravenous ketamine, mainly because it is regulated under FDA oversight and a Risk Evaluation and Mitigation Strategy (REMS) program. This system requires in-clinic administration and limits dosing frequency, which reduces the risk of misuse. He also notes that esketamine has shown minimal evidence of abuse, whereas ketamine misuse rates have been steadily increasing.
Importantly, Wilkinson warns against the growing trend of at-home ketamine use, which lacks regulatory safeguards and could lead to frequent or high-dose exposure—conditions that raise the risk of cognitive impairment and neurotoxicity.
My Everyday Observations as a ketamine and esketamine provider
While I respect Dr. Wilkinson’s commentary on this new study—and recognize the variability in how practitioners approach IV ketamine given the lack of strict regulations compared to intranasal esketamine (which is limited to fixed doses of 56 mg or 84 mg)—my clinical experience at Innerbloom has highlighted several consistent patterns:
- Earlier response with IV ketamine: Most patients who respond positively to IV ketamine do so within their first three treatments. By contrast, it’s not uncommon for patients on intranasal esketamine to require a month or more of treatment (about eight sessions) before experiencing meaningful improvement.
- Sense of control and safety: Patients often feel reassured knowing that an IV infusion can be paused mid-session if needed (for example, in the event of anxiety or an adverse reaction). This option simply isn’t available with intranasal administration.
- Dosing matters: Some patients achieve the best outcomes at doses slightly higher than what would be considered equivalent to the nasal formulation. IV infusions allow for this individualized titration.
- Broader range of indications: Beyond treatment-resistant depression, IV ketamine has shown clear benefits in patients with generalized anxiety disorder, PTSD, and chronic pain—even though it is not FDA-approved for these conditions.
- Differences in experience: Patients receiving intranasal esketamine frequently report a milder experience, often without noticeable dissociative or “psychedelic” effects. IV ketamine, in contrast, more reliably induces these states, which many patients find therapeutic when paired with psychotherapy.
- Logistical challenges with esketamine: Nasal esketamine requires many more sessions, both during the initial phase and ongoing. Coordinating rides and taking repeated time off work or other responsibilities can be a significant burden for patients.
Real-World Application: What Should Clinicians and Patients Consider?
When might IV ketamine be preferred?
- Rapid response is required: IV ketamine may be the best option in urgent situations, such as acute suicidal ideation, where immediate relief is critical.
- Lack of response to intranasal esketamine: Since IV ketamine delivers racemic ketamine (both R- and S-enantiomers) through a different route, it can be effective when esketamine has failed.
- Flexible dosing: IV infusions allow for titration, making it possible to tailor treatment for patients with specific needs, diagnoses, or sensitivities.
- Access to an experienced clinic: Patients who seek a specialized ketamine clinic with skilled providers may benefit from the greater support and oversight available with IV therapy.
When might intranasal esketamine be preferred?
- Insurance coverage is essential: Esketamine is FDA-approved and often covered by insurance, which can significantly reduce out-of-pocket costs.
- Limited access to infusion centers: In regions without experienced ketamine infusion providers, esketamine may be the only viable option.
- Preference for gradual effects: Some patients may favor esketamine’s slower onset, particularly if they are sensitive to rapid mood shifts or dissociation.
- Structured and regulated environment: The FDA-mandated REMS program ensures esketamine is administered only in a clinical setting under supervision, providing consistency and safety.
The choice often comes down to efficacy vs. accessibility. As the field awaits more definitive data from ongoing randomized trials shared decision-making between patients and providers is key.
Final Takeaway
The new study by Meisner et al. contributes valuable real-world data suggesting that IV ketamine may be both more effective and faster-acting than intranasal esketamine for treatment-resistant depression. Still, the study’s limitations—including the lack of randomization, absence of adverse event reporting, and potential socioeconomic confounders—mean the findings should be interpreted with caution rather than taken as definitive.
Dr. Wilkinson’s critique is an important reminder that treatment decisions in this space must weigh not only efficacy but also safety, accessibility, cost, and patient preference. As someone who works with patients at Innerbloom Ketamine Therapy in San Luis Obispo, CA, every day, I’ve seen firsthand that IV ketamine often produces rapid improvements within the first few treatments and allows for individualized dosing across a wider range of conditions. At the same time, intranasal esketamine remains a valuable, FDA-approved option that provides a more structured and regulated treatment pathway—particularly for patients relying on insurance coverage or without access to experienced infusion clinics.
Ultimately, the real question isn’t which approach is “better” in general, but which is better for the individual patient in front of us. Both IV ketamine and intranasal esketamine play important roles in the fight against treatment-resistant depression, and the best outcomes come from aligning the treatment with each patient’s unique needs, goals, and circumstances.
About the Author:
Dr. Ray Rivas, a former general and trauma surgeon with over a decade of experience utilizing ketamine, became a ketamine therapy specialist to treat mental health and pain after witnessing its profound impact on his hospital trauma patients and his own mental health. As the founder and medical director of Innerbloom Ketamine Therapy in San Luis Obispo, California, Dr. Rivas applies his extensive medical expertise to provide safe, evidence-based ketamine treatments for mood disorders, including depression, anxiety, PTSD, and chronic pain. His passion lies in helping patients find relief and rediscover hope through personalized, compassionate care.
Resources:
Gutierrez, Gilmar, et al. “IN Esketamine and IV Ketamine: Results of a Multi-Site Observational Study Assessing the Effectiveness and Tolerability of Two Novel Therapies for Treatment-Resistant Depression.” Psychiatry Research, vol. 340, Oct. 2024, p. 116125, doi:10.1016/j.psychres.2024.116125.
Li SW, Kumpf KT, Urrutia J, Krystal JH, Sanacora G, Wilkinson ST. Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies. Am J Psychiatry. 2025 Sep 10:appiajp20250276. doi: 10.1176/appi.ajp.20250276. Epub ahead of print. PMID: 40926573.
Meisner, Robert, et al. “Comparative Effects of Repeated Ketamine Infusion Versus Intranasal Esketamine in Patients With Treatment-Resistant Depression: A Retrospective Chart Review.” The Journal of Clinical Psychiatry, vol. 86, no. 4, 22 Sept. 2025, article 25m15789. Psychiatrist.com.
Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the Trajectory of Depression Severity With Ketamine and Esketamine Treatment in a Clinical Setting. JAMA Psychiatry. 2022;79(7):736–738. doi:10.1001/jamapsychiatry.2022.1074
Singh B, Kung S, Pazdernik V, et al. Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression: an observational study. J Clin Psychiatry. 2023;84(2):45331
Wilkinson, Samuel T., and Taeho Greg Rhee. “Ketamine and Esketamine: Is There a Meaningful Clinical Difference?” The Journal of Clinical Psychiatry, vol. 86, no. 4, 2025, p. 25com16003. Psychiatrist.com, published Sept. 22, 2025, doi:10.4088/JCP.25com16003.
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