Introduction: Understanding the Difference Between Esketamine and Ketamine

Both esketamine and ketamine have gained significant attention as rapid-acting antidepressants for treatment-resistant depression (TRD). While ketamine has long been used as an anesthetic and off-label depression treatment, esketamine (Spravato) is a FDA-approved nasal spray specifically developed for depression treatment.

💡 The key difference between esketamine and ketamine lies in their chemical structure, administration, and regulatory approval for depression.

This article will cover:
✔ Esketamine vs. Ketamine: Key Differences
✔ How They Work in the Brain
✔ Clinical Benefits of Each Treatment
✔ Side Effects & Safety Considerations
✔ Which One is Better for Depression?

Esketamine vs. Ketamine: Key Differences

Feature	Esketamine (Spravato)	Ketamine
Chemical Structure	Esketamine is one-half (S-enantiomer) of the ketamine molecule.	Ketamine consists of two enantiomers (R- and S-ketamine).
FDA Approval	FDA-approved for treatment-resistant depression (TRD) and major depressive disorder with suicidal ideation (MDD-SI).	Not FDA-approved for depression but used off-label.
Mechanism of Action	Primarily blocks NMDA receptors and enhances glutamate transmission.	Similar NMDA receptor blockade but includes additional sigma receptor effects.
Route of Administration	Nasal spray (Spravato) under medical supervision.	IV infusion, IM injection, or oral formulations.
Onset of Action	Rapid onset (within hours to days).	Similar rapid effects but depends on dosage and route.
Duration of Effect	Effects last several days to weeks.	Longer-lasting antidepressant effects compared to esketamine.
Side Effects	Dissociation, dizziness, sedation, nausea, increased blood pressure.	Similar to esketamine but higher risk of hallucinations, addiction, and cardiovascular effects.
Cost & Accessibility	Expensive; requires administration in certified medical centers.	Cheaper but not covered by insurance for depression treatment.

📌 Key Takeaway:
✔ Esketamine is an FDA-approved treatment for depression and is administered as a nasal spray under medical supervision.
✔ Ketamine is used off-label and is available in various formulations but lacks FDA approval for depression treatment.

How Do Esketamine and Ketamine Work in the Brain?

Both esketamine and ketamine work through the glutamate system, unlike traditional antidepressants (SSRIs, SNRIs) that target serotonin and norepinephrine.

💡 Key Mechanisms:
✔ NMDA Receptor Antagonism – Blocks NMDA receptors, increasing glutamate release and AMPA receptor activation.
✔ BDNF (Brain-Derived Neurotrophic Factor) Boost – Enhances neuroplasticity, helping the brain form new connections.
✔ Rapid Synaptic Repair – Improves connectivity in the prefrontal cortex, which is often impaired in depression.
✔ Dissociation & Altered Consciousness – May contribute to emotional processing and therapeutic effects.

📌 Why is This Important?
Unlike traditional antidepressants that take weeks to work, ketamine and esketamine can relieve depressive symptoms within hours to days, making them life-saving options for patients with suicidal ideation or severe depression.

Clinical Benefits of Esketamine and Ketamine for Depression

✅ Benefits of Esketamine (Spravato)

✔ FDA-approved for depression treatment
✔ More controlled administration (nasal spray under supervision)
✔ Lower risk of abuse and addiction compared to ketamine
✔ Well-documented safety profile

✅ Benefits of Ketamine

✔ More versatile administration options (IV, IM, sublingual, oral)
✔ Longer-lasting effects
✔ May have broader effects due to its interaction with multiple receptors
✔ More cost-effective for off-label use

📌 Key Takeaway:
Esketamine is safer and FDA-approved but more expensive.
Ketamine is more affordable and long-lasting but not FDA-approved for depression.

Side Effects & Safety Concerns

Although both drugs are effective for depression, they come with potential risks and side effects.

🚨 Common Side Effects of Esketamine (Spravato):

✔ Dizziness & Sedation – Common in the first hours post-administration.
✔ Dissociation – Feelings of detachment from reality.
✔ Increased Blood Pressure – Temporary spike post-dose.
✔ Nausea & Vomiting – Occurs in some patients.

🚨 Common Side Effects of Ketamine:

✔ Higher Risk of Hallucinations & Psychedelic Effects – Due to the R-enantiomer.
✔ Increased Heart Rate & Blood Pressure – More pronounced in IV ketamine.
✔ Potential for Addiction & Misuse – More common in recreational ketamine users.
✔ Bladder Toxicity (Cystitis) – Rare but seen in chronic ketamine use.

📌 Key Takeaway:
Esketamine has a more controlled administration protocol, making it safer for long-term use.
Ketamine has a higher risk of abuse but may be more effective in select cases.

Which One is Better for Treatment-Resistant Depression?

Both esketamine and ketamine offer unique advantages, and the best option depends on individual patient needs, safety concerns, and accessibility.

✔ Choose Esketamine (Spravato) if:
✅ You prefer an FDA-approved depression treatment.
✅ You want a more structured and medically supervised option.
✅ You are concerned about addiction and misuse risks.
✅ You have insurance coverage for esketamine therapy.

✔ Choose Ketamine if:
✅ You need a cost-effective, off-label alternative.
✅ You require flexibility in administration (IV, IM, oral options).
✅ You prefer a longer-lasting antidepressant effect.
✅ You have not responded well to esketamine.

📌 Key Takeaway:
Esketamine is ideal for patients who want a safe, controlled treatment for depression.
Ketamine may be a better choice for those seeking a longer-lasting and cost-effective option.

Final Thoughts: Esketamine vs. Ketamine – Which Should You Choose?

Both esketamine and ketamine represent a paradigm shift in treating depression, offering fast-acting relief and neuroplasticity benefits that traditional antidepressants lack.

🚀 Esketamine (Spravato) is the best option for those seeking a clinically approved and safer treatment.
🚀 Ketamine remains a powerful alternative for off-label depression treatment, with more flexible administration methods.

📌 Consult a psychiatrist to determine which treatment option is best suited for your depression symptoms.

Where to Seek Esketamine or Ketamine Therapy in Chennai?

🔹 Dr. Srinivas Rajkumar T
🔹 Consultant Psychiatrist, Apollo Clinic, Velachery, Chennai
📞 For appointments: 85-95-155-808