Esketamine vs. ketamine: what to ask before you refer

In my practice, more and more patients arrive with a ketamine clinic advertisement in hand. Many have already asked their primary care physician, “Should I try this?” The honest answer depends on a distinction those advertisements routinely blur: The “ketamine” offered for depression is not a single, standardized therapy.

On one side is intranasal esketamine (Spravato), the S-enantiomer of ketamine. The FDA approved it in 2019 for treatment-resistant depression (TRD) in conjunction with an oral antidepressant, and later for depressive symptoms in major depressive disorder (MDD) with acute suicidal ideation or behavior. On the other side is off-label subanesthetic intravenous racemic ketamine. It is an anesthetic in use since the 1970s, with roughly two decades of investigation in mood disorders but no FDA approval for any psychiatric indication. The two differ on every dimension a referring clinician should weigh: the quality of the evidence, the regulatory safety scaffolding, the monitoring that is mandated versus merely recommended, and who pays.

The evidence is asymmetric

Neither pathway is unambiguously superior, and honesty requires saying so. Esketamine carries the regulatory backing of registration trials. A Cochrane review judged the evidence that esketamine produces remission at 24 hours versus placebo to be of moderate certainty. It rated the comparable evidence for racemic ketamine very low to low certainty. Yet esketamine’s approval rested on only two of four positive phase 3 trials, and its maintenance signal was a delayed relapse rather than acute superiority.

Paradoxically, the real-world comparisons we have tend to favor IV racemic ketamine on speed and magnitude of response:

• A retrospective cohort of 153 patients found IV ketamine produced a faster and larger self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR) reduction than intranasal esketamine over an induction course.
• A pooled real-world analysis found larger effect sizes and higher response rates with IV ketamine.
• An observational study found similar remission rates but faster time to remission with IV ketamine.

These studies are non-randomized and confounded by indication and dosing schedule, and no adequately powered head-to-head randomized trial yet exists. The 2022 Department of Veterans Affairs and Department of Defense (VA/DoD) guideline reflects this cautious equipoise. It newly suggests either agent for patients who have failed at least two adequate antidepressant trials, while explicitly noting the absence of long-term efficacy and safety data for both.

The decisive difference is oversight

Esketamine is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. The program is built around a boxed warning for sedation, dissociation, respiratory depression, and abuse and misuse, and it is not advisory. The health care setting must be certified, the patient must be enrolled, and the drug can only be administered on site. A health care provider must directly observe administration and monitor the patient for at least two hours afterward, including blood pressure before and after dosing and pulse oximetry. Post-marketing experience has documented respiratory depression and rare respiratory arrest.

Off-label IV ketamine carries no federally mandated framework. Expert consensus calls for equivalent rigor:

• Cardiovascular, hemodynamic, and respiratory monitoring, including ECG and oxygen saturation
• Exclusion of active psychosis or substance use disorder
• Personnel skilled in diagnosing and managing mood disorders

Adherence to these recommendations is voluntary and varies by clinic.

The adverse event profiles overlap heavily. Dissociation, transient hypertension, nausea, dizziness, sedation, and anxiety predominate with both and are generally mild and self-limited. For esketamine, pharmacovigilance signals for abuse liability, and a clustering of some suicides near dosing intervals, remain unresolved concerns.

Where the advertisements mislead most

The clinics patients ask about frequently offer intramuscular, sublingual, or oral ketamine. These routes have far weaker evidence and no REMS-equivalent oversight. Here is how the four formulations a referring clinician is most likely to encounter compare:

• Intranasal esketamine (Spravato): FDA-approved for TRD and for MDD with acute suicidal ideation or behavior.
  • Evidence: The highest-certainty randomized evidence.
  • Onset: Rapid, within 24 hours, with maintenance benefit shown through delayed relapse.
  • Monitoring: REMS-mandated, with a certified site, on-site administration, and at least two hours of observation with blood pressure and pulse oximetry.
  • Diversion risk: Low, because there are no take-home doses.
• IV racemic ketamine: Off-label.
  • Evidence: Rated very low to low certainty by Cochrane, though real-world comparisons favor it on speed and magnitude.
  • Onset: Rapid, with limited durability without repeat dosing.
  • Monitoring: None federally mandated.
  • Diversion risk: Low to moderate. It is given on site, but oversight varies.
• Intramuscular racemic ketamine: Off-label.
  • Bioavailability: Roughly 93 percent, and it requires no infusion equipment.
  • Evidence: Thin, limited to case series, small cohorts, and a single double-blind dose-ranging crossover study. These suggest effects broadly similar to IV.
  • Risks: The same acute dissociative, hemodynamic, and abuse-liability concerns as IV, without any mandated monitoring.
  • Diversion risk: Moderate.
• Oral and sublingual racemic ketamine: Off-label.
  • Bioavailability: Low, about 17 to 29 percent, with correspondingly minimal dissociation and hemodynamic change.
  • Evidence: The weakest and slowest. Meta-analyses show real but modest effects emerging over roughly two weeks, and several recent randomized trials, including oral prolonged-release tablet studies, failed their primary endpoint.
  • Diversion risk: The highest, because these forms are the ones most likely to be dispensed for unsupervised home use. That is exactly where the risks of diversion, misuse, and inadequate monitoring are greatest.

Cost often makes the decision

Coverage often drives the real-world choice, and it favors esketamine for insured patients despite its higher list price. A U.S. cost-effectiveness analysis found esketamine was not cost-effective, and in fact was dominated by IV ketamine, from a health care sector perspective. From the patient’s own perspective, however, esketamine was frequently less costly because insurance covers it, whereas off-label IV ketamine is typically paid out of pocket.

This is where clinic quality separates good care from a cash-pay infusion booth. Before referring, I would ask:

• If esketamine is involved, is the setting REMS-certified?
• Is a clinician present to observe dosing and monitor vital signs and respiration for the full post-dose window?
• Is there a prescribing psychiatrist or other mental health clinician who confirms the TRD diagnosis, optimizes the concurrent oral antidepressant, and screens out contraindications such as psychosis or uncontrolled hypertension?
• Does the clinic provide longitudinal psychiatric follow-up, or does it sell only the infusion itself?

Both agents are legitimate, evidence-supported options for patients who have failed adequate antidepressant trials. Our job as referring physicians is to make sure the patient goes somewhere the pharmacology is wrapped in genuine psychiatric care, rather than sold as a standalone commodity.

Ravi Singareddy is the founder and medical director of Empower Psychiatry & Sleep in north metro Atlanta, where he leads an interventional psychiatry practice offering transcranial magnetic stimulation (TMS) and Spravato (esketamine) for treatment-resistant depression. Double board-certified in psychiatry and sleep medicine, he brings more than two decades of clinical and academic experience to patients who haven’t found relief with medications alone. He is affiliated with Emory Healthcare.

His interest in neuromodulation dates back to his years as associate professor of psychiatry at Penn State College of Medicine. There, he taught annually on vagus nerve stimulation and novel depression therapies, and he published on long-term combined electroconvulsive therapy and vagus nerve stimulation in the American Journal of Psychiatry. He has authored numerous peer-reviewed papers on sleep disorders, insomnia, anxiety, and depression, with work appearing in Sleep, the Journal of Clinical Sleep Medicine, and Psychiatry Research.

Singareddy is a Fellow of the American Psychiatric Association and the American Academy of Sleep Medicine and practices measurement-based care, tracking outcomes to guide every treatment decision. He shares updates on Instagram.