Comparing IV Ketamine to Ketamine Nasal Spray and Esketamine (SPRAVATO) for Depression

When depression doesn’t respond to typical treatments, finding the right path forward can feel overwhelming. About a third of people with major depression don’t get enough relief from standard antidepressants.[19]

Ketamine therapy offers hope as a fast-acting treatment. This article provides a comparison of IV racemic ketamine and esketamine nasal spray (SPRAVATO), the two medically supervised ketamine options backed by data and research.

What is IV ketamine for depression?

IV ketamine is ketamine medication delivered directly into the bloodstream through an intravenous (IV) infusion. Ketamine has been an FDA-approved anesthetic since 1970, with a 50+ year safety record.[7] While ketamine is FDA-approved as an anesthetic, doctors use it “off-label” for depression, which is legal and common in medical practice. IV ketamine has guidelines and consensus support from the American Psychiatric Association, the VA and DoD, as well as numerous international medical societies.[10]

When administered in specific doses, IV ketamine treats depression by triggering the regrowth of neurons that have previously died from exposure to stress and trauma over time. Ketamine acts on NMDA receptors in the brain, and triggers the growth of new connections between brain cells that helps shift negative thought patterns.[11]

Studies show that about 75% of people with treatment-resistant depression feel better after IV ketamine therapy [21].

At Ember Health, patients get started with a foundation of care which consists of four infusions over two weeks. For the 84% of our patients who have reported meaningful relief after their foundation, we help to shape a personalized care plan which has patients come in for booster care as depressive symptoms recur, typically once every 4 – 6 weeks.

What is nasal ketamine, and how does it compare to IV ketamine for depression?

Compounded nasal ketamine is generic ketamine mixed into a nasal spray by compounding pharmacies. This form is not FDA-approved for treating depression. The FDA issued warnings about compounded ketamine in February 2022 and October 2023, raising concerns about quality control, incorrect dosing, and use without proper medical supervision.[9]

Research shows that compounded nasal ketamine helps approximately 30% of people with depression, significantly lower than IV ketamine’s 75% success rate in the literature, and lower than Ember Health’s 84% treatment success rate.[21] People using compounded nasal spray often take it weekly or daily, compared to IV ketamine which typically works for an average of 6 weeks.[16]

Nasal ketamine should always be administered in a medical setting, but is also occasionally prescribed for at-home use. In their 2023 guidelines, the FDA warned against taking ketamine in at home or in medically unmonitored environments.

Unlike nasal ketamine, IV ketamine administered under physician supervision is in compliance with FDA guidelines.[9]

What is Esketamine (SPRAVATO), and how does it compare to IV ketamine for depression?

SPRAVATO is the brand name for esketamine nasal spray, developed by Johnson & Johnson and FDA-approved in 2019.[7]

Esketamine is the S-enantiomer of ketamine. Regular ketamine (used in IV treatments) is “racemic ketamine,” a 50:50 mixture of two mirror-image molecules called R-ketamine and S-ketamine. Esketamine contains only the S-ketamine portion (100% S).[12]

When a generic drug’s patent expires, pharmaceutical companies sometimes isolate one part of the molecule to obtain new patent protection, allowing them to charge significantly more than the generic version. This is a common practice among pharmaceutical companies that need to see a return from the millions of dollars they spend in research and development.

The research tells us, however, that esketamine doesn’t work meaningfully better than generic racemic ketamine.[17] Both work on the same brain receptors through the same NMDA antagonist mechanism.[11] The main differences come down to FDA approval status, cost, and how patients receive the treatment.

FDA approval status

The FDA approved SPRAVATO in March 2019, on-label for treatment-resistant depression (TRD) in adults who have tried at least two other antidepressants.[7] In August 2020, the FDA expanded approval to include depressive symptoms in adults with major depressive disorder with acute suicidal thoughts or behavior.[8]

SPRAVATO must be used together with an oral antidepressant and can only be given in certified healthcare settings with direct medical observation. Patients need to stay for a mandatory 2-hour observation period after each treatment.[3]

The FDA approved ketamine in 1970, on-label for anesthesia and sedation, and it has been used off-label since 2001 for treatment-resistant depression (TRD) in adults. 60% of all mental health medications are used off-label, making generic ketamine no different in FDA status than the majority of the medications used to treat mental health conditions.

