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Esketamine (Spravato™): a new treatment option for depression

By: Sylvia Hong (PharmD Candidate c/o 2021), Muaz Sadeia (PharmD Candidate c/o 2021)

           On March 5, 2019, Janssen Pharmaceuticals gained approval from the Food and Drug Administration (FDA) for esketamine (Spravato™), the first fast acting nasal spray antidepressant indicated for treatment of resistant depression as conjunctive therapy to oral antidepressants in adults.1 This new addition to the antidepressant toolbox comes with promise and concerns.

  Esketamine is not a new drug structurally, but rather, the purified (S)-enantiomer of ketamine – an analgesic first approved by the FDA in 1970. Ketamine, a Schedule III Controlled Substance, plays an essential role in modern day sedation during surgery but has also gained a reputation as a drug with abuse potential. In the last decade, off label uses of ketamine have increased in popularity, particularly for the pharmacotherapy of mood disorders. Generic intravenous (IV) ketamine is used off label as a treatment for depression, anxiety, and other treatment resistant psychiatric disorders in hundreds of clinics across the United States.2 Despite the apparent improvements observed in patients, no regulations or guidelines are in place for the use of ketamine in the aforementioned indications. Concerns with ketamine use include severe relapse and serious side effects such as bradycardia and respiratory depression. Now with esketamine as an FDA-approved agent, quick action can be taken with appropriate supervision by a health care professional in a more controlled and well-studied fashion. 

Typical antidepressants used to treat major depressive disorder, such as Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), have shown very moderate therapeutic effects and only display significant mood changes towards recovery after four to six weeks of adherent use. This therapeutic gap can be filled through esketamine’s quick onset.  In the final Phase III clinical trial conducted by Janssen Pharmaceuticals, TRANSFORM-1, patients who were refractory to previous antidepressant treatments showed a significant improvement in behavior after starting esketamine in conjunction with a new antidepressant over a four-week period compared to placebo.3 The placebo group consisted of patients taking a new antidepressant that differed in class from their original therapy.

Mechanism of Action

Currently, there is no clear understanding with respect to what gives esketamine its antidepressant properties. It has long been established that ketamine acts on NMDA receptors, opioid receptors, muscarinic receptors, and voltage gated calcium channels without interacting with GABA receptors, making it a unique analgesic. However, these mechanisms do not explain esketamine’s antidepressant action. Recently, a study published in Science Magazine conducted by Moda-Sava RN of Weill Cornell Medicine tested mice expressing depression and the effects of ketamine on their prefrontal cortex, focusing on neuronal spinal changes.4 Their results exhibited a regeneration effect on the dendritic spines of postsynaptic neurons in the prefrontal cortex as a long-term effect of ketamine. This suggests that a reversal in neuronal damage could potentially allow for sustained remission and decreased depressive symptoms.

Potential for abuse

As a Schedule III Controlled Substance, Spravato™, can cause dependence and tolerance as well as withdrawal symptoms including cravings, fatigue, poor appetite and anxiety.5 Due to its abuse potential, drug-seeking behavior must be monitored. Several side effects include dysphoria, disorientation, insomnia, flashback, hallucinations, feelings of floating, detachment, and feeling “spaced out”.5 Secondary to all the aforementioned effects, Spravato™ is registered in a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program only allows Spravato™ to be administered intranasally under the direct supervision of a healthcare provider who must monitor their patient for at least two hours after the drug is administered.

Spravato™ Administration

Patients must be counseled to not eat anything for at least two hours prior to administration as well as refrain from drinking liquids at least thirty minutes prior to administration. Blood pressure must be assessed prior to and forty minutes after the administration of Spravato™ because it has the propensity to increase blood pressure. There are two phases of treatment that patients should be aware of – an induction phase and a maintenance phase. Induction lasts from Week 1 to Week 4, in which Spravato™ is given twice per week. The starting dose for induction is 56 mg and subsequent doses can either be 56 mg or 84 mg. Only after the end of the induction cycles, can a healthcare provider, evaluate the therapeutic benefits and determine whether continuing with maintenance therapy will be beneficial.5

Spravato™ Device

Each device only has two sprays, one for each nostril, and delivers a total of 28 mg of esketamine. Priming should not be conducted to avoid losing drug. Given that each dose is either 56 mg or 84 mg, a single 56 mg dose requires two Spravato™ devices, and a single 84 mg dose requires three Spravato™ devices. Spacing of five minutes before the use of the second or third device is imperative to allow for drug absorption.5

 Spravato™ Counseling

Spravato™ has the propensity to increase blood pressure and as a result, blood pressure must be monitored prior to and after administration of the drug. Additionally, patients must be counseled to not operate machinery until the day after they take Spravato™ because it can cause cognitive impairment – attention, judgement, thinking, reaction, speed and motor skills are affected.5 Thus, as recommended by the manufacturer, patients should arrange for transportation and be accompanied on their way home after having the drug administered. In accordance with the REMS program, a certified pharmacy, or other certified setting, must monitor the patient for at least two hours after administration, as well as the patient’s response, throughout the induction phase. If the patient’s healthcare provider deems it appropriate, treatment can extend into maintenance phase if induction phase is successful.  


  1. FDA. FDA approves new oral drug to treat multiple sclerosis. www.fda.gov. https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-drug-treat-multiple-sclerosis. Published 03/26/2019.
  2. Wilkinson ST, Sanacora G. Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders. JAMA. 2017;318(9):793-794.
  3. Janssen Research & Development, LLC. A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression. (TRANSFORM-1)
  4. https://clinicaltrials.gov/ct2/show/NCT02417064. Published 4/18/2019.
  5. Moda-Sava RN, Murdock MH, Parekh PK, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364(6436).
  6. SPRAVATO (esketamine hydrochloride) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Revised 03/05/2019.
Published by Rho Chi Post
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