Esketamine vs Ketamine: 8 Key Differences for Depression Treatment

Depression can feel heavy, persistent, and isolating. For some people, traditional antidepressants don’t provide enough relief. If you’ve been researching new options for depression, you’ve probably come across the debate around esketamine and ketamine.

While they sound almost the same, and both have shown promise for treatment-resistant depression, they’re actually quite different. Understanding the differences can help you make informed decisions about your care.

What do esketamine and ketamine have in common?

Both medications are related to ketamine. 

Ketamine, in its original form, has been used for decades as an anesthetic. More recently, low-dose intravenous (IV) ketamine has been used off-label for depression.

Esketamine is the FDA-approved form of ketamine specifically for treatment-resistant depression. It’s available as a nasal spray under the brand name Spravato®.

Unlike traditional antidepressants that focus on serotonin, both ketamine and esketamine target glutamate receptors in the brain. This different mechanism is one reason they may help people who haven’t responded to standard medications.

What are the differences between esketamine and ketamine?

Now, let’s look at the key differences in the esketamine versus ketamine discussion.

1. FDA approval status and safety

One of the biggest differences is how the government views them.

• Esketamine (Spravato®) 

This is a brand-name nasal spray that was officially approved by the FDA in 2019 specifically for treatment-resistant depression and for depressive symptoms in adults with major depressive disorder and suicidal thoughts or actions. Because it is FDA-approved, it has undergone years of strict testing to prove it works and is safe for mental health.

• Ketamine 

While ketamine is a very old and FDA-approved anesthetic used in hospitals, it’s not officially approved by the FDA for depression. When doctors use it for mood, it’s called off-label use.

2. Form of administration

Another major difference in the esketamine and ketamine comparison is how the medication is given. If you’re someone who isn’t a fan of needles, this may be the most important part for you!

Esketamine is:

• Administered as a nasal spray
• Taken in a certified medical office
• Self-administered under supervision

Ketamine is:

• Often given through IV infusion
• Sometimes administered as intramuscular injections
• Delivered in various clinical settings

For both treatments, you must stay at the clinic for about two hours. This is to make sure you’re safe and relaxed as the medicine wears off.

3. Regulation and monitoring

Esketamine is only available through a Risk Evaluation and Mitigation Strategy, or REMS, program. 

IV ketamine clinics may follow safety protocols, but they’re not required to operate under the same FDA-regulated REMS system.

4. Chemical composition

Here is where things get slightly technical, but we’ll keep it simple.

Think about your hands. Your left and right hands are mirror images of each other, but they aren’t exactly the same.

• Ketamine is a racemic mixture, meaning it contains both “left-handed” (R-ketamine) and “right-handed” (S-ketamine) molecules.

• Esketamine is made from only the S-ketamine molecule.

Researchers found that S-ketamine may have stronger antidepressant properties. That is why it was developed into the prescription medication Spravato®.

While both affect the glutamate system, esketamine is a more targeted version. This means doctors can use a lower dose to get the same antidepressant effect, which often leads to fewer side effects for the patient.

5. Onset of effects

Both treatments can provide rapid relief compared to traditional antidepressants.

• Esketamine — Many patients notice improvement within hours to days, especially when combined with oral antidepressants and therapy.

• Ketamine (IV) — Effects can also appear within hours, making it valuable for acute depressive episodes.

Rapid action is particularly helpful for individuals in crisis or experiencing severe, persistent symptoms.

6. Insurance coverage and cost

Insurance coverage is another key difference. This is a major factor for many of our families.

Because esketamine is FDA-approved for depression:

• Many insurance plans may cover it, including Medicare.
• Prior authorization is often possible.
• VA clinics may coordinate care.

On the other hand, because traditional IV ketamine is off-label for depression, most insurance companies won’t pay for it. Patients often have to pay hundreds of dollars out-of-pocket for every single session.

If cost is a concern, this factor matters when deciding between esketamine and ketamine.

7. Treatment schedule

Esketamine follows a structured schedule:

• Two sessions per week for the first four weeks
• Weekly sessions for the next phase
• Possible maintenance sessions after that

Ketamine infusion schedules vary widely depending on the clinic.

A structured treatment plan can make it easier to plan work, family and transportation.

8. Integration with ongoing psychiatric care

Esketamine must be prescribed alongside an oral antidepressant. It’s designed to be part of a broader psychiatric treatment plan.

Esketamine is integrated with:

• Medication management
• Psychiatric follow-ups
• TMS therapy when appropriate
• Coordination with VA providers

This integrated approach ensures you’re not just receiving a single treatment, but comprehensive support.

Choosing the right option

The decision between esketamine and ketamine depends on several factors:

• Personal response to previous medications
• Convenience and access to treatment centers
• Insurance coverage and FDA-approved options
• Safety considerations and monitoring needs
• Coordination with other therapies and VA services for veterans

A thorough consultation with a trained psychiatric provider is essential. They can help determine which approach aligns with your mental health goals and lifestyle.

Psychiatry Treatment Centers can help you on your journey to mental wellness

At Psychiatry Treatment Centers, we provide a range of evidence-based treatments for depression, including TMS and Spravato®, with a focus on individualized care.

We strive to provide a welcoming, kind, and supportive environment for people of all walks of life. We’re proud to serve our military servicemembers and their families, ensuring they receive the highest level of care.

We have convenient locations in both California and Georgia. We would especially like to welcome our neighbors in Hinesville, GA. Located right near Fort Stewart, our Hinesville clinic is a dedicated hub for veteran-focused care. We work closely with VA clinics to ensure our local heroes get the advanced treatments they deserve without the red tape.

Reach out to our team by phone today for more information or to schedule an initial appointment. You can also book your initial appointment online now.