How both forms of ketamine work in your brain

Both esketamine and IV racemic ketamine work as NMDA receptor antagonists. They block NMDA receptors in your brain, triggering a cascade of changes: glutamate release, activation of growth pathways, release of BDNF (brain-derived neurotrophic factor), and rapid formation of new connections between brain cells.[11] This neuroplasticity allows the your brain to reorganize into healthier patterns.[20]

Because both work through the same mechanism, the key differences aren’t in how they work, but in how effectively the medication reaches theyour brain and how well doctors can control the dosing.[12]

Comparing clinical outcomes

A 2025 comprehensive review in the American Journal of Psychiatry analyzed all available research on esketamine and found that while it showed some benefit, the improvements were small and most clinical trials failed to demonstrate strong positive results. The review concluded that esketamine’s effectiveness is modest, comparable to adding certain antipsychotic medications to standard antidepressants.

[4] In contrast, IV ketamine research consistently shows 75% response rates,[1] with some specialized programs like Ember Health reporting 84% of patients achieving meaningful relief.[2]

The bioavailability difference is significant: IV administration delivers 100% of the medication directly to the bloodstream, while intranasal administration achieves approximately 30-40% bioavailability due to absorption barriers through nasal membranes.[14, 24]

Most patients receiving esketamine need to complete an 8-week induction phase (16 treatments) before determining whether it’s working, with effects emerging over days to weeks.[3,6] IV ketamine patients often notice improvement within 24-72 hours of the first infusion,[14] with full therapeutic response developing over 4-6 treatments.[13]

IV racemic ketamine benefits from decades of clinical use and extensive research demonstrating both safety and efficacy.[1] Esketamine’s approval in 2019 means its long-term outcomes are still being studied, though early data supports its safety when administered in controlled clinical settings with proper monitoring.[3]

Direct head-to-head comparison studies between esketamine and IV racemic ketamine remain limited. Available research suggests similar mechanisms but potentially different clinical outcomes, with the IV route offering advantages in bioavailability, dosing precision, and reported success rates.[20,22]

How doctors choose between IV ketamine and esketamine

Why doctors may choose IV ketamine

Physicians often favor IV ketamine for treatment-resistant depression based on its substantially higher effectiveness, with 75% response rates in clinical literature compared to 30-40% for intranasal esketamine.[21, 24] The 100% bioavailability of IV administration allows doctors to deliver precise, predictable dosing directly to the bloodstream, which is particularly important when titrating treatment to each patient’s individual response.[12]

The robust evidence base spanning decades of clinical use gives physicians confidence in IV ketamine’s safety profile and efficacy.[1] Additionally, the less frequent visit schedule (averaging 12 visits in the first year versus 56 visits for esketamine) makes ongoing care more convenient for patients, reducing treatment burden while maintaining therapeutic benefit.[16] The 1:1 physician supervision throughout each 40-minute infusion enables real-time monitoring and dosing adjustments based on the patient’s response.

From a practical standpoint, IV ketamine’s maintenance schedule of once every 6 weeks means fewer disruptions to patients’ work and family commitments compared to weekly or twice-weekly esketamine visits.

Why doctors may choose esketamine (SPRAVATO):

Doctors may recommend esketamine when a patient has strong in-network insurance coverage that specifically includes SPRAVATO and the person meets the required criteria for treatment-resistant depression. The on-label, FDA status can help the prior authorization processes with insurance companies, which may be particularly important for patients with limited financial resources or strict insurance requirements.[7,8]

The intranasal route of administration is technically easier to administer than IV placement, requiring less specialized training for clinical staff. For patients with significant anxiety around needles or IV placement, the self-administered nasal spray may reduce treatment-related distress, though this must be weighed against the mandatory 2-hour observation period, inability to stop the treatment once started, and more frequent visit schedule.[3]

Working with your doctor

Your doctor will consider multiple clinical factors when recommending a treatment approach, including your insurance coverage, ability to commit to the required visit schedule, prior treatment history, and individual response patterns. The most important factor is ensuring you receive treatment from qualified providers in appropriate medical settings where both options can be safely administered with proper supervision.

Making an informed decision about ketamine therapy

Both IV ketamine and esketamine nasal spray are evidence-backed treatments for depression. However, IV ketamine’s superior effectiveness (75% vs. 30-40% response rates), more convenient maintenance schedule (12 vs. 56 visits in year one), and precise dosing through 100% bioavailability make it the preferred choice for many patients and doctors. While esketamine offers FDA-approved, on-label status that may help with insurance authorization, the dramatically lower visit frequency and comparable annual costs of IV ketamine often provide better overall value and outcomes. What matters most is working with qualified providers who can deliver safe, effective treatment in appropriate medical settings.

A word from Ember Health

At Ember Health, we specialize in IV racemic ketamine therapy for treatment-resistant depression and bipolar disorder. We’ve safely administered over 36,000 infusions to more than 2,400 patients, with 84% experiencing meaningful relief.[2] Learn more about Ember’s model of care.

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Frequently Asked Questions

Is the ketamine nasal spray the same drug as the IV ketamine used by clinics?

