Esketamine

Boxed warning

Esketamine (sold under the brand name Spravato) has a boxed warning. Boxed warnings (formerly “black box warnings”) are the strongest safety-related warnings the US Food and Drug Administration (FDA) issues.¹

Some individuals who take Spravato can experience dissociation after administration. For this reason, it’s important to remain in the treatment facility for at least two hours after you have taken Spravato to be monitored for any reaction.

Spravato also has a high rate of misuse in the general population. Remember to take Spravato only as prescribed and under the supervision of a healthcare professional.

Spravato and other antidepressants have also been associated with increased suicide risk in some individuals in the adolescent and pediatric populations (note that the drug is not approved for use in children). Family members and caregivers should be advised to monitor for symptoms of depression and suicidality and communicate with the prescribing doctor if they note any worsening symptoms.

What is esketamine?

Esketamine is derived from ketamine, a rapidly acting sedative drug used for general anesthesia in a medical setting. The FDA approved Spravato, the brand name for esketamine, for treatment-resistant major depressive disorder (MDD) in 2019. The medication is indicated for use in conjunction with an oral antidepressant.²

What You Need to Know About Major Depressive Disorder

Spravato use is highly regulated. It was designated a Schedule III controlled substance by the US Drug Enforcement Administration (DEA). It is more potent than ketamine and not approved for home use. The drug is self-administered only at certified treatment centers under close supervision.³

What’s the difference between ketamine and esketamine (Spravato)?

Ketamine (Ketelar) was approved by the FDA in 1970 for use as an anesthetic. It is usually administered intravenously (IV) to induce the loss of consciousness. Intramuscular and intranasal dosing forms are also available for use in a medical setting for sedation and pain control.

In addition to its sedative activity, ketamine stimulates the cardiovascular system, relaxes the airways, and increases salivation and muscle tone. It also has anti-inflammatory and anti-depressant effects.⁴

The drug’s ability to reduce symptoms of depression and suicidal thoughts has been the subject of much research. However, amid drawbacks such as the high cost of intravenous administration, its dissociative effects, and the potential for abuse, researchers looked at other formulations and delivery methods.⁵

Ketamine is a racemic mixture, meaning it’s made up of equal amounts of two mirrored versions of the original molecule: S-ketamine and R-ketamine. The isolated S-ketamine (esketamine) form of the drug was found to be four times more potent than ketamine as an N-methyl-D-aspartate (NMDA) receptor agonist. This means it can be given in much lower doses, which reduces the risk of adverse effects like dissociation. The nasal spray formulation is also more practical.⁶ ⁷

While esketamine (Spravato) is now approved for treating MDD, ketamine is not.

What is esketamine used to treat?

Spravato has been approved for treating adults with MDD whose condition has not responded to therapy with two or more oral medications. It is also indicated for use in adults with MDD who have suicidal thoughts or behaviors.

Spravato administration is restricted in the US through the Spravato Risk Evaluation and Mitigation Strategy (REMS) program. It is only given under medical supervision in a certified setting. The drug won’t be prescribed to you for home use.⁸

Dosage forms and strengths

Esketamine is available as a nasal spray under the brand name Spravato. This formulation is available in two dosage kits: 56mg and 84mg (with two or three 28mg nasal spray units in each to make up the kit’s total dose).⁹

How do you take esketamine?

Spravato use is highly regulated by the FDA. The drug is available by prescription but administered only in a certified medical setting. It is not prescribed for home use. You must be enrolled in the REMS program and take the medicine under the supervision of a healthcare professional. Each time your dose is given, you will be monitored at the location for a minimum of two hours.

Seeing results

An improvement in depression symptoms can occur after hours or days of consistent treatment. The medication is usually administered together with an oral antidepressant. Not everyone will see improvements.¹⁰ ¹¹

Who should not take esketamine?

