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The Party Drug That Could Help Stop Depression

The anesthetic ketamine receives official FDA approval to treat depression. Is the tradeoff worth it?

Credit: Florian Gaertner/Getty Images Plus

TThe U.S. Food and Drug Administration (FDA) on March 5 approved a form of ketamine to be prescribed for treatment-resistant depression. The drug, called esketamine, is administered as a nasal spray and is the first version of ketamine to be cleared to treat depression. It’s also the first new type of antidepressant drug since Prozac was released over 30 years ago. Many psychiatrists and pharmacists see the ruling as a win for desperate patients with few options, but others have raised concerns about the drug’s possibly serious side effects and have questioned its efficacy.

“On the whole, I think they made the right choice,” says Richard Friedman, a professor of psychiatry at Weill Cornell Medical College who was not involved in the decision. “This is a group of people who are really ill and for whom there are limited therapeutics. There’s no question ketamine has antidepressant efficacy, and it’s a new target.”

Esketamine will be sold under the brand name Spravato and is made by Janssen Pharmaceutical Company, a subsidiary of Johnson & Johnson. “Because of safety concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient,” said Dr. Tiffany Farchione, acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research in a statement.

The FDA said that people who take the drug must be monitored by a health care provider for at least two hours after receiving it. Patients cannot take the spray home.

An estimated 30 to 40 percent of people with depression fail to respond to traditional antidepressant drugs like Prozac (a selective serotonin reuptake inhibitor or SSRI) and Cymbalta (a serotonin-norepinephrine reuptake inhibitor or SNRI), classifying them as “treatment resistant.” These patients have few alternative options, as all current antidepressants act on the same three neurochemicals: serotonin, dopamine, and norepinephrine. Ketamine, by contrast, acts on an entirely different pathway: the glutamate system, which is the brain’s primary excitatory neurochemical and is involved in learning.

Scientists aren’t exactly sure how ketamine acts as an antidepressant, but it may do so by increasing the number of connections, or synapses, between cells in the brain, particularly in the prefrontal cortex. Stress and depression degrade these connections, and ketamine could reverse the damage, regrowing the lost synapses. “It’s like fertilizer in the brain,” says Friedman.

There’s no question ketamine has antidepressant efficacy, and it’s a new target.”

The first study of ketamine as an antidepressant was published in 2000, with a single dose of the drug dramatically improving depression symptoms in a majority of people. A rush of clinical trials followed, in addition to the opening of ketamine clinics where doctors provide people with the drug off-label. On an anecdotal basis, the drug has proven remarkable, with suicidal people reporting that the drug saved their lives.

Researchers, though, are much more measured. “I think any hope that this is a new wonder drug should be tamped down,” says Steven Meisel, director of medication safety at Fairview Health Services and a member of the FDA advisory committee that initially recommended ketamine. “This is a drug that will benefit a minority of people greatly, and a majority of people not at all. For those it does help, it could be dramatic, but it’s going to be a minority.”

In its review, the FDA evaluated esketamine based on five clinical trials presented by Janssen. However, only two of the studies showed significant positive results compared to a placebo. In one, roughly 53 percent of people who used esketamine twice a week for a month had a significant improvement in their depression scores, compared with 39 percent of people who took a placebo. The other study showed that people who initially responded to esketamine relapsed when they were switched to a placebo, whereas people who remained on the drug did not.

Many health professionals are concerned about ketamine’s notable side effects, particularly the ones that gained it notoriety as a party drug. Ketamine was first developed as an anesthetic in the 1960s. By the 1990s, ketamine had become a popular club drug for its dissociative qualities. At high doses, people are so sedated they become out of touch with their surroundings, feel unable to speak or move, and can start to hallucinate — an experience often referred to as a “k-hole.” But if you’re not looking to get high, these psychoactive effects might be off-putting.

“This drug is known as a pretty nasty drug,” says Meisel. “One of the well-known side effects is what’s called dissociation, which means that you don’t feel a part of your body anymore, you feel like you’re in a different place. And that could be very troublesome for some folks.”

Other side effects include long-term changes in blood pressure and bladder problems. Ketamine also activates the opioid system in the brain, which has led many researchers and clinicians to worry about the drug’s potential for abuse.

Because of these concerns, as well as its side effects, the FDA committee recommended a strict risk mitigation plan for the drug. Ketamine will only be available at specialty pharmacies, clinics, and doctor’s offices, and it has to be administered on-site. The patient must wait for a minimum of two hours for the drug’s psychoactive effects to wear off before they can go home.

The FDA hopes the plan will help prevent ketamine from being abused by patients or diverted into the community for recreational use on the black market. But the need to visit a clinic for several hours every week will likely be a burden for many people and could limit access for people who live in more rural areas.

While the risk for side effects and abuse is not insubstantial, Meisel, Friedman, and the FDA believe the benefits outweigh them. People with treatment-resistant depression are 15 times more likely to attempt suicide than people without depression, so a new effective form of treatment could be a literal lifesaver. “The risk is there. On the other hand, the risk of untreated treatment-resistant depression is far greater. I mean, the risk of suicide is orders of magnitude higher in those people,” says Friedman. “So you’re balancing the risk and the benefit. The risk of the drug is real, but the risk of the untreated disease is far greater.”

Health and science writer • PhD in 🧠 • Words in Scientific American, STAT, The Atlantic, The Guardian • Award-winning Covid-19 coverage for Elemental

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