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SPRAVATO® (Esketamine): A new, fast-acting treatment for people with treatment-resistant depression

Why are new treatment options important?
Nearly 1 in 10 American adults experience a depressive episode each year, and about two-thirds of these episodes cause severe impairment.1 Most people who seek help for their depression will receive treatment with standard antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). These medications reduce depressive symptoms by increasing the levels of depression-regulating neurotransmitters (or brain chemicals) that remain in the brain.

Unfortunately, an estimated 10-30% of people who take these medications are considered treatment-resistant, meaning that their depression does not improve after treatment with antidepressant drugs.2 Millions of people suffer with treatment-resistant depression each year, and many live with the high burden of undesirable side effects associated with traditional antidepressants. Novel drugs and therapies for depression may offer them a renewed optimism for recovery and a fuller, healthier quality of life.

How was esketamine discovered?
For many, this hope came in the form of a compound called esketamine, which in 2019 received FDA approval as a medication for adults with treatment-resistant depression or depression with suicidal behavior.3 The drug has had a long history prior to its clinical application as a psychiatric treatment. Fifty years ago, the FDA approved ketamine (a compound containing esketamine and another similar molecule, arketamine) as a general anesthetic and sedative during surgery and to treat postoperative pain. Physicians found the drug to be so exceptionally safe and effective that the World Health Organization (WHO) added ketamine to their Essential Medicines List in 1985.4

As ketamine became one of the most commonly used anesthetics worldwide, scientists and physicians began to observe an unexpected side effect: depressed patients waking from sedation showed rapid improvements in their depressive symptoms.5 Researchers recognized the immense potential of ketamine as an alternative or supplement to traditional antidepressants, and they began to test the drug in patients with major depressive disorder and bipolar disorder as early as 2000.6

What’s the evidence base?
Before approving esketamine as an intranasal spray called Spravato®, the FDA conducted three short-term studies (TRANSFORM 1, 2, and 3) and two long-term studies (SUSTAIN 1 and 2) of the drug in 1,709 adults with treatment-resistant depression. Given the immediate risks associated with depression, all of the study participants received treatment with traditional antidepressants; half also received twice-weekly treatment with intranasal esketamine (at either 84mg or 56mg per dose), and half received a placebo treatment. Researchers observed that participants who received esketamine at either dosage showed rapid therapeutic response (including improved depressive symptoms and reduced suicidal ideation) within two days of treatment compared to the placebo group.7

Given the positive response to short-term treatment, researchers initiated longer-term (56 weeks) research studies comprising participants from the short-term studies who wished to continue treatment. The purpose of the first study, SUSTAIN-1, was to determine the long-term efficacy of esketamine and to identify the rate of depression relapse during the maintenance period. The study found that esketamine reduces relapse by 50-70% (dependent on each participant’s initial response) compared to placebo. The second study, SUSTAIN-2, aimed to identify the safety of long-term treatment with esketamine. Findings indicated that up to 90% of participants who received esketamine experienced adverse effects, the most common being dizziness, headache, and dissociation.8 Critically, FDA protocols for administration of intranasal esketamine account for these potential adverse effects, ensuring that the therapy is safe and tolerable for long-term use.

Other studies have investigated the efficacy of esketamine delivered by alternative routes of administration. Several studies have demonstrated that intravenous9,10 and subcutaneous11 esketamine produces similar antidepressant effects as intranasal esketamine and may be equally safe and effective for long-term use. However, the intranasal route is preferable for rapid, easy delivery (particularly compared to intravenous esketamine, which may take 40-60 minutes to administer), and, at this time, only intranasal esketamine has FDA approval.

What is treatment like?
Having identified short-term adverse effects associated with esketamine, the FDA carefully developed a treatment protocol that protects the health and safety of patients who receive this drug. The Spravato® Risk Evaluation and Mitigation Strategy (REMS)12 requires that intranasal ketamine be administered under the direct supervision of a health care provider, who ensures that the treatment is delivered safely and monitors the patient for adverse effects. Because many patients briefly experience sedation, dissociation, cognitive impairment, and other changes in mental state immediately after receiving esketamine, they must remain under observation for at least two hours after each treatment session. Most adverse effects resolve within 1.5 hours.13

A typical treatment with intranasal esketamine involves two doses per week for four weeks, followed by one or two dose per week depending on the patient’s response. After nine weeks, patients may receive one dose per week or every two weeks depending on response. Dosing frequency is tailored on an individual basis to ensure that each patient receives the minimal dosing to maintain remission from depressive symptoms.

Many patients will show reduced depressive symptoms and suicidal ideation within two to four hours after treatment.13 Some studies find that 65% of patients will show a 50% or greater reduction in depressive symptoms by day 74 of treatment,14 and more than half will continue to experience improved depression throughout the maintenance phase with low risk of relapse.15

How does it work?
Esketamine belongs to a class of drugs known as N-methyl-D-aspartate (NMDA) receptor antagonists. These medications chemically bind to and block the activity of NMDA receptors, which help to regulate neuronal signaling in the brain. Reduced NMDA receptor activity causes significant short-term effects on the central nervous system, including the dissociative and pain-killing properties that make ketamine an effective anesthetic. Neuroscientists have only recently discovered that NMDA receptor activity also plays a role in depression, although the exact mechanisms remain unclear. They strongly suspect that many other molecular processes occur alongside NMDA receptor blockage, creating a complex chemical reaction in the brain that rapidly reduces depressive symptoms. Critically, these antidepressant effects appear to be unique to ketamine and its derivatives, as other NMDA receptor antagonists do not produce the same sustained antidepressant effects. Researchers are still investigating the specific properties that differentiate ketamine from other drugs in its class.16 

Why is it better?
Traditional antidepressants target monoamine systems in the brain, which regulate serotonin and norepinephrine. Although each of these antidepressants use a different chemical formula to change the function of the monoamine system, people with treatment-resistant depression show little or no response to these monoamine-targeted drugs. Esketamine, on the other hand, targets the glutamate system (which includes NMDA receptors), which may be key for improving depression and suicidal ideation in people who do not respond to monoamine system modulation.

