Mental health treatment continues to evolve, and two of the more notable developments for difficult-to-treat depression are ketamine and esketamine. Though both act on a similar brain chemical, they differ significantly in composition, regulatory status, side effects, and how they’re delivered.
What Is Ketamine?
Originally developed and used for decades as a surgical anesthetic, ketamine boosts activity in the NMDA receptors in the brain, which in turn elevates overall brain function and mood. It’s known for producing hallucinogenic effects, though these are carefully managed and monitored in clinical settings.
What Is Esketamine?
Esketamine is a compound derived from ketamine, but it acts more selectively on NMDA receptors and doesn’t cause the same hallucinogenic response. Marketed under the brand name Spravato®, esketamine has full FDA approval as a treatment for difficult-to-treat depression.
Spravato® vs. Ketamine: Key Differences
Both drugs address severe depression, but they deviate in several important ways, including chemical structure, FDA status, and delivery method. Additionally, ketamine treatment typically isn’t covered by insurance, while Spravato® is far more likely to receive approval for people with treatment-resistant depression.
Here’s how Spravato® and ketamine compare:
Chemical Composition
Ketamine exists as a racemic mixture, or a combination of two mirror-image molecules, R-ketamine and S-ketamine. Esketamine isolates just the S-ketamine component. This more concentrated form appears to be more effective against depressive symptoms and tends to produce fewer side effects.¹
FDA Approval & Regulation
Ketamine is used off-label for depression, meaning it hasn’t received formal FDA approval for this specific use, despite evidence of effectiveness. Spravato® hold full FDA approval for difficult-to-treat depression, making it a more tightly regulated and monitored option.
Clinical Use & Administration
Ketamine is generally delivered via IV or intramuscular injection in a clinical environment. Spravato®, by contrast, is administered as a nasal spray, making it a less invasive and more convenient approach for most patients.
Ketamine infusion schedules usually run two to three sessions weekly across a total of six to eight treatments. Spravato® follows a different pattern: Twice weekly for the first month, weekly for the next month, then weekly or biweekly maintenance dosing for as long as needed based on individual response.
Side Effects & Efficacy
Both drugs act on NMDA receptors in the brain, though Spravato®’s more targeted mechanism is thought to reduce side effects and improve overall treatment outcomes.
Side effect profiles overlap significantly between the two, with dissociation, drowsiness, dizziness, and a short-term rise in blood pressure common in both. Ketamine’s effects can run somewhat more intense, though, including hallucinations, and it also carries a higher potential for misuse outside supervised clinical settings.
Cost & Insurance Coverage
Because it’s used off-label for depression, ketamine treatment tends to be costly and generally isn’t covered by insurance. Spravato®, on the other hand, is covered under many insurance plans, making it a more financially accessible option for most clients.
Which Is More Effective, Ketamine or Esketamine?
Current research suggests ketamine and esketamine perform comparably well in reducing symptoms of treatment-resistant depression. That said, some studies point to esketamine’s more selective action as an advantage for targeted symptom relief.¹
Because esketamine holds FDA approval for depression treatment while ketamine doesn’t, more direct comparative research between the two is still needed.
The Benefits of Spravato® for Hard-to-Treat Depression
Spravato® takes a fundamentally different approach than standard antidepressants, working faster and more effectively for people who haven’t found relief from other medications.
Benefits of Spravato® include:
- Faster onset than most depression medications, with many clients notice relief within hours or days
- Meaningful improvements to daily functioning, especially when paired with other medications and talk therapy
- Greater convenience and accessibility compared to IV ketamine treatment
- Neuroplasticity from Spravato® can make therapy more effective
Start Spravato® Treatment in Pennsylvania at New Directions Mental Health
At New Directions Mental Health, we’re committed to bringing comprehensive, advanced depression treatment options to clients across Pittsburgh, Monroeville, Wexford, and across Western Pennsylvania. Many of our clinics provide Spravato®, offering people with difficult-to-treat depression a genuinely promising path forward.
Ready to take the next step in your mental health care? Schedule an appointment or call us at 724.374.7414 to learn more.
Source:
- Kawczak, P., Feszak, I., & Bączek, T. (2024). Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. Biomedicines, 12(10), 2283. https://doi.org/10.3390/biomedicines12102283