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Living with depression can be quite challenging at times, especially if the standard treatments haven’t worked for you. If it feels like you’ve tried every antidepressant medication available and you’re still feeling depressed, it may be time to consider more creative options.
Esketamine is a new way to treat depressive symptoms that could radically change life for people living with treatment-resistant depression. It works completely differently from oral antidepressants.
What is esketamine?
Esketamine (S-ketamine) or brand name Spravato is a nasal spray device. It’s a different version of ketamine, an anesthetic drug that’s also used for treatment-resistant depression. The U.S. Food and Drug Administration (FDA) approved esketamine in 2019 for treatment-resistant depression and major depressive disorder with suicidal ideation. It is the first FDA-approved psychedelic medication (FDA, 2019).
Esketamine is for adults aged 18 and over. You can only use esketamine if you have already taken an oral antidepressant like a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) (Janssen Pharmaceuticals, 2019).
Esketamine is given for treatment-resistant depression (TRD). TRD is when your depressive symptoms don’t improve despite taking at least two different antidepressant medications. TRD affects between 10 to 30% of people with major depressive disorder (Jaffe, 2019).
What is the difference between esketamine and ketamine?
Ketamine is FDA-approved as an anesthetic drug in surgery for humans and animals. When ketamine is used for depression, the doses are much lower than typically used for surgery. Ketamine does not have FDA approval to treat depression and is used “off-label” for this purpose. Off-label means your healthcare provider is using an FDA-approved drug for an unapproved use because they have determined you need this medication (Thase, 2020).
Ketamine tends to be significantly more affordable than esketamine, which is one reason why some healthcare providers may choose to use ketamine off-label to help with treatment-resistant depression.
Esketamine is a stronger relative of ketamine. Many chemical compounds come in different presentations—with their atoms set up in one direction, set up in the mirror opposite direction, or as a mixture of molecules set up in both directions (this mixture is called a racemic isomer). Ketamine is the racemic isomer, combining two mirror molecules called “R” and “S” ketamine. Esketamine is composed only of the S-ketamine isomer, hence its name (Thase, 2020).
Ketamine for depression: how it works, benefits, risks
How do you take ketamine for depression?
Ketamine for depression is given in clinics intravenously (IV), directly into your vein. The dosing is based on your weight and how you react to the medication. Treatments are usually done two or three times per week, lasting about 40 minutes to an hour. People who take ketamine infusions are typically monitored for 30 minutes afterward (Thase, 2020).
How do you take esketamine for depression?
Esketamine (Spravato) is a nasal spray that goes directly into the nose. Due to current federal regulation, Spravato can only be taken in certified medical clinics and given to people who are enrolled in a registry (Janssen Pharmaceuticals, 2019).
Each Spravato device contains 28 mg of esketamine and delivers two sprays. If you are taking esketamine for treatment-resistant depression, you may follow this schedule (Janssen Pharmaceuticals, 2019):
- Weeks 1–4 is the induction phase. The first dose is 56 mg. It is recommended to take intranasal esketamine spray twice a week during the induction phase. You may receive a higher dose of 84 mg if your body tolerates the medication.
- Weeks 5–8 is the maintenance phase. Your dose will be 56 mg or 84 mg, once a week, depending on your tolerance level.
- Week 9 and onward, depending on your tolerance and symptoms, your dose will be 56 mg or 84 mg, taken every two weeks or, if needed, once a week.
If you are a candidate for esketamine, you will spray the medicine yourself, but under medical supervision. You will be monitored for two hours afterward for any adverse effects. Once the two hours are up, someone will need to take you home. You will not be permitted to drive or operate machinery after taking esketamine until the morning after receiving your dose because this medication can impair your motor skills and reaction time (Janssen, 2019).
Depression: symptoms, causes, diagnosis, and treatment
How does esketamine work?
Ketamine and esketamine treat depression differently than the current standard treatment. The typical treatments for most forms of depression include antidepressants and psychotherapy. Antidepressants typically used work on increasing or balancing neurotransmitters like serotonin, norepinephrine, or dopamine in the brain.
In contrast, the mechanism of esketamine and ketamine isn’t fully known. They may help relieve depressive symptoms by influencing glutamate and GABA (gamma-aminobutyric acid), which help balance the brain’s activity. There’s also evidence that esketamine and ketamine can lower inflammation and stress levels in the brain and may even encourage the formation of new connections between neurons (Carboni, 2021).
What’s the research on esketamine?
There have been a small number of short-term studies on the effectiveness and safety of esketamine. In one study, between 25–65% of study participants saw their depressive symptoms resolve by over 50%. Most people felt better within hours of esketamine treatment, and this effect lasted through the entire study (Thase, 2020).
Two longer-term studies on esketamine showed that participants remained stable or in remission for more extended periods than with placebo (Thase, 2020).
Esketamine research continues to find optimal dosing and the long-term effects of esketamine treatments.
Clinical trials found that esketamine significantly reduces depressive symptoms within hours, even in some people with acute suicidal ideation (Ionescu, 2020). In comparison, most antidepressants take weeks to take effect.
Treatment-resistant depression: what are my options?
What are the side effects of esketamine?
Esketamine (Spravato) is a new treatment, and the manufacturer continues to monitor reactions.
