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What Is Esketamine?
More in Depression
A fast-acting nasal spray might be the best treatment for depression.
By Amy Morin, LCSW
Medically reviewed by Steven Gans, MD
Who Shouldn't Take It
Alternative Options
Esketamine was approved by the FDA in 2019 to treat depression that hasn't responded to other treatment. Unlike oral antidepressants, which often take four to six weeks to take effect, esketamine is administered via nasal spray and becomes effective within hours.
It's estimated that 5 million people in the United States have a depressive disorder that hasn't resolved with current treatments. Esketamine may help those with treatment resistant depression experience much needed relief.
Esketamine is marketed by the brand name Spravato. Its effectiveness was evaluated in three short-term clinical trials and one longer-term maintenance trial. While it does have some risks associated with it, the FDA determined the benefits outweigh the risks, citing the need for additional effective treatments for treatment-resistant depression, a serious and potentially life-threatening condition.
In the United States, suicide is the 10th-leading cause of death. In 2016, it claimed the lives of almost 45,000 people. Many of those individuals had untreated depression.
Esketamine may offer relief to individuals who haven't been able to find relief from other depression treatments and it may reduce the risk for suicide.
Esketamine isn't a new drug. It's been around for a long time. This is just the first time it's being used as a nasal spray to treat depression.
Ketamine hydrochloride is a selective NMDAR antagonist that has been used primarily as an anesthetic drug since the 1960s. It may also be used for pain management in low doses. Emergency departments may use it to manage acute pain or to control pain during a procedure.
At one time, ketamine was known as a party drug and it was often referred to as "Special K." Abusers enjoyed its dissociative effects. Individuals who abused it often reported a sense of detachment, saying they felt an "out-of-body experience."
When abused, ketamine distorts perceptions of sight and sound. Some individuals who abused it experienced euphoria. Others reported hallucinations or temporary paralysis.
Initial Drug Trials
In 2000, a pilot trial reported a rapid and robust antidepressant effect following a single IV dose of ketamine at a lower dose than is used for anesthetic purposes. Following the trial, several more studies supported the findings.
Most of the trials focused on a 40-minute IV fusion of ketamine. Following the infusion, the majority of patients experienced a significant relief in symptoms such as depressed mood, anhedonia, and suicidal thoughts. Improvements were often noted within two hours of ketamine administration. The therapeutic effects peaked at 24 hours and lasted up to two weeks.
Despite the positive results, IV ketamine was associated with mild and transient dissociative effects, neurocognitive and sensorimotor disturbances, and short-lasting elevations in heart rate and blood pressure.
It also wasn't widely available in IV form. Without FDA approval, off-label use of ketamine infusions for the treatment of depression wasn't covered by insurance, and it often cost more than $500 per treatment.
In clinical trials, esketamine nasal spray has been effective in reducing symptoms for individuals with treatment-resistant depression. One randomized trial involved adults under 65 who were also taking an oral antidepressant. After one month, roughly 70 percent of patients responded to treatment, compared to just over half in the placebo group.
Despite decades of research, the molecular mechanisms underlying depression are poorly understood. Consequently, scientists aren't exactly certain how esketamine reduces depression.
What is clear is that it is fast-acting. Within hours, individuals may experience changes to the brain that reduce symptoms of depression.
Current antidepressants target the monoamine neurotransmitter systems—predominantly serotonin, norepinephrine, and dopamine levels in the brain. Antidepressants often take four to six weeks to become fully effective, and they are not always effective.
It's thought that esketamine affects the function of the brains' glutamate neurotransmitter system. Many oral antidepressants affect the serotonin neurotransmitter system.
Esketamine is derived from ketamine. The only difference is that ketamine is a mixture of two mirror images of a molecule and esketamine is just one of those molecules.
Esketamine is delivered via nasal spray. Each device contains 28mg and delivers two sprays.
It must be administered under medical supervision and will not be available for patients to bring home. Patients must go to the doctor's office or clinic to access the nasal spray, according to the conditions of FDA approval.