No. The nasal spray is esketamine (SPRAVATO®), which is the S-enantiomer. IV ketamine is typically racemic (a 50/50 mix of S- and R-enantiomers).

Can I take the esketamine (SPRAVATO®) nasal spray at home?

No. Spravato is only available through a REMS program and must be administered in a certified healthcare setting under supervision, followed by a mandatory observation period (2 hours).

Does insurance cover the ketamine nasal spray?

Sometimes, but only for specific criteria. Coverage for the branded nasal spray (SPRAVATO®) is often available for patients who meet the strict criteria for treatment resistant depression (TRD) and have failed 2-4 prior treatments. However, coverage is dependent on the specific payer, requires complex prior authorization, and costs can add up with the far more frequent visits.

References

[1] Murrough JW, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. https://pubmed.ncbi.nlm.nih.gov/23982301/

[2] Ember Health. Patient Outcomes. 84% meaningful relief rate from 2,400+ patients and 36,000+ infusions. https://emberhealth.co/outcomes/

[3] FDA. SPRAVATO (esketamine) CIII Nasal Spray REMS. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000REMS.pdf

[4] Fountoulakis, K. N., Saitis, A., & Schatzberg, A. F. (2025). Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. The American journal of psychiatry, 182(3), 259–275. https://doi.org/10.1176/appi.ajp.20240515

[5] Wilkinson ST, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150-158. https://pubmed.ncbi.nlm.nih.gov/28969441/

[6] Daly EJ, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139-148. https://pubmed.ncbi.nlm.nih.gov/29282469/

[7] FDA. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. March 2019. https://www.prnewswire.com/news-releases/fda-approves-new-nasal-spray-medication-for-treatment-resistant-depression-available-only-at-a-certified-doctors-office-or-clinic-300807354.html

[8] Janssen Pharmaceutical Companies. (2020, August 3). Janssen announces U.S. FDA approval of SPRAVATO® (esketamine) CIII nasal spray to treat depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Johnson & Johnson. https://www.jnj.com/media-center/press-releases/janssen-announces-u-s-fda-approval-of-spravato-esketamine-ciii-nasal-spray-to-treat-depressive-symptoms-in-adults-with-major-depressive-disorder-with-acute-suicidal-ideation-or-behavior

[9] FDA. FDA Warns Patients and Health Care Providers About Potential Risks Associated with Compounded Ketamine. October 2023. https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine

[10] Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., Summergrad, P., Nemeroff, C. B., & American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments (2017). A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA psychiatry, 74(4), 399–405. https://doi.org/10.1001/jamapsychiatry.2017.0080

[11] Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509-523. https://pubmed.ncbi.nlm.nih.gov/25341010/

[12] UpToDate. Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. Available at: https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects

[13] Murrough JW, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256. https://pubmed.ncbi.nlm.nih.gov/22840761/

[14] Phillips JL, et al. Early symptomatic improvements as a predictor of response to repeated-dose intravenous ketamine. Biological Psychiatry. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/33031861/

[15] Phillips JL, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401-409. https://pubmed.ncbi.nlm.nih.gov/30922101/

[16] Bahji A, et al. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542-555. https://pubmed.ncbi.nlm.nih.gov/33022440/

[17] Correia-Melo FS, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527-534. https://pubmed.ncbi.nlm.nih.gov/31743681/

[18] Singh B, Kung S, Pazdernik V, Schak KM, Geske J, Schulte PJ, Frye MA, Vande Voort JL. 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):22M14548. https://pubmed.ncbi.nlm.nih.gov/36724113/

[19] Gaynes BN, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. BMJ. 2023. Available at: https://pubmed.ncbi.nlm.nih.gov/37491091/

[20] Price RB, et al. Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression. Translational Psychiatry. 2023. Available at: https://www.nature.com/articles/s41398-023-02451-0

[21] Mathew, S. J., Murrough, J. W., aan het Rot, M., Collins, K. A., Reich, D. L., & Charney, D. S. (2010). Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. The international journal of neuropsychopharmacology, 13(1), 71–82. https://doi.org/10.1017/S1461145709000169

[22] Murrough, J. W., Perez, A. M., Pillemer, S., Stern, J., Parides, M. K., aan het Rot, M., Collins, K. A., Mathew, S. J., Charney, D. S., & Iosifescu, D. V. (2013). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological psychiatry, 74(4), 250–256. https://doi.org/10.1016/j.biopsych.2012.06.022

[23] Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. https://pubmed.ncbi.nlm.nih.gov/16894061/

[24] Ouyang, Y., & Li, J. (2025). Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies. Medicine, 104(9), e41495. https://doi.org/10.1097/MD.0000000000041495