Ketamine vs. Esketamine: What's the Difference for Treating Depression?

You’ve probably heard about ketamine, and you may have questions. We’re here to clear things up, with a brief look at ketamine’s past, an update on how it’s being used today, and an introduction to esketamine, an FDA-approved version of ketamine that goes by the brand name Spravato®. To understand ketamine vs esketamine, which have similar effects but some important differences, read on.

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What is ketamine and how does it work?

Ketamine has been used as an anesthetic in medical settings since the 1960s. In fact, if you’ve ever had surgery or a procedure requiring IV sedation, ketamine may have been part of the medication mix ensuring you felt no pain. When given at the high doses used in anesthesia, ketamine blocks the brain’s ability to process sensory inputs and connect them to conscious experiences, an effect called "dissociation." Ketamine is also sold and used illegally by people seeking its intoxicating, sometimes euphoric effects. 

Ketamine works by blocking your brain’s receptors of a neurotransmitter called NMDA, increasing the available levels of another one called glutamate. That leads your brain to release growth factors like Brain-Derived Neurotrophic Factor (BDNF), which stimulate the brain to grow new synapses. (Synapses are the gaps between nerve cells where they talk to each other through chemical or electrical signals.)^[1]

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Ketamine for depression

More recently ketamine has gained a reputation as a treatment for depression. By stimulating the rapid growth of new synapses, ketamine changes brain “wiring,” which can positively impact mood and thought patterns.^[2] Because it influences the brain’s glutamate system, ketamine has a different mode of action than standard antidepressant medications (which often adjust levels of the neurotransmitters serotonin or norepinephrine). So healthcare providers may prescribe ketamine for patients whose symptoms haven’t been adequately relieved by other antidepressants. However, this is an “off-label” use of ketamine, meaning that it hasn’t been FDA-approved and usually isn’t covered by insurance.

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What is esketamine (SPRAVATO®) and how is it different?

In 2019 esketamine, which goes by the brand name Spravato, was approved by the FDA for treatment-resistant depression (TRD) and for major depressive disorder (MDD) accompanied by suicidal thoughts or actions.^[3] Like ketamine, esketamine increases glutamate levels and synaptic connections in the brain, which can rapidly decrease depression symptoms. Research demonstrates that Spravato leads to rapid improvement in symptoms of depression as soon as 24 hours after treatment, and significant improvement in Montgomery-Asberg Depression Rating Scale (MADRS) compared to a placebo.^[4]

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How esketamine is different

However esketamine is a form of ketamine that more precisely acts on NMDA receptors. You might be wondering “Is esketamine weaker than ketamine?” but the answer is no. Esketamine was designed to have more potent effects than ketamine with reduced side effects. Another important difference between ketamine and esketamine is that because Spravato (esketamine’s brand name) is FDA approved, treatment is covered by most insurance plans, including Medicare and TRICARE.  

Ketamine is usually administered through an IV, but esketamine is taken as a nasal spray. Esketamine must be administered in a supervised clinic setting, where a medical provider will monitor your vital signs and how you respond to treatment. Spravato may have temporary side effects such as elevated blood pressure, dissociation, dizziness, nausea or sedation, which is why sessions happen under supervision. Any side effects are usually short-lived and the care team that knows how to manage them

Although ketamine clinics may provide the medication as a standalone, Salma Health administers Spravato as part of a  personalized care plan. At Salma Health every patient receives a comprehensive evaluation that allows your care team to understand your current symptoms, personal and family history, prior treatments and overall health—this helps us understand which treatment plan will be most effective for you. We make sure that there are no risk factors that could put you at risk for complications. After treatment your care continues, possibly incorporating therapy, psychiatry and on-going follow-up to make sure you experience meaningful sustained improvement. 

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Differences between esketamine vs ketamine

If you’ve wondered “Is Spravato the same as ketamine?” the answer is “not exactly.” Here are the key differences:

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Chemical structure and mechanism of action 

Both work by blocking NMDA receptors and changing glutamate activity in the brain. Ketamine is a 50/50 blend of two mirror-image molecules, called S-ketamine and R-ketamine. Esketamine is only the more potent S-ketamine molecule, allowing for a stronger effect at a lower dose than ketamine.^[5],[6] 

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Clinical uses and administration

Ketamine is used in anesthesia, and also prescribed in smaller doses off-label for depression and other mental health conditions. Esketamine is FDA-approved specifically for treatment-resistant depression and major depressive disorder with suicidal thoughts or action. Esketamine is always administered as a nasal spray, but ketamine may be given as an IV, injection or pill.

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Setting and safety

Esketamine is administered under clinical supervision for safety, according to evidence-based, established guidelines. In comparison, the safety of ketamine depends on the prescriber, dose and level of supervision.

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Insurance coverage

Esketamine is usually covered by insurance because it is FDA-approved, but ketamine is rarely covered by insurance since depression treatment is an “off label” use.

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Ketamine vs. esketamine: which is right for you?

When you’re deciding between ketamine vs esketamine for depression, start by considering your symptoms and treatment goals. Spravato may be prescribed for:

• Treatment-resistant depression in adults, which means depression symptoms that haven’t adequately responded to two or more other medications

• Major depressive disorder with acute suicidal thoughts or actions, meaning that even if you haven’t already tried two other antidepressants the fact that you have suicidal thoughts makes you a candidate for Spravato.

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An evaluation to help you decide

If you’re deciding whether Spravato/esketamine would be the best choice for you, a Salma Health licensed clinician can help you understand your options. During a comprehensive evaluation we’ll look at your symptoms, history and goals (and may include imaging or biomarker testing), then we’ll create a treatment plan that may include Spravato/esketamine or other advanced treatments like TMS therapy or SAINT® (accelerated TMS) delivered at one of our clinic locations. Salma Health clinics are certified to deliver Spravato, deeply experienced with this treatment and laser-focused on patient safety.  Your care at Salma Health will always be coordinated, science-backed and personalized to you. 

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^{Cited sources:}

^{[1] Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016;10:612. doi:10.3389/fnhum.2016.00612}

^{[2] Lullau APM, Haga EMW, Ronold EH, Dwyer GE. Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression. Front Neurosci. 2023;17:1223145. doi:10.3389/fnins.2023.1223145}

^{[3] US Food and Drug Administration. SPRAVATO (esketamine) prescribing information. Updated January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf}

^{[4] Janik A, Qiu X, Lane R, et al. Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2025;82(9):877-887. doi:10.1001/jamapsychiatry.2025.1317.}

^{[5] ałaciak K, Pytka A. Ketamine, esketamine, and arketamine: their mechanisms of action and applications in the treatment of depression and alleviation of depressive symptoms. Int J Mol Sci. 2024;25(20):10955. doi:10.3390/ijms252010955}

^{[6] Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542-555. doi:10.1016/j.jad.2020.09.071}