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Esketamine for Treatment-Resistant Depression

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There’s good news for people with severe treatment-resistant depression: Esketamine is a groundbreaking therapy that can provide relief from major depression within hours. “For the first time in 60 years, we have a new antidepressant therapy that isn’t just a spinoff of existing drugs,” says Adam Kaplin, M.D., Ph.D., a psychiatrist with Johns Hopkins Medicine. “For some people, esketamine therapy is revolutionary, giving them the chance to experience life without depression for the first time in decades.

What is esketamine?

Esketamine is made from a drug called ketamine, an anesthetic that has also been used for many years to treat depression. But it wasn’t until recently that esketamine, a more potent version of ketamine, earned FDA approval specifically for use as a nasal spray for those with treatment-resistant depression.

Esketamine is derived from part of the ketamine molecule,” says Kaplin, who has studied the drug for three years. “Because it’s more potent, you can use it at a lower dose and theoretically have fewer side effects. Now that it’s available in an intranasal version and approved by the FDA, it’s more likely that insurance companies will cover the treatment.

What is esketamine treatment like?

Esketamine, like ketamine, has the potential to distort your perception during the first two hours after treatment, so it has to be administered in a clinic setting. Treatment for esketamine nasal spray is done on an outpatient basis.

With the nasal spray, you give yourself three doses, spaced five minutes apart, under doctor supervision. You remain in the clinic under doctor observation until potential side effects have passed.

Esketamine must be used in conjunction with a conventional antidepressant. The intention is that esketamine provides rapid relief from depression symptoms until the other medication takes effect.

Who is a good candidate for esketamine therapy?

Currently, esketamine is approved for people with treatment-resistant depression. That means you’ve tried at least two other antidepressants (for at least six weeks each) and haven’t experienced remission or at least a 50% improvement in mood.

For people who haven’t had success with other antidepressants, esketamine gives them the chance to see what it’s like to not have depression,” says Kaplin. “It gives them hope that they can feel better with the right treatment.

How does esketamine treat depression?

Esketamine, and its related drug ketamine, are highly effective depression treatments for a number of reasons:

Esketamine’s antidepressant function works through a different mechanism than other drugs. Conventional antidepressants increase levels of naturally occurring chemicals such as serotonin, norepinephrine and dopamine. These chemicals are messengers that relay communication between brain cells. The theory is that having greater quantities of these neurotransmitters allows for better communication between brain cells and positively affects mood.

Esketamine works in a similar fashion, but unlike other antidepressants it increases levels of glutamate, the most abundant chemical messenger in the brain. The result? A greater impact on more brain cells at one time.

People with Depression Get Rapid Relief

Common antidepressants are slow-acting. It often takes several weeks to make a noticeable difference in how people with depression feel, says Kaplin. On the other hand, esketamine immediately impacts brain cells, offering relief from depressive symptoms within hours.

Esketamine Decreases Suicidal Thoughts

Conventional antidepressants may actually increase suicidal thoughts at the beginning of treatment, especially in children and young adults. Esketamine is the only drug besides lithium, a drug commonly prescribed for bipolar disorder, that’s proven to decrease suicidal thoughts, says Kaplin. Although esketamine isn’t currently approved for this purpose, the FDA is considering it.

It’s Effective for Treatment-Resistant Depression

Up to 33% of people with depression don’t respond to multiple kinds of conventional antidepressants. Esketamine reduces depression symptoms in a majority of these people in clinical trials.

The only other approved drug therapy for treatment-resistant depression is a combination of olanzapine (an antipsychotic drug) and fluoxetine (a conventional antidepressant). However, this treatment has significant long-term effects that include substantial weight gain, metabolic changes, diabetes and high blood pressure.

Esketamine Helps the Brain Form New Connections

Research suggests that untreated depression causes long-term brain damage and is a risk factor for dementia. Studies show that people with depression have up to 20% shrinkage of the hippocampus, a region of the brain critical for memory and learning. But esketamine may counteract the harmful effects of depression.

Animal studies indicate that connections between brain cells diminish under chronic stress, but esketamine reverses these stress-related changes. “Esketamine is different than any other antidepressant in that it not only prevents the neurotoxic effects of depression on the brain, but it also seems to have a growth-promoting effect,” explains Kaplin.

Does Esketamine Have Side Effects?

People can experience a wide range of side effects from esketamine therapy. The most dramatic are hallucinations and feeling disconnected from yourself or reality. However, side effects tend to peak at 40 minutes and wear off within two hours of treatment.


You can expect the most intense side effects during the first two treatments. Symptoms usually lessen after that. Other side effects may include:
  • Nausea
  • Drowsiness
  • Increased blood pressure
  • Feeling drunk
  • Headache

If you feel treatment for depression isn’t working, talk to your psychiatrist to see if esketamine therapy is an option for you.


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