Esketamine for Depression: Is It Safe?

Esketamine nasal spray has emerged as a breakthrough for people with treatment-resistant depression. Unlike standard antidepressants, it works rapidly on the brain’s glutamate system, offering hope for patients who have not responded to traditional medications. But how safe is it? This article reviews clinical trial data, side effects, safety protocols, and real-world use. It also explains when online consultations are appropriate, introduces trusted Doctors365 psychiatrists, and provides tips on preparing for your appointment. If you’re struggling with depression, find out if esketamine could be the right option for you.

Disclaimer: This article is for educational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. If you are experiencing a mental health crisis, suicidal thoughts, or any medical emergency, please seek immediate in-person medical attention or call your local emergency number.

Author: Dr. Diellza Rabushaj

Depression is one of the most pressing health issues of our time, affecting more than 280 million people worldwide [1]. While traditional antidepressants such as SSRIs and SNRIs are commonly prescribed, up to one-third of patients do not achieve significant improvement, even after trying multiple medications [2]. This group, often referred to as having treatment-resistant depression (TRD), faces a higher risk of chronic disability, hospitalization, and suicide.

In recent years, a new therapy has emerged that offers hope where traditional options have failed: esketamine nasal spray. Approved by regulatory agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), esketamine represents a paradigm shift in depression treatment. But the question remains—is it safe?

1. What is Esketamine?

Esketamine is the S-enantiomer of ketamine, a medication that has been used for decades as an anesthetic. Unlike standard antidepressants that work on serotonin, dopamine, or norepinephrine, esketamine acts as an NMDA receptor antagonist. By modulating glutamate, the brain’s most abundant excitatory neurotransmitter, esketamine promotes synaptic plasticity—essentially helping the brain "rewire" itself [3].

The intranasal form, marketed under the name Spravato, allows for rapid absorption and is always administered under medical supervision.

2. Why is Esketamine Used for Depression?

2.1 Treatment-resistant depression (TRD)

TRD is diagnosed when a patient does not respond adequately to at least two different antidepressants, taken at proper doses and duration [4]. Esketamine is specifically indicated for TRD because of its rapid onset of action, often showing improvement in mood within hours or days, compared to weeks with traditional antidepressants.

2.2 FDA and EMA approvals

• 2019: FDA approved esketamine nasal spray in combination with an oral antidepressant for adults with TRD [5].
• 2020: EMA approved esketamine across Europe for TRD.

2.3 Unique benefits

• Works on a different neurotransmitter system (glutamate).
• Provides rapid relief, especially useful in patients with suicidal ideation [6].
• Can help restore function in patients who have failed other treatments.

3. How Safe is Esketamine Nasal Spray?

Safety is a central concern when introducing any new psychiatric medication. Research over the past decade has provided a growing body of evidence about esketamine’s short-term and long-term safety.

3.1 Common side effects

Most side effects are transient, peaking within hours after dosing and resolving the same day [7]:

• Dizziness
• Dissociation or “out-of-body” feeling
• Sedation
• Nausea
• Increased blood pressure

3.2 Serious risks

• Blood pressure spikes: Esketamine can cause temporary increases in blood pressure, so patients with uncontrolled hypertension require close monitoring [8].
• Cognitive effects: Dissociation and perceptual disturbances may impair driving or operating machinery.
• Abuse potential: Esketamine is chemically related to ketamine, which has a history of recreational misuse. This is why administration is strictly supervised in clinics.
• Long-term safety: Current data (up to 1 year of follow-up) suggest esketamine is generally well tolerated with no evidence of brain damage or addiction when used as prescribed [9].

3.3 Safety monitoring requirements

Because of these risks, patients:

• Must be monitored for at least 2 hours after dosing.
• Cannot take the spray home—it’s always administered in a certified clinic.
• Require periodic assessment of blood pressure, mental state, and overall functioning [10].

4. Doctors365 and Esketamine Consultations

At Doctors365.org, patients seeking psychiatric help—including for TRD—can connect with experienced specialists who can guide them through evaluation, diagnosis, and personalized treatment options.

