Esketamine For Depression - What It Is & How It Works
Depression is one of the most common mental health conditions worldwide, and for many, traditional antidepressants just don’t work. While medications like SSRIs and SNRIs can be life-changing, an estimated one in three people with depression are considered treatment-resistant, meaning they’ve tried two or more antidepressants with little to no relief.
Enter esketamine, a fast-acting, FDA-approved nasal spray that’s giving new hope to patients and providers alike.
What is Esketamine?
Esketamine is a chemical cousin of ketamine, a well-known anesthetic that researchers in the early 2000s discovered could dramatically reduce symptoms of depression in a matter of hours. After years of clinical trials and research, the S-enantiomer of ketamine, known as esketamine, was developed into a nasal spray medication called Spravato and approved by the FDA in 2019.
Unlike traditional antidepressants, esketamine doesn’t primarily affect serotonin or norepinephrine levels. Instead, it works through the glutamate system, helping promote neuroplasticity which is the brain’s ability to form new connections and reset dysfunctional circuits involved in mood regulation.
How Does Esketamine Work?
Esketamine is believed to work by blocking the NMDA receptor, a key component of the glutamate signaling pathway. This blockade leads to a cascade of neurological events, including increased levels of brain-derived neurotrophic factor (BDNF), a protein that helps grow and strengthen synaptic connections. These changes may explain why some patients report noticeable improvements in mood just hours after treatment.
In essence, esketamine acts like a reset switch for the brain, offering fast-acting relief when nothing else seems to work.
Who Can Benefit from Esketamine Treatment?
Esketamine is FDA-approved for two primary conditions:
Treatment-resistant depression (TRD) – for adults who haven’t responded to at least two oral antidepressants.
Major depressive disorder with suicidal thoughts or behaviors – where rapid symptom reduction can be life-saving.
It’s not a first-line treatment, and it’s not for everyone but for those who qualify, it can be transformative. In clinical studies, over 65% of patients with TRD experienced significant improvement with esketamine combined with an oral antidepressant.
What is Treatment Like?
Esketamine isn’t something you pick up at the pharmacy. It must be administered under medical supervision at a REMS-certified Eskeatmine treatment center. Here’s what a typical appointment looks like:
Arrival and Check-In – Patients are welcomed to a private treatment room where vital signs are recorded.
Self-Administration – Esketamine is administered intranasally (nasal spray), typically in 2-3 doses spaced a few minutes apart.
Monitoring Period – Patients remain on-site for about two hours to be monitored for side effects such as dizziness, dissociation, or increased blood pressure.
Post-Treatment – Since esketamine may cause temporary sedation or dissociation, patients must arrange for someone to drive them home.
Treatment typically begins with twice-weekly sessions for 4 weeks, tapering to once weekly or biweekly for maintenance.
Is Esketamine Safe?
Esketamine is considered safe when administered in a clinical setting. Common side effects include:
Dissociation (feeling detached from reality)
Dizziness or nausea
Fatigue or headache
Increased blood pressure (usually temporary)
Because of these effects, esketamine isn’t prescribed for at-home use. All patients must be enrolled in the Spravato REMS program, which ensures proper monitoring and safety standards.
How Much Does Esketamine Cost?
Esketamine is typically covered by insurance when prescribed for treatment-resistant depression. However, coverage varies depending on your provider and plan. Most certified clinics will verify insurance benefits before starting treatment and discuss any out-of-pocket costs in advance.
How Is Esketamine Different from Ketamine?
While both ketamine and esketamine work on the brain’s glutamate system, there are important differences:
Esketamine is the S-enantiomer (a mirror-image form) of ketamine and is available as an FDA-approved nasal spray called Spravato.
Ketamine is typically administered intravenously (IV) and is used off-label for depression, meaning it's not FDA-approved for that specific purpose but is still widely offered.
Esketamine has undergone rigorous clinical testing and is part of a regulated program (REMS), while ketamine infusions vary in oversight and accessibility. Both can be effective, but only esketamine is covered by most insurance plans.
How Do I Find an Esketamine Provider?
Because of federal safety regulations, esketamine can only be prescribed and administered by REMS-certified treatment centers. Here’s how to find one:
Check the Spravato Provider Directory: Visit spravato.com and use their locator tool to find certified clinics near you.
Ask Your Psychiatrist: Many psychiatric practices can refer you or initiate treatment internally if they’re certified.
Search Regionally: Use terms like “Esketamine treatment near me,” “Spravato clinic in [Your City],” or “REMS certified esketamine provider” on Google Maps or health directories.
Call Your Insurance: Your health insurance provider can often give you a list of in-network clinics that offer Spravato.
Tip: If you're in the Chicago area, practices like Lott Behavioral Health were early adopters and have extensive experience with esketamine treatment.
Can I Drive After Treatment?
No. Esketamine may cause sedation, dizziness, or disorientation for several hours after treatment. You must arrange for a ride home, driving yourself is not allowed and can be dangerous. Many clinics will ask for proof of transportation before proceeding with each appointment.
How Soon Will I Feel Better?
Some patients begin to notice symptom relief within 24 hours of the first dose. However, for most, significant improvement happens over the first 2 to 4 weeks, especially when combined with an oral antidepressant and continued treatment.
Esketamine is not a one-time fix, it’s part of a longer-term treatment plan that often includes multiple sessions over several weeks.
Is Esketamine Addictive?
This is a common concern due to ketamine’s known recreational use. However, when esketamine is administered in a controlled medical setting with strict monitoring, the risk of addiction is considered low. It is never dispensed for home use and is always supervised by licensed medical staff.
Can I Continue Other Medications or Therapy?
Yes. Esketamine is intended to be used alongside an oral antidepressant, and most patients continue psychotherapy and other medications as recommended by their provider. Always let your psychiatrist know about any supplements, prescriptions, or therapies you’re using to avoid interactions.
What Are the Alternatives?
Esketamine isn’t the only option for people with treatment-resistant depression. Other alternatives include:
Transcranial Magnetic Stimulation (TMS)
Electroconvulsive Therapy (ECT)
Vagus Nerve Stimulation (VNS)
Ketamine infusions (IV-based, not FDA-approved but widely used off-label)
Combination therapy with psychotherapy and lifestyle interventions
Each treatment has its own pros and cons, and it’s important to work with a psychiatric provider to figure out the best path forward.
Final Thoughts
Esketamine (Spravato) represents one of the most exciting developments in psychiatric care in decades. For individuals who have felt stuck, hopeless, or out of options, it offers a new mechanism, a new hope, and often a new beginning.
If you or someone you love is struggling with treatment-resistant depression, ask a qualified provider whether esketamine nasal spray might be the next step in your journey toward healing.