Common side effects found in clinical trials include (Janssen Pharmaceuticals, 2019):
- Decreased sense of touch or sensation
- Dissociation (feeling disconnected from yourself or having an out-of-body experience)
- Dizziness and vertigo
- Extreme tiredness
- Feeling drunk
- Increased blood pressure
- Nausea and vomiting
- Sedated feeling
This is not a complete list of all common side effects. If you are receiving intranasal esketamine, your healthcare provider will give you additional side effect information. This information is also available on the Spravato website.
Serious adverse effects found in clinical trials include (Janssen Pharmaceuticals, 2019):
- Profound changes in mood or behavior
- Bladder issues
- Extreme drowsiness where it’s hard to wake up
- Suicidal thoughts
- Worsening depressive symptoms
Esketamine has an FDA boxed warning cautioning that people are at risk for sedation, dissociation (difficulty with thinking, judgment, and attention), the potential for abuse and misuse of the medication, and suicidal thoughts and behaviors after taking the drug (Janssen Pharmaceuticals, 2019).
If you have suicidal or self-harming thoughts, call the National Suicide Prevention Helpline at 1-800-273-8255 for support. If you or a loved one are in immediate danger, call 911 or go to the nearest emergency room.
If you are allergic to ketamine or esketamine or any of the ingredients in Spravato, you cannot take esketamine nasal spray.
Esketamine nasal spray is not a first-line treatment for depression. It is intended for people with treatment-resistant depression who have used at least two antidepressant medications without experiencing relief of their depressive symptoms.
SSRIs: everything you need to know
Who should not take esketamine?
You should not take esketamine if you have had any of the following conditions (Janssen Pharmaceuticals, 2019):
- Aneurysm (a blood vessel disease)
- Arteriovenous malformation (AVM—an abnormal tangle of blood vessels)
- A history of bleeding in your brain
Your healthcare provider will want to know your complete medical history. Let them know if you have ever had:
- Any condition that causes increased pressure in your brain
- Brain injury
- Family history of depression
- Heart conditions: heart attack, heart failure, heart valve disease, heart rate, and rhythm disturbances
- High blood pressure
- Liver disease
- Mental health conditions
- Substance use disorders: alcohol or drug addictions
- Suicidal thoughts or behaviors
You may not be able to take esketamine if you are pregnant or breastfeeding. Esketamine may cause fetal harm and be passed in breastmilk (Janssen Pharmaceuticals, 2019).
Currently, esketamine is only approved for adults. More research is needed to see if esketamine is appropriate for children and teens.
Esketamine drug interactions
Esketamine interacts with some medications, including some antidepressants and supplements you may already be taking. Please let your healthcare provider know everything you take, including prescription and over-the-counter medications, supplements, and herbs.
What does depression feel like?
Some people may not be able to take Spravato if they regularly take (Janssen Pharmaceuticals, 2019):
- Anti-anxiety medications
- Anticonvulsant (seizure) medications
- Monoamine oxidase inhibitors (MAOIs), a type of antidepressant
- Opioid pain medications, whether prescribed or recreational
- Sedatives and tranquilizers
- Sleep medications, including over-the-counter drugs
Alcohol may severely increase the sedating side effects of esketamine, causing extreme drowsiness, confusion, dizziness, difficulty thinking, and serious motor impairment.
Esketamine may be addictive. Your healthcare professional will balance the possible risks and benefits of esketamine if you have a history of substance use disorder.
An innovative treatment option
If you or your loved one have treatment-resistant depression or major depression with suicidal ideation, esketamine intranasal spray is an innovative way to treat your symptoms. It may provide relief to people who have not had success with other antidepressant medications. However, esketamine is not suitable for everyone. Please speak to a healthcare professional to help you find alternative treatment options so you can feel better.
- Carboni, E., Carta, A. R., Carboni, E., & Novelli, A. (2021). Repurposing ketamine in depression and related disorders: can this enigmatic drug achieve success?. Frontiers in Neuroscience, 15. Retrieved from https://www.frontiersin.org/articles/10.3389/fnins.2021.657714/full
- Ionescu, D. F., Fu, D. J., Qiu, X., Lane, R., Lim, P., Kasper, S., et al. (2021). Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). International Journal of Neuropsychopharmacology, 24(1), 22-31. doi: 10.1093/ijnp/pyaa068. Retrieved from https://academic.oup.com/ijnp/article/24/1/22/5899217
- Jaffe, D. H., Rive, B., & Denee, T. R. (2019). The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry, 19(1), 1-11. doi: 10.1186/s12888-019-2222-4. Retrieved from https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-019-2222-4
- Janssen Pharmaceuticals. (2019). Spravato: esketamine. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf
- National Institute of Mental Health (NIMH). (nd). Rapidly-acting treatments for treatment-resistant depression (RAPID). National Institute of Health. Retrieved from https://www.nimh.nih.gov/research/research-funded-by-nimh/research-initiatives/rapidly-acting-treatments-for-treatment-resistant-depression-rapid
- Thase, M., Connolly, KR. (2020). Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. Retrieved from https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
- US Food and Drug Administration (FDA). (2019). FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
Dr. Steve Silvestro is a board-certified pediatrician and Senior Manager, Medical Content & Education at Ro.