Treating Depression With Ketamine: What We Know

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About 17 million Americans suffer from clinical depression, and of these, about a third—5 to 6 million—can't get sufficient relief from antidepressant medication. If you have tried two different antidepressants without success, you may have what's called treatment-resistant depression. Recently, a new treatment became available for this condition based on ketamine, an anesthetic that is sometimes used illegally as a party drug (‘Special K’) due to its hallucinogenic properties. Doctors found it can relieve serious depression symptoms—sometimes in a matter of hours or days.

How does ketamine depression treatment work?

If you have depression, you've likely been treated with medications called SSRIs (selective serotonin reuptake inhibitors), which include Paxil, Prozac and Lexapro, among others. These drugs work by boosting a brain transmitter known as serotonin, which is thought to help relieve depression. Other types of conventional antidepressants work on different brain transmitters. However, it can take four to six weeks or more for such drugs to take full effect. That timing is not helpful if you or a loved one is considering suicide or so depressed you can't work. About a third of depressed people don't respond to these treatments at all.

Enter ketamine. The 50-year-old anesthetic drug has been found to rapidly—sometimes within hours—lift patients out of depression. Ketamine works differently than common antidepressants by targeting the glutamate system, thus reactivating brain circuits hobbled by depression. The drug also appears to use opioid pathways, which has led some researchers to fear its use could lead to addiction in susceptible patients.

Nonetheless, bolstered by research showing ketamine's effectiveness, ketamine clinics have popped up around the United States in the past few years, providing the drug (usually intravenously) to people with depression, as well as other conditions, such as chronic pain and post-traumatic stress disorder.

Doctors—often anesthesiologists or pain specialists—provide ketamine on an ‘off-label’ basis to treat depression. Off-label use is a common way doctors can legally provide drugs not specifically approved by the FDA (U.S. Food and Drug Administration) to treat a particular condition.

In March 2019, a newer form of ketamine, called esketamine, was approved by the FDA to treat people with treatment-resistant depression. Esketamine (brand name Spravato) is two to five times more potent than ketamine, and is delivered through nasal spray, rather than intravenously.

In approving esketamine, the FDA required that:

  • It is given only to people with treatment-resistant depression.
  • It is taken only at a certified doctor's office or clinic, with patients administering it themselves under supervision.
  • Patients are monitored for at least two hours afterward for side effects.
  • Patients must make arrangements to be taken home, since they may be sleepy the rest of the day.
  • The drug is taken in conjunction with an oral antidepressant that the patient hasn't already tried.

What are esketamine and ketamine depression treatment results?

Studies have found both ketamine and esketamine can lift treatment-resistant depression in as little as two hours in some people. This includes shutting down suicidal urges strong enough to require hospitalization.

A Yale study found 70% of patients with treatment-resistant depression who were given esketamine plus an oral antidepressant improved, compared to just over half who did not receive the esketamine. Researchers found more than half of treatment-resistant participants showed significant improvement in just 24 hours.

Because esketamine is so new, researchers are still studying how long its effects might last. One study funded by the drug's manufacturer, Johnson & Johnson, found that after 16 weeks, those who took esketamine plus an antidepressant were 51 to 70% less likely to have experienced a depression relapse than those on a placebo and antidepressant. Another study found that after 74 days, 65% of people taking esketamine remained significantly less depressed than before taking the drug.

However, critics point out that two of the three clinical trials used to obtain FDA approval showed the drug did not perform better than a placebo. Researchers both in the United States and in other countries continue to study esketamine and ketamine results in clinical trials.

Concerns over ketamine treatment costs and side effects

Both ketamine and esketamine are costly treatments. Ketamine is less likely to be covered by insurance than esketamine, due to its FDA approval.

A round of IV ketamine for depression costs $400 to $800. Typically, someone with depression might be given four to six treatments over a couple of weeks. Your bill, then, might range from $1,600 to $4,800. People who are helped by the drug also may continue to have maintenance doses periodically after the initial treatments.

Esketamine (Spravato) costs from $590 to $885 per session. A typical regimen for someone with treatment-resistant depression might involve two doses per week for a month, followed by fewer doses in subsequent months. This price tag covers only the drug, not necessarily the office cost for supervision and monitoring. However, because of its FDA approval, it may be covered all or in part by insurance.

Side effects are another issue. Both drugs can create feelings of dissociation, or "out of body" experiences, though these usually are less pronounced after the first one or two treatments. In a study comparing esketamine plus an antidepressant to a placebo plus an antidepressant in 568 patients with treatment-resistant depression, people taking esketamine were more likely to report dissociation, dizziness, nausea and feeling sleepy, among other effects.

Ketamine can cause increases in blood pressure and heart rate during the time the drug is active, as well as such temporary effects as anxiety, blurred vision or other perceptual disturbances, dizziness, headache, nausea or vomiting.

Researchers also are exploring the possibility that patients may develop tolerance to the drug, so that over time, you would need to take increasing amounts to achieve the same effect. If you have a history of substance use disorder, ketamine also may not be the best choice for you, as you may be more susceptible to its possible addictive properties. Your mental health professional is the best resource to help determine if ketamine—or its cousin, esketamine—is an appropriate treatment to help relieve your depression.

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Medical Reviewer: William C. Lloyd III, MD, FACS
Last Review Date: 2020 Jun 2
  1. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. U.S. Food & Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
  2. New Research: Ketamine Activates Opioid System to Treat Depression; Experts Caution Against Widespread Use Due to Potential for Tolerance, Abuse and Dependence. American Psychiatric Association. https://www.psychiatry.org/newsroom/news-releases/new-research-ketamine-activates-opioid-system-to-treat-depression-experts-caution-against-widespread-use-due-to-potential-for-tolerance-abuse-and-dependence
  3. Efficacy, Safety of Long-Term Ketamine Administration Still In Question. Psychiatry Advisor. https://www.psychiatryadvisor.com/home/depression-advisor/efficacy-safety-of-long-term-ketamine-administration-still-in-question/
  4. Abdallah CG, De Feyter HM, Averill LA, et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 2018;43(10):2154‐2160. doi:10.1038/s41386-018-0136-3
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  6. Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
  7. Ketamine for major depression: New tool, new questions. Harvard Health Publishing/Harvard Medical School. https://www.health.harvard.edu/blog/ketamine-for-major-depression-new-tool-new-questions-2019052216673
  8. Highlight: Ketamine: A New (and Faster) Path to Treating Depression. National Institute of Mental Health. https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treating-depression.shtml
  9. How New Ketamine Drug Helps with Depression. Yale Medicine. https://www.yalemedicine.org/stories/ketamine-depression/
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  12. Key Substance Use and Mental Health Indicators in the United States: Results from the 2018 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHNationalFindingsReport2018/NSDUHNationalFindingsReport2018.pdf
  13. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial [published online ahead of print, 2019 Jun 5]. JAMA Psychiatry. 2019;76(9):893‐903. doi:10.1001/jamapsychiatry.2019.1189
  14. J&J’s new esketamine drug for depression may solve an unmet need, but may not be cost-effective. StatNews. https://www.statnews.com/pharmalot/2019/03/22/antidepressants-cost-effective-johnson-and-johnson/
  15. Opinion: The New Ketamine-Based Antidepressant Is a Rip-off. Vice. https://www.vice.com/en_us/article/pajkjy/opinion-the-new-ketamine-based-antidepressant-is-a-rip-off
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