Health Technology Brief

supporting sound, evidence-based decision making

Esketamine (Spravato) for Treatment Resistant Major Depressive Disorder

November 6, 2019

Health Problem: Major depressive disorder (MDD), a serious and life-threatening condition, is one of the most common mental disorders in the United States and a leading cause of disability worldwide. MDD is a chronic disease associated with high rates of morbidity and excess mortality. Approximately 30% to 40% of patients fail to respond to first-line treatment, including oral antidepressants or psychotherapy. Treatment resistant MDD is typically defined as depression that does not respond to at least 2 attempts of treatment of adequate dose and duration with antidepressants; however, there is no official consensus regarding the definition.

Technology Description: The drug-device combination comprises esketamine for intranasal administration intended for the treatment of treatment resistant MDD. Esketamine is the S-enantiomer of ketamine, a Food and Drug Administration–approved general anesthetic agent. Ketamine is an N-methyl-D-aspartate glutamate (NMDA) receptor antagonist that enhances glutamine release in the brain. Esketamine has greater affinity for the NMDA receptor and greater dopamine transporter inhibition than ketamine; it is a more potent anesthetic than ketamine but has a more rapid metabolism. Esketamine is available in a nasal spray device that delivers 2 sprays (1 spray for each nostril) containing a total of 28 milligrams (mg) of esketamine. Larger doses may be delivered by using 2 (56 mg dose) or 3 (84 mg dose) devices with a 5-minute rest between use of each device.

Controversy: Ketamine has been identified as a drug of abuse by the Drug Enforcement Agency; it is a schedule III non-narcotic substance under the Controlled Substances Act. Esketamine has also been designated a schedule III controlled substance and may be subject to abuse and diversion. As a treatment, esketamine has the potential to be a disruptive therapy; treatment requires that a healthcare professional monitor patients when they self-administer the medication and patients must continue to be monitored for transient dissociative and blood pressure changes prior to leaving the healthcare setting.

Key Questions: 

  • Is esketamine as an adjunct to an oral antidepressant effective in reducing symptoms of major depressive disorder (MDD) in patients with treatment-resistant depression (TRD)?
  • How does esketamine as an adjunct to an oral antidepressant compare with alternative treatments for treatment-resistant MDD?
  • Is esketamine as an adjunct to an oral antidepressant safe?
  • Have definitive patient selection criteria been established for esketamine as an adjunct to an oral antidepressant in patients with treatment-resistant MDD?