Developed in the early 1960s, ketamine first gained popularity as a battlefield anesthetic for wounded soldiers.
By the mid-1980s, it had achieved a second life as a club drug, due to its trippy, psychedelic effects and the accompanying sense of euphoria achieved by snorting an illicit powder version.
Now, a variant of the chemical, esketamine, has found a third incarnation as an antidepressant nasal spray from Janssen, the pharmaceutical division of the health-products giant Johnson & Johnson that won approval March 5 from the Food and Drug Administration.
It was a decision greeted with enthusiasm as well as skepticism. While it marks the first new depression treatment since the class of drugs like Paxil and Prozac that boost serotonin, a chemical that generates a sense of well-being, safety advocates worry it wasn’t studied thoroughly enough.
Doctors who specialize in ketamine treatments for post-traumatic stress disorder, on the other hand, say it suppresses some of the therapy’s most important benefits.
Esketamine is based on S-ketamine, one half of the mirror-image molecules that make up ketamine and the piece believed to be less prone to causing hallucinations or dream-like states, according to the National Institutes of Health. The medication is believed to work by modulating neurotransmission receptors to restore communication between brain cells, according to Janssen.
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Because of its history and the potential for abuse, the FDA approved its use only for people with treatment-resistant depression, those who have tried at least two other antidepressant medications without success.
Each spray — marketed under the brand name Spravato — must be administered in medical offices where healthcare personnel can monitor reactions for at least two hours, and patients aren’t allowed to take it home, according to Janssen and the FDA.
In clinical trials, one of which measured effects on 1,700 adults, “We saw this therapy provide sustained improvement to patients with treatment-resistant depression,” said Dr. Michael Thase, a professor at the University of Pennsylvania’s School of Medicine who has served as a paid consultant to Janssen.
“When I began treatment with esketamine and my symptoms started to lift, I could see very clearly just how depressed I had been,” said one clinical trial participant cited by Janssen who described feeling emotionally numb before therapy began. “My long-term goals have taken shape and actually seem attainable.”
But the FDA’s decision to grant esketamine its “Fast Track” and “Breakthrough Therapy” designations, which are designed to bring new drugs addressing serious unmet medical needs to patients more quickly, raised questions for MedShadow Foundation founder Suzanne Robotti.
“With the severity of depression and suicide, and increases in suicide over the past few years, I can understand why doctors are reaching for any tool that might work,” Robotti, whose organization educates patients on the risks and benefits of medicines, told the Washington Examiner.
Fast-tracking should nonetheless be rare, she added, given the frequency with which significant side effects are discovered after a medication receives regulatory approval.
“It’s not like the drug hasn’t been around for a while,” having had decades of use both in surgeries and the club scene, said Robotti, who was named to the FDA’s Drug Safety and Risk Management Advisory Committee as a consumer representative in 2017. “Just because people like to party with it doesn’t really make it a remedy for depression. People like to party with alcohol, and it’s a well-known depressant.”
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On the flip-side, esketamine’s suppression of the psychedelic effects of ketamine may deprive patients with the most severe depression of one of the treatment’s best benefits, said Dr. Carl Bonnett, medical director at Klarisana, which operates clinics in the southwestern U.S. that offer ketamine infusions.
Each of the treatments administer ketamine intravenously for an hour, during which the patient is monitored by a medic and may talk with a therapist as well.
The transpersonal effects of the drug, which allow patients to mildly disconnect from themselves in a clinical setting, can give a “different perspective of yourself and the way you relate to your world,” said Bonnett, who served 20 years in the Army National Guard, including deployments in Afghanistan and during the Iraq war.
That change in perception can be crucial for PTSD sufferers such as rape survivors or combat veterans, and it’s a “huge part of the treatment,” he said.
“If you accept the premise that the creative experiential psychedelic experience actually leads to a transformational idea where you change your perspective and your view of the problem, then that is very disruptive,” he said, and counter to the purely biomechanical approach of a nasal spray like esketamine.
He likened the difference to ordering jalapeno poppers at a restaurant, but taking out the jalapenos. “What are you left with?” he asked. “You’re getting rid of the thing that does it.”
