Esketamine for treatment-resistant depression

By The Health News Team | September 11, 2025

Therapist writing notes during a session with a patient

Depression is a serious medical condition that is more common than people realize. In fact, according to the National Institute of Mental Health (NIMH), major depressive disorder (MDD) affects over 8% of U.S. adults.

There are many ways depression is treated, varying from talk therapy to medication, and treatment options are often combined to improve results. If patients are unresponsive to two or more of these treatments, an intranasal spray, known as esketamine, is a relatively new treatment option that care teams may consider.

Esketamine, which was approved by the Food & Drug Administration (FDA) in 2019, is a safe, very low dose of ketamine — a powerful anesthetic — proven to reduce symptoms of severe depression. It is also known under the brand name Spravato™.

“Esketamine is considered for patients who may not respond positively to traditional treatments, such as oral antidepressants and talk therapy,” says Dr. Brian Miller, medical director for Sharp Grossmont Hospital for Behavioral Health.

Answers to your top questions about esketamine

Several misconceptions surround the use of esketamine in the treatment of severe depression. While esketamine has been proven to be an effective medication, common questions and concerns remain, including:

How does it work?

The fast-acting drug is thought to affect neurotransmitters in the brain, restoring synapse connections that are disrupted during major depressive disorder.

Research has shown that supervised use of esketamine may also help reduce suicidal thoughts. The effects are felt almost immediately, as opposed to the several weeks it may take to feel significant relief from antidepressant medications.

Who is eligible for the treatment?

The intranasal spray can be prescribed to patients with major depressive disorder who have not responded positively to at least two other antidepressant treatments. Individuals may not be eligible, and should talk with their doctor, if they are pregnant, had a previous negative response to esketamine, have hypertension or heart disease, or have a history of substance abuse or psychosis.

How is it administered?

Esketamine is not administered by patients, it is available at approved and certified treatment centers, under the supervision of a clinician.

Why is it controversial?

Esketamine in higher doses has been known to be used as a recreational drug and can produce hallucinations and other potentially harmful side effects. However, the approved therapeutic dose of esketamine (the FDA-approved intranasal spray) is much smaller, although not without side effects, which can include dizziness, drowsiness and elevated blood pressure.

The most serious side effects include dissociative or “out-of-body” episodes very shortly after taking the drug, which is why it will be administered under supervision in a licensed facility.

Is esketamine addictive?

While clinical trials tested the safe use of esketamine for depression for up to one year, its effect over a longer period was not tested.

Talk with your doctor if you are experiencing symptoms of severe depression or other mental health concerns. Together, you can determine the appropriate treatment options available to you.

Call or text the 988 Suicide & Crisis Lifeline at 988 if you are having thoughts of suicide and need help. Learn more about mental health services at Sharp HealthCare.

The Health News Team

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The Sharp Health News Team are content authors who write and produce stories about Sharp HealthCare and its hospitals, clinics, medical groups and health plan.