Spravato is not recommended for everyone. It is contraindicated for individuals with any of the following conditions:¹²

• History of an allergic reaction to esketamine or ketamine

• History of bleeding in the brain due to an aneurysm, trauma, or a hemorrhagic stroke

• History of an arteriovenous malformation

• A known aneurysm in the brain, lung, aorta, or vessels in other locations

• Severe liver disease

Esketamine should be used with caution in patients with any of the following:¹³

• Cerebrospinal fluid pressure elevation

• Coronary artery disease

• Liver dysfunction

• History of suicidal ideation

• History of dissociation or psychosis

• Chronically high blood pressure

• Cognitive impairment

• History of or current alcohol or substance use disorder or intoxication

• Cerebrovascular disease

Women of reproductive age should also take esketamine with caution.

Potential side effects of esketamine

Ketamine has numerous possible side effects that vary from slight to severe.

The most common side effects of esketamine include any of the following:¹⁴ ¹⁵

• Nausea, vomiting

• Dry mouth

• Loss of appetite, change in taste perception

• Dizziness or a sensation of spinning

• Feeling of dissociation (feeling disconnected from yourself or your environment), feeling drunk or numb

• Drowsiness, lethargy

• Confusion

• Headache

• Dysphoria (sense of unease and dissatisfaction)

• High blood pressure

• Tremor

• Nasal discomfort

• Sweating

Some people have reported adverse effects that are not often seen, including the following:

• Anxiety, panic attack

• Suicidal thoughts or self-injury

• Constipation

• Rapid heart rate

• Joint pain

• Bladder problems, such as difficulty urinating, painful urination, or a frequent need to urinate

Overdose

Spravato is only administered in a clinical setting by a healthcare professional, so the chance of overdose is low. However, the drug can be misused or abused.

Overdose symptoms are likely to include any of the side effects mentioned above. Overdoses can be more severe if there is concomitant use of alcohol or other sedative drugs.

If you experience any of these symptoms, call your doctor or 911. You can also contact the National Poison Control Center helpline at 1-800-222-1222.

Allergy information

It is possible to have an allergic reaction to esketamine, particularly if you have a known allergy to ketamine. Allergic symptoms can range from mild, such as a rash, to anaphylactic shock. This would also involve breathing problems and wheezing, vomiting, swelling of the face, tongue, or throat, peeling skin, or even a loss of consciousness.

If you experience any allergic symptoms after taking esketamine, contact your doctor immediately or call 911, depending on the severity of your reaction.

Long-term use of esketamine

Doctors typically prescribe treatment with Spravato for 4–6 weeks. Because administration is highly regulated, long-term use of esketamine is generally safe.¹⁶

Long-term off-label or recreational use could lead to drug dependence and tolerance. You may experience withdrawal symptoms after stopping esketamine abruptly. There have been some reports of effects on cognition and memory with misuse of Spravato.¹⁷

Pregnancy category

Esketamine is not currently assigned an FDA pregnancy category. This means that this drug’s use in pregnant or breastfeeding people warrants further research.

Esketamine and pregnancy

Spravato is not recommended to be given during pregnancy.¹⁸

Animal studies have shown fetal skeletal abnormalities with high-dose intranasal ketamine along with developmental delays. However, the risk of treatment-resistant depression can be substantial. Therefore, doctors may decide to prescribe esketamine during pregnancy if the benefits are expected to outweigh the unconfirmed risks.

Esketamine can be found in human breast milk, but there is not enough research in humans to determine any detrimental effects. Animal studies have shown some adverse effects on the developing brain. Additionally, the drug is not approved for use in the pediatric population because its safety has not yet been determined. Your doctor will review the benefits and potential risks and evaluate the options in your case.

Missed doses

If you miss a Spravato dose, your healthcare professional will adjust the schedule for you.¹⁹

Drug interactions

Esketamine may interfere with the use of other drugs, such as:²⁰

• Antidepressants:

  • Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac) and citalopram (Celexa)

  • Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine (Cymbalta)

• Antihistamines like diphenhydramine (Benadryl), doxylamine (Unisom), and carbinoxamine (Ryvent)

• Antinausea drugs, such as trimethobenzamide (Tigan), metoclopramide (Reglan), and promethazine (Phenergan)

• Antipsychotic medications, such as aripiprazole (Abilify) and clozapine (Clozaril)

• Antiseizure medications like valproic acid (Depakene), topiramate (Topamax), and phenytoin (Dilantin)

