Spravato Esketamine: What we know so far….

The FDA approved a new esketamine nasal spray medication for treatment-resistant depression called Spravato, trade name for Esketamine on March 5, 2019. We’ve had many inquiries about the medication at our practice and I thought it would be beneficial to all of you to share the information I have regarding this new medication.

Spravato is a new antidepressant medication manufactured by Johnson & Johnson’s pharmaceutical company, Janssen, for management of Treatment Resistant Depression. According to the FDA, “Patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment are considered to have treatment-resistant depression.”

How is Spravato administered? 

Spravato comes as an intranasal spray. The FDA set strict guidelines for the administration of Spravato which has a Boxed Warning. The Boxed Warning states that “the patients are at risk for sedation and difficulty with attention, judgement and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.” Therefore, the patient must self-administer Spravato at a doctor’s office and the patient cannot take the medication home. After self-administration, the patient must be watched and monitored for 2 hours after administration. In addition, the patient must arrange for a driver since they will not be allowed to operate any heavy machinery after the treatment. The frequency of the administration is as follows: the first month- the medication must be taken twice a week; the second month- the medication must be taken once a week; and thereafter- once every other week. Click here for Janssen’s prescribing package insert

Does Spravato work?  

The FDA reported 3 short-term (four week) clinical trials and one longer-term maintenance-of-effect trial. “In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. In light of the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trails did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patient in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.” [i]

What is the cost of Spravato?  

The wholesale acquisition cost, or list price, will be between $590 and $885 per session. This means the first month of treatment will range from $4720 to $6785. This does not include the costs of a physician visit and monitoring. The medication will most likely be added to most major health insurance plan’s formulary. There is no information yet regarding in what specialty tier Spravato will be placed and what the out of pocket expenses will be for the patients. In addition, we are uncertain what the pre-authorization approval process from the insurance companies will entail.

Where can I get Spravato?

The FDA says, “due to safety concerns, the drug will only be available through a restricted distribution system and must be administered by a certified medical office where the health care provider can monitor the patient.” Only clinics that are certified in REMS (Risk Evaluation and Mitigation Strategy) can treat and monitor patients enrolled in REMS. In addition, only specialty pharmacies that are certified in REMS will be allowed to dispense Spravato directly to the medical offices. REMS is a program required by the FDA to manage known or potential serious risks associated with a drug product.

Will Optimum Ketamine Center [or Spring Center of Hope] become a REMS center and offer Spravato?

We are currently obtaining more information regarding this process. We already know it is a multistep process that will require some time. In addition, we have yet to receive any information from the Center for Medicare and Medicaid Services (CMS), who is responsible for coding and setting the fee schedules for Medicare. All private insurers follow the guidelines set by CMS. Therefore, there are still quite a few unanswered questions regarding the logistics of treating with Spravato.   We hope to have more answers for you in the coming months.

What is Esketamine, the main compound in Spravato?

Esketamine is half of the active ingredient of the medication Ketamine. Ketamine is a medication containing equal parts R-ketamine and S-ketamine (Esketamine). R-ketamine and S-ketamine are mirror images of each other. The pharmaceutical company Janssen isolated the S-ketamine molecule to create a medication they can patent and sell. At Optimum Ketamine Center [and Spring Center of Hope], we use Ketamine (containing both active components) to treat mood disorders. This includes both the R-ketamine and the S-ketamine.

What is Ketamine?

Ketamine is a medication that is FDA approved for anesthesia. It is being used off-label for the management of treatment resistant depression. It is a NMDA (N-methyl-D-Aspartate) receptor antagonist. NMDA receptors are found on nerve cells where they transmit and receive signals. They are critical for the development of the central nervous system, generation of rhythms for breathing and movement, and the processes underlying learning, memory, and neuroplasticity[ii] (your brain’s ability to adapt to new situations or injury).

Are Esketamine (S-ketamine) and R-ketamine the same?  

No. They have different properties.[iii] [iv]

S-ketamine R-ketamine
  • Greater affinity for the NMDA receptor than R-ketamine
  • Greater anesthetic potency
  • Greater psychotomimetic effects (greater chance of experiencing altered states of consciousness)
  • Less affinity for the NMDA receptor than S-ketamine
  • Fewer psychotomimetic effects (less likely to experience altered state of consciousness)
  • Greater potency anti-depressant than S-ketamine
  • Longer lasting antidepressant effects than S-ketamine


The studies we have so far regarding R vs S Ketamine have all been from mice and rat models. Nevertheless, it appears that the R- and not the S-Ketamine is the more potent anti-depressant and has longer lasting antidepressant effects. Furthermore, the S-Ketamine exerts a greater dissociative effect than R-ketamine.

Is Ketamine and Esketamine absorption the same whether it is given intranasal or intravenously?

No. Intranasal administration has been shown to be less predictable with greater variability in onset times and peak blood levels[v] than with intravenous administration. The amount available after intranasal administration varies anywhere from 8% to 45%[vi][vii] whereas the amount available after intravenous administration is nearly 100%.

Disclaimer: Dr. June Lee is the Medical Director of Optimum Ketamine Center. She is a board certified with the American Board of Anesthesiologists and a member of the American Society of Ketamine Physicians.  Optimum Ketamine Center website does not provide medical advice, diagnosis, or treatment. Dr. Lee’s blog is not intended for medical diagnosis or treatment. The information provided on this website is intended for general consumer understanding only. The information provided is not intended to be a substitute for professional medical advice. For medical advice or assistance, readers should consult their healthcare professional.

About the Author
Ketamine doctors

June Lee, MD

June Lee, MD, MBA is Medical Director of a thriving ketamine infusion center, Optimum Ketamine Center in the Chicago area.  For more information visit her webpage: https://www.optketamine.com/our-doctors/

Optimum Ketamine Center

665 W. North Ave, #101

Lombard, IL 60148

(708) 244-8663


[i] FDA approves new nasal spray medication for treatment-resistant depression; available only at a cerfified doctor’s office or clinic. March 5 2019 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm

[ii] Activation Mechanisms of the NMDA Receptor. Blanke and VanDongen, Biology of the NMDA receptor. CRC Press/Taylor & Francis; 2009. https://www.ncbi.nlm.nih.gov/books/NBK5274/

[iii] R-Ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Yang, Shirayamata et al. Transl Psychiatry (2015) 5, e632;doi:10, 1038, published on-line 1 September 2015 https://www.nature.com/articles/tp2015136.pdf

[iv] R (-) ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Zhang, Li, Hashimoto. Pharmacol Biochem Behav. 2014 Jan;116:137-41. E published 3 December 2013https://www.sciencedirect.com/science/article/pii/S0091305713003328?via=ihub

[v] S-ketamine and s-norketamine plasma concentrations after nasal and I.V. administration in anesthetized children. Weber et al. Pediatric Anesthesia, December 2004 Volume 14, Issue 12 p983-988

[vi] Plasma concentration profiles of ketamine and norketaminafter administration of various ketamine preparations to healthy Japanese volunteers. Yanagihara et al Biohpar Drug Dispos, 2003 Jan: 24(1):37-43

[vii] Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Yeaman et al. Emerg Med Australas. 2014 June;26(3):237-42

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  • Treatment resistant depression
  • Suicidal Ideations
  • Post-Traumatic Stress Disorder

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