Can Esketamine Nasal Spray Treat Depression?

Updated Jul,2022
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Esketamine is an NMDA (N-methyl-D-aspartate) receptor antagonist used to treat adults with treatment-resistant depression (TRD). Esketamine comes as a nasal spray and is said to rapidly reduce suicidal ideations and depressive symptoms.

Approved by the U.S. Food and Drug Administration (FDA) in March of 2019 to treat TRD, esketamine nasal spray must be used in conjunction with an oral antidepressant. It is the first FDA-approved psychedelic medicine and the second drug approved to treat TRD.

As many as two-thirds of people with depression do not respond to the first medication prescribed and are considered to have TRD. TRD is a term used to describe depression that has failed to respond to at least two different antidepressants.


Esketamine nasal spray is approved for use in adults 18 and over, in conjunction with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI). To be considered for this treatment, patients must have tried at least two other antidepressants without success.

Most oral antidepressants need weeks or even months to take effect. Clinical trials suggest that esketamine nasal spray can significantly reduce symptoms in as little as 24 hours.

Esketamine vs. Ketamine

Esketamine is derived from ketamine, a powerful anesthetic and popular "club drug." Though both drugs have similar makeup (ketamine is a mixture of two mirror-image molecules, and esketamine is one of those molecules), esketamine is more potent.

Clinical Drug Trials

Esketamine effectiveness was evaluated in three short-term (four weeks) studies, one maintenance study, and a long-term safety study. Two of these studies demonstrated that esketamine rapidly reduces depressive symptoms in people with TRD.4

One was a short-term trial involving adults under age 65 who were started on an oral antidepressant and intranasal esketamine. After one month, roughly 70% of patients (compared to just over half in the placebo group) who received esketamine saw at least a 50% reduction in depressive symptoms.

The other positive study was the maintenance study that assessed relapse prevention. Data from this trial showed that esketamine reduces relapse rates. Specifically, those treated with esketamine nasal spray plus an oral antidepressant had a 50% to 70% lower risk of relapse than patients who only received an oral antidepressant.

More research is still needed to determine the optimal dosing, assess other possible side effects, and establish the safety of esketamine in the longer term.

Before Taking

Esketamine should never be used as a first-line of treatment. Instead, it is intended for individuals with TRD, meaning they have had adequate trials of two other antidepressant medications first and didn’t experience relief.

Precautions and Contraindications

Esketamine is not appropriate for everyone. You should not take esketamine if you are allergic to esketamine or ketamine, or if you have or have had any of the following medical conditions:

  • A blood vessel disease (aneurysm)
  • A history of bleeding in the brain
  • An abnormal connection between your blood vessels (arteriovenous malformation)

You should also talk to your doctor if you have ever had:

  • A family history of depression
  • Alcoholism or drug addiction
  • Brain injury or any condition where there is increased pressure in the brain
  • Heart attack or stroke
  • Heart valve disease or heart failure
  • High blood pressure
  • Liver disease
  • Mental illness or psychosis
  • Slow or fast heartbeats that cause shortness of breath, chest pain, lightheadedness, or fainting
  • Suicidal thoughts or actions

Esketamine may cause fetal harm and women who are pregnant or considering becoming pregnant should talk to their doctors. Women should not breastfeed while undergoing treatment.

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