Esketamine vs Ketamine: What’s the Difference?

Living with treatment-resistant unipolar major depression can be extremely overwhelming and discouraging. Recently, ketamine and esketamine emerged as new treatment options for unipolar major depression and suicidal ideation. Providers may recommend ketamine or esketamine for depressed patients who have failed to respond to traditional treatments like antidepressant medications and psychotherapy. Ketamine therapy can provoke a response (50% or greater reduction in baseline symptoms) in patients with treatment-resistant unipolar major depression and/or suicidal ideation as soon as 2-4 hours after receiving their first treatment. Upon administration of ketamine or esketamine, patients should be under the consistent care of a psychiatrist able to monitor their individual progress and treatment outcomes.

The form of ketamine typically administered intravenously is a racemic mixture of two ketamine enantiomers (molecules that are non-superimposable, mirror images of each other) — R-ketamine and S-ketamine (esketamine). Both enantiomers have been shown to quickly reduce depressive symptoms implicated in treatment-resistant unipolar major depression and suicidal ideation. Usually, racemic ketamine is administered intravenously whereas esketamine is administered intranasally. Both racemic ketamine and esketamine are antagonists to the N-methyl-D-aspartate (NMDA) receptor in the brain; however, esketamine binds more potently to the NMDA receptor than racemic ketamine. When the NMDA receptor gets blocked, glutamate, an important neurotransmitter in the brain, gets released. This activates the AMPA receptor, which is capable of increasing neurotrophic factor signaling, ultimately lending to the efficacy of ketamine and esketamine as antidepressants. Some studies have shown that esketamine is a more effective antidepressant than racemic ketamine with minimized side effects, while other studies have found both forms of the drug to elicit comparable antidepressant effects. More research needs to be conducted on the topic to discover which form of ketamine is most efficacious in the clinical setting.

Patients can utilize an esketamine nasal spray device for self-administration under the supervision of a provider; the device dispenses two doses — one for each nostril. The patient is then monitored for two hours after each use. Racemic ketamine infusions are delivered at a controlled rate over a 40 minute period, and patients are monitored post-infusion. This method is more widely used because intravenous delivery is more reliable, ensuring accurate dosage and absorption of the medication. It should be noted that ketamine infusion and esketamine nasal spray are associated with potential side effects, including dissociation, increased blood pressure, headache, nausea, fatigue, and dizziness. With repeated use, any adverse effects tend to lessen in severity. Interested patients should consult with their provider about the availability of racemic ketamine and esketamine as well as which option would work best for them.

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