Featured specialists in psychiatry:

• Dr. Dejan Dimitrijevic – Psychiatry and Psychology (Book here)
• Dr. Gorica Djokic – Psychiatry, Psychology, Neurosurgery and Neurology (Book here)
• Dr. Zoran Pavlovic – Psychiatry and Psychology (Book here)

These doctors provide online consultations to:

• Assess eligibility for treatments like esketamine.
• Manage ongoing depression care.
• Provide therapy and lifestyle guidance alongside medication.

How Doctors365 works:

1. Browse: Find a psychiatrist or psychologist.
2. Pick a time: Choose a slot that suits you.
3. Confirm & pay: Secure and transparent pricing.
4. Attend visit: Confidential and encrypted video consultation.
5. Get summary/prescriptions: Receive treatment guidance and follow-up.

5. Benefits of Online Care for Depression

• 24/7 availability: Book consultations at your convenience.
• Privacy: Speak from home, reducing stigma.
• Convenience: No travel or long waiting lists.
• Cost savings: Lower than traditional in-person visits.

6. What’s Online-Appropriate vs In-Person?

Suitable for online consultations:

• Follow-up visits.
• Monitoring side effects.
• Psychoeducation and therapy.
• Discussing suitability for advanced treatments like esketamine.

Requires in-person or emergency care:

• Active suicidal intent or plan.
• Severe psychosis or mania.
• Uncontrolled hypertension.
• Allergic reaction or severe side effects.

If you ever experience worsening suicidal thoughts, please do not wait for an online consultation—seek emergency care immediately.

7. Pricing & Availability

Doctors365 offers transparent pricing:

Appointments are available throughout the week with psychiatrists like Dr. Dimitrijevic, Dr. Djokic, and Dr. Pavlovic and many other doctors.

8. Practical Tips for Preparing for an Online Consultation

• Write down symptoms: Mood, sleep, appetite, suicidal thoughts.
• Medication history: List all antidepressants tried.
• Side effects log: Track reactions to current medication.
• Private setting: Choose a quiet, confidential space.
• Stable internet: Ensure connection for video consultation.

9. Conclusion

Esketamine nasal spray represents a safe and innovative option for patients with treatment-resistant depression, provided it is used under strict medical supervision. While it carries some risks—such as blood pressure changes and dissociation—its benefits for rapid symptom relief in severe depression are well documented.

If you or someone you know is struggling with depression that has not responded to traditional medications, consider booking an online consultation with a Doctors365 psychiatrist.

Find a psychiatrist today

10. FAQs

1. How quickly does esketamine work?
Some patients notice improvement within hours, while most respond within 1–2 weeks [6].

2. Is esketamine addictive?
When used under supervision, esketamine has a low risk of addiction. Unlike recreational ketamine, it is tightly regulated [9].

3. Can esketamine replace antidepressants?
No. It is prescribed with an oral antidepressant for better results [5].

4. How often do you need treatments?
Initially twice weekly, then reduced to once weekly or less depending on response [7].

5. Who should avoid esketamine?
Patients with uncontrolled hypertension, history of aneurysms, or severe substance use disorder may not be suitable [8].

11. References

1. World Health Organization. Depression [Internet]. 2023 [cited 2025 Sep 30]. Available from: https://www.who.int/news-room/fact-sheets/detail/depression
2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps. Am J Psychiatry. 2006;163(11):1905–17.
3. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338(6103):68–72.
4. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37(2):134–45.
5. U.S. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression [Internet]. 2019.
6. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–48.
7. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray plus oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–38.
8. Wajs E, Aluisio L, Morrison RL, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: safety of long-term treatment. J Affect Disord. 2020;277:913–21.
9. Singh JB, Fedgchin M, Daly E, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intranasal esketamine in treatment-resistant depression. Int J Neuropsychopharmacol. 2016;19(7):pyw017.
10. Drevets WC, Popova V, Musliner KL, et al. Placebo-controlled study of the safety of esketamine nasal spray in treatment-resistant depression. Int J Neuropsychopharmacol. 2022;25(1):57–66.