November 14

How Does Esketamine Work?

 November 14

by Elijah Zoarski

Although ketamine’s mechanism of action (MOA) as an anesthetic has been extensively studied, the MOA of esketamine’s antidepressant effect is poorly understood. Suggested mechanisms include improved brain plasticity via the stimulation of brain-derived neurotropic factor (BDNF) production and activation of the mammalian target of rapamycin.

– National Library of Medicine (2019)

Esketamine is a medication that is used for the treatment of treatment-resistant depression (TRD). It is a form of ketamine, an anesthetic agent that has been found to have rapid-acting antidepressant effects. Esketamine is thought to work through its interaction with the glutamate system in the brain, specifically by antagonizing the N-methyl-D-aspartate (NMDA) receptor.

Here’s a more detailed explanation of how esketamine works:

  1. Glutamate System: Glutamate is a neurotransmitter in the brain that plays a crucial role in synaptic plasticity, learning, and memory. The NMDA receptor is a type of glutamate receptor. Dysregulation of the glutamate system has been implicated in mood disorders such as depression.
  2. NMDA Receptor Antagonism: Esketamine, like ketamine, is an NMDA receptor antagonist. This means that it blocks or antagonizes the activity of the NMDA receptor. By doing so, it influences the release of other neurotransmitters, including glutamate itself.
  3. Rapid Onset of Action: One notable feature of esketamine and ketamine is their rapid onset of action. Traditional antidepressants may take weeks or even months to produce noticeable effects, but esketamine has been shown to have a more immediate impact, with some patients experiencing improvement within hours or days.
  4. Neuroplasticity and Synaptic Connections: The effects of esketamine on the glutamate system are thought to lead to changes in neuroplasticity. Neuroplasticity refers to the brain’s ability to reorganize itself, forming new neural connections. This process may be involved in the antidepressant effects of esketamine.
  5. Potential Mechanisms Beyond NMDA Receptor: While the NMDA receptor is a key target, recent research suggests that ketamine and its derivatives may have effects on other neurotransmitter systems and signaling pathways. These additional mechanisms are still an area of active investigation.

What Does an Esketamine Treatment Appointment Look Like?

Esketamine treatment is typically used for individuals with treatment-resistant depression (TRD) who have not responded adequately to other antidepressant treatments. Esketamine is administered under the supervision of our healthcare professionals in a controlled setting, and its use is subject to a Risk Evaluation and Mitigation Strategy (REMS) to ensure safe and appropriate use. Here’s an overview of what an esketamine appointment usually looks like:

  1. Screening and Assessment:
    • Before starting esketamine treatment, individuals undergo a thorough screening and assessment process. This includes a comprehensive evaluation of their medical history, current medications, mental health history, and the severity of their depressive symptoms. You can take our free depression test to see if this treatment may be a good fit for you.
  2. Preparation and Education:
    • Patients are provided with information about the treatment, its potential benefits, and possible side effects. They are also given instructions on what to expect during the treatment sessions.
  3. Administration:
    • Esketamine is typically administered as a nasal spray. The patient self-administers the nasal spray under the supervision of healthcare professionals. The administration is carried out in a healthcare setting, such as a doctor’s office or a clinic.
  4. Treatment Sessions:
    • The treatment is usually conducted in multiple sessions. Initially, there may be an induction phase where individuals receive esketamine more frequently, followed by a maintenance phase with less frequent sessions.
    • The duration and frequency of treatment sessions can vary based on the individual’s response and the clinician’s assessment.
  5. Monitoring and Observation:
    • During and after the administration of esketamine, patients are monitored closely for any immediate side effects or adverse reactions. This monitoring helps ensure the safety of the patient.
  6. Post-Administration Observation:
    • After receiving esketamine, patients are typically required to remain at the treatment site for a period of time to be observed for any potential side effects, including dissociation or changes in perception.
  7. Integration and Follow-Up:
    • Integration sessions are an important aspect of esketamine treatment. These sessions involve discussing and processing the experiences and insights gained during the treatment. They help individuals integrate these experiences into their daily lives.
    • Regular follow-up appointments are scheduled to assess the ongoing effectiveness of the treatment and to make any necessary adjustments to the treatment plan.
  8. Combination with Oral Antidepressants:
    • Esketamine is often used in conjunction with an oral antidepressant. The specific antidepressant and dosage may be determined based on the individual’s needs and response to treatment.

If you are considering esketamine treatment or have questions about its mechanism of action, it’s essential to consult with a qualified healthcare provider who can provide personalized information based on the latest medical knowledge and your specific circumstances.


Bahr, R., Lopez, A., & Rey, J. A. (2019). Intranasal Esketamine (SpravatoTM) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant. P & T : a peer-reviewed journal for formulary management44(6), 340–375.

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