Furthermore, esketamine produces a rapid response compared to traditional antidepressants, which typically take six to eight weeks to reach full effectiveness.17 Many people with depression—particularly those experiencing severe functional impairment, an acute depressive crisis, or imminent risk of self-harm or suicide—cannot safely wait two months to see improvement in their symptoms. Esketamine offers near-immediate relief and may be a life-saving measure for people with severe suicidal ideation or behavior.

Compared to traditional antidepressants, esketamine shows a more preferable long-term side effect profile. An estimated 10-15% of people stop taking their antidepressants due to unpleasant side effects,17 which can include nausea, fatigue, weight gain, sexual dysfunction, insomnia, and many other undesirable outcomes. While esketamine causes immediate nervous system effects, these resolve quickly within hours of treatment and are generally well tolerated. Longer-term side effects from prolonged treatment are yet unknown but may still be preferable to the adverse side effects associated with traditional antidepressant drugs. 

What are future directions?
Esketamine’s success as a therapy for major depressive disorder has prompted researchers to study the drug for other related mental illnesses, such as bipolar disorder.18 Researchers are also working to determine the efficacy of esketamine as a standalone treatment without supplementation with oral antidepressants.

For people living with treatment-resistant depression, Spravato® (esketamine) may offer new hope where traditional antidepressants have failed. Cutting-edge treatment with ketamine and its derivatives represents substantial progress in the ongoing mission to improve health, happiness, and quality of life among the millions of Americans who suffer from mental illness. We are happy to offer this evidence based, cutting-edge esketamine treatment, Spravato®, at our clinic, Depression Doctors.

If you think that you or a loved one may be suffering from depression, talk to a health care provider or mental health professional as soon as possible. If you or someone you know is experiencing a mental health crisis, call 911 or call the toll-free, 24/7 National Suicide Prevention Lifeline at 1-800-273-TALK.

The most common side effects of SPRAVATO™ when used along with an antidepressant taken by mouth include: dissociation, dizziness, nausea, sedation, spinning sensation, reduced sense of touch and sensation, anxiety, lack of energy, increased blood pressure, vomiting, and feeling drunk.

1 National Institutes of Mental Health (NIMH). (2020). Major Depression. Retrieved from https://www.nimh.nih.gov/health/statistics/major-depression.shtml.

2 Al-Harbi KS. (2012). Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient Preference and Adherence, 2012(6):369-388.

3 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.

4 World Health Organization (WHO). (2019). WHO Model Lists of Essential Medicines. Retrieved from https://www.who.int/medicines/publications/essentialmedicines/en/.

5 Li L & Vlisides PE. (2016). Ketamine: 50 years of modulating the mind. Frontiers in Human Neuroscience, 10:612.

6 Wei Y, Chang L, & Hashimoto K. (2020). A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacology Biochemistry and Behavior, 190(2020):172870.

7 Fedgchin M, Trivedi M, Daly EJ, et al. (2019). Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: Results of a randomized, double-blind, active-controlled study (TRANSFORM-1). International Journal of Neuropsychopharmacology, 22(10):616-630.

8 Kaur U, Pathak BK, Sing A, & Chakrabarti SS. (2019). Esketamine: A glimmer of hope in treatment-resistant depression. European Archives of Psychiatry and Clinical Neuroscience.

9 Berman RM, Cappiello A, Anand A, et al. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4):351-354.

10 Zarate CA, Singh JB, & Carlson PJ. (2006). A randomized trial of an N-methyl-D-asparatate antagonist in treatment-resistant depression. Archives of General Psychiatry, 63(8):856-864.

11 Rodovalho Fava VA, Sarin LM, Lucchese AC, et al. (2020). The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression. Psychiatry and Mental Health, S1888-9891(20):30117-20118.

12 FDA. (2019). Esketamine nasal spray access data. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf.

13 Popova V, Daley E, Trivedi EJ, et al. (2019). Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study. American Journal of Psychiatry, 176(6).

14 Bahr R, Lopez A, & Rey JA. (2019). Intranasal esketamine (Spravato®) for use in treatment-resistant depression in conjunction with an oral antidepressant. Pharmacy and Therapeutics, 44(6):340-342.

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

16 Molero P, Ramos-Quiroga JA, Martin-Santos R, et al. (2018). Antidepressant efficacy and tolerability of ketamine and esketamine: A critical review. CNS Drugs, 32(5):411-420.

17 InformedHealth.org. (2006). Depression: How effective are antidepressants? Cologne, Germany: Institute for Quality and Efficiency in Health Care. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK361016/.

18 Włodarczyk A & Jerzy Cubała W. (2020). Safety and tolerability of ketamine use in treatment-resistant bipolar depression patients with regard to central nervous system symptomatology: Literature review and analysis. Medicine (Kaunas), 56(2):67.