Introduction: Ketamine vs. Esketamine
Quick Answer: Ketamine vs. Esketamine: The two medications work for adults suffering from treatment-resistant depression, but they are formulated differently, administered in different ways and approved for treatment use by the Food and Drug Administration (FDA).
Ketamine is given IV for depression, and esketamine (Spravato) is a nasal-spray formulation approved by the FDA that is administered under a supervised treatment program. Both work on the NMDA receptors, but not all may be a fit for all. A psychiatrist will be able to make some conclusions about what might be appropriate according to the symptoms, the history, the previous treatment and the needs.
What is Ketamine?
Ketamine is a drug that was first created as a sedative or anesthetic. Its use in medical contexts has been around for decades, and is even being researched for its antidepressant effect. Low doses of ketamine injected intravenously (IV) might be an option for adults with depression who do not respond to other treatment.
Next, ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, while typical antidepressants work on serotonin, norepinephrine, and dopamine pathways. One of its effects on glutamate signaling is thought to account for some of the rapid mood shifts that some might experience with its use. But IV ketamine depression treatment is an off-label application, this means it is not formally approved by the FDA for treating depression.
What is Esketamine?
Esketamine is the S-enantiomer form, which is half of the molecule, of ketamine. Sold as Spravato, it is taken as a nasal spray under the guidance of healthcare professionals.
Esketamine nasal spray has been approved by the FDA for the treatment of treatment-resistant depression (TRD) in adults.
Also indicated for depressive symptoms in adults with major depressive disorder (MDD) and acute suicidal ideation or suicidal behavior, in combination with an oral antidepressant. Importantly, though, the FDA says Spravato has not been proven to prevent suicide or alleviate suicidal thinking or actions. It should NOT be used in place of clinically indicated hospitalization.
Ketamine vs. Esketamine: Important Differences
The main difference between the drugs is how they are formulated and the fact that esketamine is not approved for use in the United States. Depression use of ketamine is usually done through IV infusion and is off-label. Esketamine is a nasal-spray drug approved by the Food and Drug Administration (FDA) for certain kinds of depression and is a restricted safety program drug.
Feature | Ketamine | Esketamine (Spravato) |
Medication type | Racemic ketamine, containing two enantiomers | S-enantiomer of ketamine |
Common psychiatric route | Intravenous infusion | Intranasal spray |
FDA approval for depression | No, IV use for depression is off-label | Yes, for specified adult depressive conditions |
Treatment-resistant depression | Used off-label in clinical settings | FDA-approved indication |
Administration | Typically administered by clinical staff | Patient self-administers under direct supervision |
Monitoring | Clinical monitoring based on treatment protocol | At least 2 hours of observation after each session |
REMS program | No federal Spravato REMS requirement | Required REMS-certified treatment setting |
Insurance coverage | May vary; often self-pay | Coverage depends on plan and eligibility |
Potential side effects | Dissociation, dizziness, nausea, blood pressure changes | Dissociation, sedation, dizziness, nausea, blood pressure increases |
It’s not a matter of which is the more forceful drug. The clinician needs to take into account safety, accessibility of treatment, the previous response to treatment, and patient preferences.
How Does Ketamine/Esketamine Work?
Both drugs act on the same receptor, called the NMDA receptor, that plays a role in the glutamate brain pathways. Glutamate is a key neurotransmitter that plays a role in communication with other nerve cells, learning, and memory.
Scientists think that treatments with ketamine could be changing the brain’s “signal” that helps with its plasticity, how it adapts and makes connections. These might contribute to the idea that some patients might improve their mood sooner than with traditional antidepressant drugs. The exact way it works as an antidepressant is not completely understood, however, and everyone reacts differently to the medication.
What’s More Effective for Depression?
Despite these findings, IV ketamine is not currently proven to be more effective than intranasal esketamine in the treatment of depression.
In 2025, a systematic review and meta-analysis of eight comparative studies (involving 978 participants) was conducted. In total, seven studies with 915 people were included in the IV ketamine versus intranasal esketamine meta-analysis.
There was no statistically significant difference between the short-term responses or the rates of remission found in the analyses, though the numbers of those responding seemed to favor IV ketamine. The majority of studies included were observational in nature and findings should be interpreted with caution.
Both treatments can be effective for some individuals who haven’t been adequately treated with traditional antidepressant medications. But effectiveness is dependent upon individual clinical factors and results are not guaranteed.
How Quickly Do Ketamine and Esketamine Work?
For people taking ketamine or esketamine, they might experience a change in depressive symptoms in hours or days. Rapid antidepressant effects are seen with IV ketamine in clinical studies, and esketamine may have an inconsistent effect from one person to another and from one treatment session to another.
There is no assurance that if it is done quickly, it will be sustained. In both treatments, there may be an induction phase, reassessment, and then continuation of treatment if appropriate. The frequency is set by the prescribing clinician according to the response, safety, and desired treatment of the patient.
Side Effects and Safety: Ketamine vs. Esketamine
All medications have side effects that may be temporary and treatment must be undertaken with professional monitoring.
Side effects can include (and may not be limited to):
- Separation or sense of outsideness
- Dizziness or lightheadedness
- Nausea or vomiting
- Sedation or sleepiness
- High transitory blood pressure.