If you are taking esketamine, you will likely receive a treatment one or two times per week. You will remain in the office setting for a couple of hours so you can be monitored closely by medical personnel for two hours. Medical providers will ensure you are not experiencing adverse reactions before allowing you to leave.
Esketamine is to be taken in conjunction with another oral antidepressant, like Prozac, Zoloft, or Lexapro. In fact, it was approved for use in combination with oral antidepressants.
How Do Doctors Decide Which Antidepressant to Prescribe?
Esketamine isn't likely to be used as a first line of treatment. Instead, it is intended for individuals with treatment-resistant depression, meaning they have had adequate trials of two other medications first and didn't experience relief.
In general, esketamine is contraindicated in individuals with psychotic depression, since psychotic symptoms are sometimes reported as side effects when it is administered at anesthetic doses.
Esketamine may cause an increase in blood pressure or heart rate, so it should be used with caution if an individual has angina, a history of stroke, or poorly-controlled blood pressure.
Esketamine may cause fetal harm and women who are pregnant or considering becoming pregnant should talk to their doctors. Women should not breastfeed while undergoing treatment.
Like any new treatment, manufacturers will continue to monitor any adverse reactions. Johnson & Johnson, who developed esketamine, is taking steps to ensure it will only be used as intended.
In clinical trials, the most common side effects included the following:
Disassociation
Decreased feeling
Feeling inebriated
The label for esketamine will include a black box warning—the most serious safety warning the FDA issues. It will caution users they may experience sedation, problems with attention, judgment, and thinking. It will also warn users that there's potential for abuse and suicidal thoughts.
Patients should not drive or operate heavy machinery until the next day after a restful sleep. It can impair reaction time and motor skills.
Esketamine may be an option for individuals who are at an acute risk of suicide. Individuals who are in crisis may need a fast-acting drug that can offer immediate relief.
Esketamine isn't the only option for individuals with treatment-resistant depression. Other options may include:
A different antidepressant: Just because the first two antidepressants didn't work doesn't mean a third medication won't be effective. A doctor may try a different type of antidepressant (such as changing from a SSRI to a SNRI) or add another medication that could make an antidepressant more effective (such as an antipsychotic or anticonvulsant medication).
Talk therapy: Depression is often best treated with a combination of medication and therapy. A psychiatrist may refer a patient to psychotherapy to help reduce symptoms. Cognitive behavioral therapy (CBT) has been found to be especially effective in treating treatment-resistant depression.
Electroconvulsive therapy (ECT): ECT produces electric currents through the brain to trigger a brief seizure. It seems to cause changes in brain chemistry that improve and stabilize mood. It can have side effects such as short-term memory loss and confusion, but is generally considered safe and currently the most effective treatment for treatment-resistant depression. It may require six to 12 sessions of treatment.
Vagus nerve stimulation (VNS): VNS involves implanting a pacemaker-like device that sends electrical currents to the vagus nerve. The vagus nerve is thought to stimulate parts of the brain that regulate mood. It can take up to several months for VNS to be effective.
Repetitive transcranial magnetic stimulation (rTMS): rTMS uses a magnet to stimulate certain areas of the brain to reduce symptoms of depression. Although it doesn't carry some of the side effects of ECT, it is not generally thought to be as effective.
A Word From Verywell
If you or a loved one has treatment-resistant depression, talk to your doctor about the potential risks and benefits of esketamine versus other treatment options.
While esketamine may not be right for everyone, it may provide much-needed relief for some individuals who haven't been able to get relief from their depression from other treatment methods.
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Ajub E, Lacerda ALT. Efficacy of Esketamine in the Treatment of Depression With Psychotic Features: A Case Series. Biol Psychiatry. 2018;83(1):e15-e16.
Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018;175(7):620-630.
Office of the Commissioner. Press Announcements - FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic. U S Food and Drug Administration Home Page. Published March 5, 2019.
Singh JB, Fedgchin M, Daly E, et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry. 2016;80(6):424-31.
Targum SD, Daly E, Fedgchin M, Cooper K, Singh JB. Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression. J Psychiatr Res. 2019;111:68-73.
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