Staff Perspective: Is Ketamine a Cure for Treatment-Resistant Depression?

Staff Perspective: Is Ketamine a Cure for Treatment-Resistant Depression?

Did you know that approximately 25% of American adults living with depression don’t benefit or benefit very little from available depression treatments, including medications and psychotherapies?

This statistic makes me think about a Vietnam Veteran I treated at the San Francisco VA Medical Center who struggled with chronic depression and PTSD. The patient was a lovely man—that is the best way to describe him. He had a heart of gold and a tranquility about him, yet he was suicidal nearly all of the time. His treatment-resistant depression and suicidal thinking perplexed me because he was in a warm and loving relationship with a supportive wife of many years and had various interests and talents. For example, he enjoyed painting beautiful water colors of the outdoors that he shared with me. He also was an avid athlete and loved kite surfing, which he was apparently quite good at. He had worked in mortuary affairs when he served in the military. A few traumatic experiences in that role led to intense out-of-body experiences, which we came to realize were his way of coping with the horror he had witnessed.

On March 5, 2019, the US Food and Drug Administration (FDA) approved the nasal spray medication Spravato (esketamine) for treatment-resistant depression in adults like my patient, although he struggled with both chronic depression and PTSD. Some people are applauding this new medication as a much-needed shift from the era of antidepressants, including Prozac, Zoloft, and Paxil. “Finally, a drug that uses a different mechanism of action than these older antidepressants,” they cheer. Esketamine is a glutamate receptor modulator that is believed to help restore synaptic connections in a depressed person’s brain cells. Other critics are more skeptical, concerned it won’t be the panacea we’ve been looking for.

Spravato is a fast-acting drug derived from an old anesthetic, ketamine. In 1970, ketamine was approved as an anesthetic agent by the FDA and continues to be used for adult and pediatric anesthesia and analgesia. And yes, ketamine was a popular club drug known by one of its street names, "Special K," in the 1980s and 90s that produced out-of-body and hallucinogenic sensations.

Administered intravenously, ketamine has been and continues to be used to help patients with treatment -resistant depression in clinics around the country. In fact, it has been found to be generally helpful, safe, and well-tolerated. However, intravenously administered ketamine isn’t typically covered by insurance because it’s not an FDA-approved medication. So part of the hype around the new FDA-approved nasal spray is that it likely will be covered by insurance plans and hopefully will have more modest side effects.

Speaking of side effects, common ones identified so far from Spravato include dissociation, dizziness, nausea, sedation, anxiety, vomiting, decreased sensitivity, increased blood pressure, and others. Because of this, Spravato’s label warns that patients are at risk for sedation and problems related to attention, judgment, and thinking (dissociation), plus abuse and misuse and suicidal thoughts and behaviors after it is administered.

Given these potential adverse side effects, Spravato can only be obtained through a restricted distribution system under a Risk Evaluation and Mitigation Strategy (REMS). In a certified clinic, the patient self-administers the spray under a health care provider’s supervision, and he or she cannot take the spray home. The REMS also requires that patients be monitored for at least two hours (i.e., they must be safe before leaving the clinic to go home) and not drive or use heavy machinery that day. Spravato is recommended twice weekly for four weeks with boosters as needed, and it’s always used in conjunction with an oral antidepressant. (The FDA requires this).

But what about its effectiveness? Spravato was evaluated in three short-term (four-week) clinical trials and one longer-term maintenance trial prior to the FDA’s approval in March. It should be noted that, given the serious nature of treatment-resistant depression and the importance of patients receiving some type of treatment during the trials, they all started a new oral antidepressant at the time of randomization, which was continued throughout.

In two of the four studies, Spravato worked well. In other words, based on four trials, 50% of the time it helped the patients more than a placebo nasal spray. Specifically, one of the short-term studies showed a statistically significant effect as compared to the placebo nasal spray when assessing the severity of depression from baseline to post-treatment. Moreover, some positive effects were detected in just a few days. Additionally, in the longer-term trial, patients in stable remission or with a stable response who continued treatment with Spravato experienced a statistically significant longer time before relapsing (i.e., their depressive symptoms rebounded) than patients on the placebo nasal spray.

While the findings from these two trials are promising, clearly more research is needed on Spravato, especially on the long-term impact. Or will this medication serve a niche function as an acute treatment for a subset of depressed patients in crisis (e.g., patients at imminent risk for suicide) by providing them with rapid, temporary relief? Although a potential side effect of this medication may be suicidal thoughts and behaviors in a subset of individuals, esketamine is actually being studied to determine if it might promote fast symptom reduction in the short term for acutely suicidal individuals. For instance, it would be given to these patients as a lifeline while they waited for a standard antidepressant to kick in. Bloomberg Businessweek expounds that results from these studies may lead to an FDA filing for esketamine’s use in suicidal depressed patients in 2020. You can read this fascinating article at:

Yet how would this medication work for individuals like the Vietnam Veteran I treated who had co-occurring PTSD? Is PTSD a rule-out for using it? Spravato offers hope, but I’m eager to see more studies on it and to hear directly from patients if it is helping them and for how long.

Share your comments about using ketamine to treat depression in adults, including Veterans.

The opinions in CDP Staff Perspective blogs are solely those of the author and do not necessarily reflect the opinion of the Uniformed Services University of the Health Science or the Department of Defense.

Paula Domenici, Ph.D., is Director of Training and Education at the Center for Deployment Psychology at the Uniformed Servies University of the Health Sciences in Bethesda, Maryland.


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U.S. Food and Drug Administration. (2019, March 5). FDA approves new nasal spray medication

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