This week, the Food and Drug Administration approved Johnson & Johnson’s Spravato, the nasal spray version of a ketamine-like sedative, for certain cases of depression. And the drug is already being heralded as a “game-changer” for depression and suicide treatment. But chief among the major questions the average person might have about the new drug is: Who exactly will it be for?
For starters, it’s important to sum up why people are so excited about Spravato in the first place. As things stand currently, the oral antidepressants we have available largely work on a basic principle: People with clinical depression tend to have lower levels of the neurotransmitter serotonin than the general public, and these drugs can boost those levels. Some antidepressants boost other neurotransmitters too, such as norepinephrine, (and newer ones do so with fewer side effects) but serotonin remains a major focus.
But not everyone with depression responds to these drugs or other treatments, like psychological counseling; still others can build up a tolerance over time. As a result, a third or more of patients with depression are considered treatment-resistant. That’s where ketamine, or in this case, esketamine, comes in.
Since it was discovered in the 1960s, high doses of ketamine have been used as a sedative for animals and people. More infamously, in smaller doses, it can also be used as a trance-inducing and hallucinogenic recreational drug, with colorful nicknames like Special K or Vitamin K. But starting in the 2000s, researchers began finding evidence that very small doses of ketamine could also help people with depression and suicidal thoughts—and in a different way than how other antidepressants work.
Rather than targeting serotonin, ketamine inhibits receptors coded to N-methyl-d-aspartate, or NMDA. NMDA in turn interacts with glutamate, an essential neurotransmitter that helps nerve cells communicate with one another quickly. Research has shown people with depression also tend to have an overabundance of glutamate, though, so it’s likely that ketamine relieves symptoms in part by stabilizing that activity. NMDA and glutamate probably aren’t the only things in the brain that ketamine is influencing for the better, but the important part is that it’s attacking depression from a fundamentally different angle than any other drug we have available.
It’s not just the novelty of ketamine that makes its potential so huge, though. Unlike other antidepressants, its positive mood-boosting effects takes days or mere hours to happen, not weeks of sustained treatment. It even seems to quickly nudge some people away from suicidal ideation, something that could be a godsend for those in the middle of a crisis.
In short, ketamine and ketamine-based drugs like Spravato give people who haven’t responded to other antidepressants a new, fast-acting option. The new drug may help people like 68-year-old Jeff, who asked that his last name not be used to protect his medical privacy. Jeff received the traditional infusion ketamine therapy as a part of a study run at Mount Sinai Hospital in New York in 2017.
“The next morning after my first infusion, I was entirely free of depression. I had never experienced that ever before. It was like being able to see for the first time,” he told Gizmodo. Prior to his ketamine treatment, Jeff said he had taken 20 drugs to manage his depression and other conditions, including alcohol use disorder, sometimes as many as seven at once.
Jeff fits the criteria of people for whom Spravato is approved: Patients who have failed to respond to at least two oral antidepressants for their current depressive episode. But use of the drug will be heavily regulated from the get-go.
Per the FDA, the drug will be only available to take at clinics or medical offices certified to distribute it (and has to be taken with another oral antidepressant). In addition, patients and doctors will have to sign a form acknowledging the risks of the drug, which include disorientation, high blood pressure, and an out-of-body feeling we call dissociation. While patients will self-administer the nasal spray, they’ll be monitored for at least two hours before being allowed to leave, and they’ll be asked to not drive or operate heavy machinery for at least a day. The drug might also not be safe for developing fetuses, so women are asked to consider using contraception while taking it; they also should avoid breastfeeding if they’re already nursing a child.
Jeff’s experience, as freeing as it was, also highlights the complexity of depression treatment, even with ketamine in the picture. Echoing many other self-reports, he did experience a trippy feeling within the first hour of getting infusions. But ultimately, it wasn’t the side effects that dissuaded him from continuing to take the drug after the study ended—it was the short-lasting nature of his relief.
People on ketamine typically receive infusions twice or once a week over a period of several weeks, and a similar structure has been set in place for people taking Spravato. They can then either end the sessions if they no longer need them or continue weekly maintenance doses. Jeff felt that he would need to use ketamine forever, a decision he didn’t feel comfortable with. And he’s not alone. A significant percentage of patients don’t respond well enough to ketamine to no longer need treament. Older people like Jeff are even less likely to benefit enough from it, a reality that was affirmed in clinical trials of Spravato.
That’s not a fatal blow to Spravato, though, according to John Mann, a neuroscientist at Columbia University who has studied the effects of ketamine and runs Columbia’s own ketamine clinic.
“Look at every drug that’s ever been approved, whether it’s for cancer, heart disease, or anything else. None of these drugs will help every single person get better,” Mann told Gizmodo. “But the research out there suggests that the proportion of people who benefit from ketamine might be higher than existing antidepressants currently.”
Gizmodo spoke to Mann shortly before Spravato’s expected approval. He said that in the event of its approval, Columbia’s clinic would incorporate the nasal spray as an alternative option to the infusion, a trend that other clinics will follow.
One major challenge for people previously seeking ketamine has been the large costs they had to pay out-of-pocket, since its use for depression was off-label and rarely covered by insurance. According to NPR, the wholesale costs of Spravato are roughly in line with what people have been paying for ketamine infusions, ranging from $590 to $885 per dose. But insurance coverage and patient rebates should drive down the out-of-pocket costs of the spray for a significant chunk of patients (That said, it’s worth noting that ketamine itself, having existed since the 1960s, is a generic drug, meaning a nasal spray version specifically derived from that would likely be much cheaper).
As for Jeff, he’s now taking electroconvulsive therapy (ECT), another avenue that has increasingly shown promise for people with treatment-resistant depression, to manage his symptoms. For him, ECT has been as every bit as helpful as taking ketamine was, but requires much less upkeep. Despite his own journey with ketamine though, he was nothing but excited about Spravato’s then expected approval.
“I’m absolutely delighted it will be available,” he said. “The more options we have out there, the more people will get the help they need.”