In March 2019, the Food and Drug Administration approved esketamine (SPRAVATO™) nasal spray to be used in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.¹ TRD affects almost one-third of patients with depression and is identified by non-response to treatment from antidepressants of at least two different drug classes. Esketamine is described to work via a different mechanism of action compared to other antidepressant medications. Although it is known to work through targeting of the N-methyl-D-aspartate (NMDA) receptor, the complete mechanism is unknown.² An editorial by George described a Stanford study in which pretreatment with naltrexone blocked antidepressant effects, which may suggest that opioid receptors may be involved in the antidepressant effects from ketamine.³

The more well-known product, ketamine, is a racemic mixture of both R-ketamine and S-ketamine (esketamine) enantiomers and was approved by the FDA in 1970 as an anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. In clinical trials, the S-ketamine isomer was found to be more potent than the R-ketamine isomer.4 The higher potency of S-ketamine may allow for a desired effect to take place in the body at lower doses, minimizing the occurrence of side effects.

Patients interested in esketamine treatment should note that they should have failed at least two antidepressant classes of medications prior to starting esketamine; and if started, that esketamine is used in addition to a daily oral antidepressant. Nasal corticosteroids or decongestants, if needed, should be used at least one hour prior to esketamine treatment. To decrease nausea or vomiting, it is recommended to avoid eating two hours before and drinking liquids 30 minutes before treatment.

Due to the commonly observed adverse effects of sedation and dissociation, esketamine is only available through a restricted  program under a Risk Evaluation and Mitigation Strategy (REMS). Patients administer esketamine themselves under the supervision of a healthcare professional and must be monitored for at least 2 hours following each treatment session. On treatment days, patients should plan for transportation to and from a certified treatment center, as driving or operating machinery should not take place until after a full night of rest after treatment.

The most common side effects reported by patients in clinical trials include dissociation (41%), dizziness (29%), nausea (28%), sedation (23%), and spinning sensation (23%). Less encountered side effects include reduced sense of touch and sensation, anxiety, lack of energy, increased blood pressure, vomiting, and feeling drunk.²


¹SPRAVATO™ [Prescribing Information]. Titusville, N.J., Janssen Pharmaceuticals, Inc.

²About SPRAVATO™: How SPRAVATO™ may work differently. Available at: Accessed April 15, 2019.

³George MS. Is there really nothing new under the sun? Is low-dose ketamine a fast-acting antidepressant simply because it is an opioid? Am J Psychiatry 2018;175(12):1157-8.

4Domino EF. Taming the ketamine tiger. Anesthesiology 2010;113:678-84.