Can Esketamine Nasal Spray Treat Depression?

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Esketamine is an NMDA (N-methyl-D-aspartate) receptor antagonist used to treat adults with treatment-resistant depression (TRD). Esketamine (brand name Spravato) comes as a nasal spray and is said to rapidly reduce suicidal ideations and depressive symptoms.

Approved by the U.S. Food and Drug Administration (FDA) in March of 2019 to treat TRD, esketamine nasal spray must be used in conjunction with an oral antidepressant. It is the first FDA-approved psychedelic medicine and the second drug approved to treat TRD.

As many as two-thirds of people with depression do not respond to the first medication prescribed and are considered to have TRD. TRD is a term used to describe depression that has failed to respond to at least two different antidepressants.  

Uses

Esketamine nasal spray is approved for use in adults 18 and over, in conjunction with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI). To be considered for this treatment, patients must have tried at least two other antidepressants without success.

Most oral antidepressants need weeks or even months to take effect. Clinical trials suggest that esketamine nasal spray can significantly reduce symptoms in as little as 24 hours.

Esketamine vs. Ketamine

Esketamine is derived from ketamine, a powerful anesthetic and popular "club drug." Though both drugs have similar makeup (ketamine is a mixture of two mirror-image molecules, and esketamine is one of those molecules), esketamine is more potent.

Clinical Drug Trials

Esketamine effectiveness was evaluated in three short-term (four weeks) studies, one maintenance study, and a long-term safety study. Two of these studies demonstrated that esketamine rapidly reduces depressive symptoms in people with TRD.

One was a short-term trial involving adults under age 65 who were started on an oral antidepressant and intranasal esketamine. After one month, roughly 70% of patients (compared to just over half in the placebo group) who received esketamine saw at least a 50% reduction in depressive symptoms.

The other positive study was the maintenance study that assessed relapse prevention. Data from this trial showed that esketamine reduces relapse rates. Specifically, those treated with esketamine nasal spray plus an oral antidepressant had a 50% to 70% lower risk of relapse than patients who only received an oral antidepressant.

More research is still needed to determine the optimal dosing, assess other possible side effects, and establish the safety of esketamine in the longer term.

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.

Before Taking

Esketamine should never be used as a first-line of treatment. Instead, it is intended for individuals with TRD, meaning they have had adequate trials of two other antidepressant medications first and didn’t experience relief.

Precautions and Contraindications

Esketamine is not appropriate for everyone. You should not take esketamine if you are allergic to esketamine or ketamine, or if you have or have had any of the following medical conditions:

  • A blood vessel disease (aneurysm)
  • A history of bleeding in the brain
  • An abnormal connection between your blood vessels (arteriovenous malformation)

You should also talk to your doctor if you have ever had:

  • A family history of depression
  • Alcoholism or drug addiction
  • Brain injury or any condition where there is increased pressure in the brain
  • Heart attack or stroke
  • Heart valve disease or heart failure
  • High blood pressure
  • Liver disease
  • Mental illness or psychosis
  • Slow or fast heartbeats that cause shortness of breath, chest pain, lightheadedness, or fainting
  • Suicidal thoughts or actions

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.

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.

But esketamine isn’t the only option for individuals with TRD. 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 TRD.
  • 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 TRD. 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.

Dosage

Esketamine is a nasal spray that must be used in a healthcare setting. You will give yourself the nasal spray while being supervised by a healthcare professional.

Each device contains 28 milligrams (mg) and delivers two sprays. The recommended dosage for TRD is as follows:

  • Induction phase (weeks 1 through 4): During this phase, you will take the drug twice a week. The first dose is 56 mg. Subsequent doses are 56 mg or 84 mg, depending on how well your body tolerates the medication.
  • Maintenance phase (week 5 and after): During weeks 5 through 8, you'll take 56 mg or 84 mg once a week. Starting at week 9, you will take 56 mg or 84 mg every 2 weeks or once weekly.

You will need to remain in the healthcare setting for at least two hours after being treated. During this time, your healthcare provider will closely monitor you for adverse reactions. When it is safe for you to leave, you will need someone to drive you home.

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
  • Dizziness
  • Extreme tiredness (lethargy)
  • Feeling disconnected from mind and body (disassociation)
  • Feeling drunk
  • Increased blood pressure
  • Nausea
  • Reduced sense of touch and sensation
  • Sedation
  • Spinning sensation (vertigo)
  • Vomiting

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

Call your doctor if you experience severe side effects including:

  • Changes in mood or behavior
  • Extreme drowsiness
  • Hallucinations
  • Suicidal thoughts
  • Worsening depression

Get emergency medical help if you have signs of an allergic reaction including hives, difficulty breathing, or swelling of the face, throat, lips, or tongue.

Warnings and Interactions

The esketamine labeling contains a Boxed Warning that cautions that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.

If you are having suicidal thoughts, contact the National Suicide Prevention Lifeline at 1-800-273-8255 for support and assistance from a trained counselor. If you or a loved one are in immediate danger, call 911.

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

Drug Interactions

Esketamine can interact with a number of other medications and supplements. These substances may impact the way that your antidepressant works or your antidepressant may influence the effects of those substances.

Drugs that are known to interact with esketamine include:

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

Using alcohol while taking this drug may also increase the severity of side effects including drowsiness, difficulty thinking, confusion, motor impairment, and dizziness.

In order to minimize the risk of potentially dangerous interactions, you should always tell your doctor about any other prescription medications, over-the-counter drugs, vitamins, herbs, or other supplements you're currently taking or plan on taking.

Esketamine also has the potential for misuse and can cause physical dependence. Doctors are advised to balance the possible benefits with the potential risks, particularly for people at higher risk for substance misuse and addiction.

A Word From Verywell

If you or a loved one has TRD, 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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7 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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  4. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354. doi:10.1016/s0006-3223(99)00230-9

  5. 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

  6. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. doi:10.1001/jamapsychiatry.2019.1189

  7. Center for Drug Evaluation and Research. FDA briefing document: Psychopharmacologic drugs advisory committee (PDAC) And drug safety and risk management (DSaRM) Advisory committee meeting. U.S. Food and Drug Administration; 2019.

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