Can Esketamine Nasal Spray Treat Depression?

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 is 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 names Ketanest and Spravato. Its effectiveness was evaluated in three short-term clinical trials and one longer-term maintenance trial. While it does carry some risks, the FDA determined that 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.

Uses

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, people may experience changes to the brain that reduce symptoms of depression.

Currently available 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.

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.

Off-Label Uses

Esketamine isn’t a new drug. It’s been around for a long time, but it is only recently that it has been 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.

Ketamine

Ketamine is known as a party drug—often referred to as “Special K.” People who misuse ketamine report dissociative effects as well as a sense of detachment, saying they felt an “out-of-body experience.”

When misused, ketamine distorts perceptions of sight and sound. Some people on ketamine experience euphoria, while others report 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 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% of patients responded to treatment, compared to just over half in the placebo group.

Before Taking

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 antidepressant medications first and didn’t experience relief.

Research suggests that around 30% of people who receive treatment for depression do not have a response to standard, front-line treatment approaches.

Alternative Treatment Options

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.

Precautions and Contraindications

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.

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 is also contraindicated in those who have a hypersensitivity to esketamine or ketamine.

Dosage

Esketamine is delivered via nasal spray. Each device contains 28 milligrams (mg) 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 was approved for use in combination with oral antidepressants like Prozac (fluoxetine), Zoloft (sertraline), or Lexapro (escitalopram).

Modifications

The safety and efficacy of esketamine have not been established for pediatric use. Guidelines for use among people 65 and older are the same as those for other adults.

Side Effects

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.

Common

In clinical trials, the most common side effects included the following:

  • Anxiety
  • Decreased feeling
  • Disassociation
  • Dizziness
  • Feeling inebriated
  • Increased blood pressure
  • Lethargy
  • Nausea
  • Sedation
  • Vertigo
  • Vomiting

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 people that there’s potential for abuse and suicidal thoughts.

Patients should not drive or operate heavy machinery after taking esketamine until the next day after a restful sleep as it can impair reaction time and motor skills.

Severe Side Effects

Call your doctor if you experience severe side effects including extreme drowsiness, changes in mood or behavior, worsening depression, hallucinations, or suicidal thoughts.  Call emergency services immediately if you have signs of an allergic reaction including hives, difficulty breathing, or swelling of the face, throat, lips, or tongue.

Warnings and Interactions

Before taking esketamine nasal spray, you should tell your doctor about any other medications, both prescription and nonprescription, that you are taking, as well as any vitamins or herbal supplements that you currently take or plan on taking.

You will be closely monitored for potential interactions with other medications you may be taking including:

  • Amphetamines
  • Anti-anxiety medications
  • Monoamine oxidase inhibitors (MAOIs)
  • Opioid pain medications
  • Sedatives
  • Seizure medications
  • Sleeping aids
  • Tranquilizers

The use of alcohol should be limited when taking esketamine, as combining the two may increase the severity of side effects including drowsiness, difficulty thinking, confusion, motor impairment, and dizziness.

Esketamine also has the potential for misuse. Doctors are advised to weigh the potential benefits of this treatment against this risk, particularly in people who have a higher risk of substance misuse and addiction. The prolonged use of esketamine can cause physical dependence, which can lead to withdrawal symptoms when use is discontinued or when the dosage is reduced. 

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.

If you or a loved one are struggling with depression, contact the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information on support and treatment facilities in your area.

For more mental health resources, see our National Helpline Database.

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  1. Popova V, Daly E, Trivedi M, et al. Randomized, double-blind study of flexibly-dosed intranasal esketamine plus oral antidepressant vs. active control in treatment-resistant depression. Biological Psychology. 2018;83(9):S390. doi:10.1016/j.biopsych.2018.02.1002

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