- Illusion or anxiety
Esketamine is contraindicated for sedation, and there are FDA boxed warnings for dissociation, increased respiration and abuse or misuse. Patients should be monitored for a minimum of two hours after the dose. Spravato comes with a Risk Evaluation and Mitigation Strategy (REMS) program.
Ketamine is also known to be abused and can have an impact on blood pressure, thought, and perception. For some cardiovascular diseases, substance use problems, and other medical problems, a careful evaluation is necessary. Medication should not be used without qualified medical supervision for either medication.
Who May Be a Candidate for Ketamine or Esketamine Treatment?
A ketamine-based treatment may be an option for depressed adults who suffer from treatment-resistant depression or those who have not yet achieved enough relief with conventional treatment methods.
A psychiatrist will consider:
- Using previous antidepressant medications and treatment outcomes.
- Depression symptoms as present; severity
Cardiovascular health, medical history… - Past drug or medicine abuse
Any medication and potential interactions - Preferential treatment, access, and ability to attend monitored sessions
The esketamine drug can only be used for certain conditions. Ketamine is still an off-label drug for depression. An extensive psychiatric evaluation is required to decide on the use of either therapy.
Esketamine vs. Ketamine: Which Treatment is Best for You?
Different answers depend on the situation. Esketamine may be helpful to people who prefer a nasal spray and desire treatment in an FDA-approved/REMS-certified treatment program. When there is an infusion-based protocol available to use, clinicians may consider using IV ketamine when off-label treatment is appropriate.
It is best done with a good psychiatrist who can describe the available evidence, the potential risks, the monitoring requirements, treatment expense, and alternatives. Patients should not select a treatment solely because it is implied that it will work quicker or bear greater results.
Visit Orlando Premier Psychiatry to learn more about depression treatment options.
The first step is getting to know more about ketamine and esketamine if you are having depression that doesn’t respond to conventional treatment. Orlando Premier Psychiatry offers psychiatric services and can help you talk about your symptoms, treatment history and options.
Call (407) 565-3546 today to schedule a psychiatric assessment and learn more about Ketamine-based treatments available at Orlando Premier Psychiatry that might be suitable for you. A qualified provider can explain the ways in which it may benefit you, the risks associated with it, and what you can expect to do next.
Frequently Asked Questions
1. Is ketamine the same as esketamine?
No. Esketamine is one of the two mirror-image chemical forms of ketamine. Ketamine used in psychiatric care typically contains both forms, while esketamine is the S-enantiomer and is available as an FDA-approved nasal spray for specific depressive conditions.
2. Is esketamine better than ketamine for depression?
Not conclusively. A 2025 meta-analysis of comparative studies found no statistically significant difference in short-term response or remission between IV ketamine and intranasal esketamine. Treatment selection should consider clinical evidence, medical history, safety, access, and patient preferences.
3. Is ketamine FDA-approved for depression?
IV ketamine is not FDA-approved specifically for depression. Its use for depressive disorders is considered off-label. Esketamine nasal spray, sold as Spravato, is FDA-approved for treatment-resistant depression in adults and certain depressive symptoms associated with acute suicidal ideation or behavior.
4. How quickly does esketamine work?
Some patients may experience improvement in depressive symptoms relatively quickly, but response varies. Esketamine treatment typically involves repeated sessions during an induction phase. A psychiatrist evaluates symptom changes over time to determine whether treatment should continue.
5. Can ketamine and esketamine cause addiction?
Both medications have potential for abuse and misuse. Ketamine is a Schedule III controlled substance, and esketamine is also classified as Schedule III. Supervised administration, appropriate screening, and monitoring are important, particularly for people with a history of substance use disorders.
6. How long do ketamine and esketamine treatments last?
The duration of benefit differs between individuals. Some patients experience short-term improvement, while others may require ongoing treatment. The treating psychiatrist evaluates response, symptom recurrence, side effects, and the need for maintenance sessions.
7. Does esketamine require medical supervision?
Yes. Esketamine must be administered under direct healthcare professional supervision through the Spravato REMS program. Patients are monitored for at least two hours following administration because of potential sedation, dissociation, respiratory depression, and blood pressure changes.
8. Can ketamine or esketamine replace traditional antidepressants?
Not necessarily. Esketamine may be prescribed alongside an oral antidepressant for certain FDA-approved indications, although it is also approved as monotherapy for treatment-resistant depression. IV ketamine is used off-label. Treatment decisions should be individualized by a psychiatrist.
9. Who should avoid ketamine or esketamine treatment?
People with certain medical conditions, including aneurysmal vascular disease, arteriovenous malformations, or a history of intracerebral hemorrhage, may have contraindications to esketamine. Other risks require individualized evaluation. A psychiatrist should review medical history, medications, and potential complications before treatment.
Medical Disclaimer
This content is for educational purposes only and does not replace professional medical advice, diagnosis, or treatment. Ketamine and esketamine are prescription medications with important risks. Always consult a qualified psychiatrist or healthcare professional before considering treatment. Do not start, stop, or change medications without medical guidance. If you are experiencing a mental health emergency or immediate risk of suicide, contact emergency services or a crisis hotline.
References
- UAMS Psychiatric Research Institute. Ketamine Infusions.
- Systematic Review and Meta-Analysis. Intravenous Ketamine Versus Esketamine for Depression.
- U.S. Food and Drug Administration. Spravato (Esketamine) Prescribing Information.