• Migraine medications, such as dihydroergotamine (Migranal), ergotamine (Cafergot), and butalbital (Fioricet)

• Monoamine oxidase inhibitors (MAOIs), such as isocarboxazid (Marplan), phenelzine (Nardil), and selegiline (Eldepryl, Emsam, Zelapar)

• Non-steroidal anti-inflammatory drugs, such as meloxicam (Mobic), naproxen (Naprosyn), and ibuprofen (Advil, Motrin)

• Over-the-counter supplements and others: PeptoBismol, licorice, melatonin, valerian, passionflower, German chamomile, caffeine

• Pain and sedative medications:

  • Opiates, such as hydrocodone (Vicodin), meperidine (Demerol), and tramadol (Ultram)

  • Benzodiazepines, including lorazepam (Ativan), diazepam (Valium), and alprazolam (Xanax)

  • Sleeping pills like zolpidem (Ambien)

  • Muscle relaxants, such as metaxalone (Skelaxin) and baclofen (Lioresal)

  • Barbiturates like secobarbital (Seconal)

  • Alcohol

  • Recreational drugs, such as cocaine, kratom, kava, opium, ephedra, marijuana, and methamphetamine

• Stimulant medications, such as amphetamine (Adderall), methylphenidate (Concerta), modafinil (Provigil), and armodafinil (Nuvigil)

This is not an exhaustive list of drugs that can potentially interact with esketamine. Make sure to tell your doctor about all the medications, supplements, and herbal products you take regularly or even occasionally.

Can I drink alcohol while taking esketamine?

Alcohol increases the central nervous system side effects experienced when you take esketamine. This could lead to slower breathing, coma, and even death.

What to discuss with your doctor before starting esketamine

Before you start taking esketamine, you should review these important points with your doctor:

• Your medical history, including hemorrhagic stroke, brain hemorrhage, arteriovenous malformation, aneurysm, coronary artery or other heart disease, past history of a heart attack, abnormal heart rhythms, heart valve disease, high blood pressure, increased intracranial or intraocular pressure, seizures, and liver disease

• Any medication allergies or history of an adverse reaction to esketamine or ketamine

• Current medications, including prescribed and over-the-counter drugs, supplements, and herbal medicines

• Contraception and pregnancy planning

• Your alcohol or substance use and history

• Any history of depression, psychosis, or suicidal thoughts or actions

• Planned surgeries or other medical or dental procedures

• The potential side effects of esketamine

Ask your doctor what to do if you experience any side effects, miss a dose, or decide to stop the treatment.

Stopping esketamine

If you are taking esketamine, don’t stop going for your scheduled doses without discussing further treatment options with your doctor.

Drug approval history

• In 1970, the US FDA approved ketamine as a general anesthetic.²¹

• In 2019, the US FDA approved esketamine (Spravato) for treating major depressive disorder in adults with specific circumstances.²²

Tips for taking esketamine

• Spravato is administered in a controlled medical setting. Keep your appointments at the frequency prescribed by your doctor, and be sure to discuss any adverse effects you may have after your doses.

• People sometimes get nauseated with their doses, so it’s a good idea to avoid eating for two hours before your dosing appointment.

• Because Spravato may make you feel confused or dizzy, it’s recommended to avoid driving or operating machinery until the following day. Have someone drive you home after your treatment.

• Continue all your other prescribed medications while taking Spravato unless your doctor recommends discontinuing them. 

• Let your doctor know if you start taking any new medicines while you are on Spravato therapy.

• Be aware of any changes in your emotional health, such as a new onset of suicidal thoughts or worsening of your depressive symptoms. Inform your doctor immediately if any of these issues occur.

• Inform your doctor right away if you become pregnant while you are undergoing Spravato therapy.

Frequently asked question

What does esketamine treat?

Esketamine (Spravato), the nasal spray, is indicated for the treatment of adults with major depressive disorder that doesn’t respond to other medications.

Does esketamine (Spravato) replace antidepressants?

No, your doctor will prescribe a combination of medications for your condition, including an antidepressant. Esketamine therapy is only approved for its indicated use when combined with antidepressants.