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.
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.
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.
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 brainAn abnormal connection between your blood vessels (arteriovenous malformation)
You should also talk to your doctor if you have ever had:
A family history of depressionAlcoholism or drug addictionBrain injury or any condition where there is increased pressure in the brainHeart attack or strokeHeart valve disease or heart failureHigh blood pressureLiver diseaseMental illness or psychosisSlow 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:
AnxietyDizzinessExtreme tiredness (lethargy)Feeling disconnected from mind and body (disassociation)Feeling drunkIncreased blood pressureNauseaReduced sense of touch and sensationSedationSpinning 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 behaviorExtreme drowsinessHallucinationsSuicidal thoughtsWorsening 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.
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. For more mental health resources, see our National Helpline Database. Drugs that are known to interact with esketamine include:
AmphetaminesAnti-anxiety medicationsMonoamine oxidase inhibitors (MAOIs)Opioid pain medicationsSedativesSeizure medicationsSleeping aidsTranquilizers
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.
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.
