A primary care doctor at the University of Vermont Health Network will soon start treating depression with a mind-altering drug that's shown promise in helping people who don't respond to traditional medicine.

The medication — known as esketamine and sold by Johnson & Johnson under the brand name Spravato — is chemically similar to ketamine, a substance that's been used in medical settings as an anesthetic, on the streets as a party drug and, more recently, as an off-label treatment for mood disorders.

The U.S. Food & Drug Administration approved esketamine in 2019 as a fast-acting treatment for patients who have failed to find relief from at least two other antidepressants. It comes in a nasal spray that's prescribed in conjunction with a traditional antidepressant and must be taken under the supervision of medical professionals because it can cause dizziness, blood pressure spikes and psychedelic, out-of-body experiences. The manufacturer recommends starting patients on once- or twice-weekly treatments for the first two months and encourages doctors to use their best judgment from there.

Several providers already offer esketamine in Vermont, but its embrace by the state's largest health care network suggests that it could eventually become far more accessible here. That would be a welcome development for the many Vermonters whose hard-to-treat depression places them at greater risk for hospitalization or suicide.

But lingering questions about the drug's long-term safety and effectiveness — fueled by an FDA approval process that's been criticized by some researchers — has left certain providers wary. Among them: a group of nurses at the UVM-affiliated clinic that will soon start offering the drug.

In an interview last month, nurses at Primary Care — Middlebury expressed concern about their employer's decision to offer esketamine, citing, among many misgivings, the drug's unknown risks.

"We don't know if we're hitting folks with another addiction, much like we handed out an addiction to OxyContin and oxycodone," nurse Lynda Reiss said. "I would really hate to know that I've been partially responsible for starting another problem."

The doctor overseeing the new program, Natasha Withers, said she believes in the FDA and its process for reviewing and approving drugs. "We're really at the cutting edge of this, so we're not going to have all the answers," Withers said. "[But] we have to trust the systems that we have in place."

Esketamine was held up as a potential game changer several years ago when Johnson & Johnson sought approval. It was the first new type of drug for depression treatment since the launch of Prozac and related antidepressants in the late 1980s. Esketamine targets a different brain chemical, and it works much faster — sometimes within an hour, instead of the four to six weeks typical of older antidepressants.

Not everyone was convinced. Some experts, including a few on an FDA advisory committee, were dubious about the drug's effectiveness after reviewing the manufacturer's data. For instance, of the three randomized, double-blind trials that Johnson & Johnson conducted with esketamine, only one showed statistically significant improvements in patients' symptoms when compared to placebo treatments.

The company also did not disclose any information about the drug's safety for long-term use beyond 60 weeks. And it dismissed concerns raised after three patients killed themselves while receiving the drug; there were no suicides in the placebo groups. Nevertheless, the FDA approved the drug in 2019, determining that the unmet need for new depression treatments outweighed the potential risks.

Still, citing esketamine's potential for harm — including the risk of misuse and addiction — the FDA imposed a safety protocol that experts say is the most restrictive ever for an outpatient drug. It has two dozen requirements, including that clinics supervise patients for up to two hours and report any adverse effects directly to Johnson & Johnson.

Solid data on esketamine's efficacy have been hard to find even four years after its approval. A study last year found only "modest" results, while a more recent study in China concluded that the improvements patients saw in the 24 hours after their first dose were no longer evident after 28 days of treatment. Meanwhile, the stringent safety protocol poses logistical hurdles that have contributed to a slow nationwide rollout.

An informal survey of the handful of doctors currently certified to offer the drug in Vermont suggests that the 200 or so esketamine patients have had largely positive experiences.

Since 2019, roughly two-thirds of the 100 esketamine patients at Treatment Associates in Montpelier have reported a full remission of their symptoms within three months of their first treatment, according to providers there. The rest have shown at least some decrease in their symptoms, based on a metric used to gauge depression severity, while about a dozen or so patients haven't received any benefit (some stopped early because of side effects).

"These are people who are dysfunctional, curled up in bed, on disability. They can't maintain a relationship. They can barely get themselves out to do food shopping," said J.S. Stone, one of the psychiatric practice's doctors. "You get them on Spravato, suddenly their marriage is thriving again. They're ready to go back to work. They're interacting with their children appropriately."

Dr. Lance Thigpen has noticed similar life-changing effects in some of his patients at Brattleboro Retreat, which recently began accepting outside referrals to its own esketamine clinic after running a small-scale pilot program. Of the 27 patients enrolled to date, only three haven't reported a notable decrease in their depression symptoms. "Had I not seen with my own eyes the improvements, I would be pretty skeptical," said Thigpen, the medical director of outpatient services.

Over the past year in Chittenden County, about a dozen suicidal people seeking care through the UVM Medical Center emergency department have started on the medication. After their initial consultation, those patients have continued treatment with Dr. Hobie Fuerstman at Preventive Medicine in Colchester.

Lori Chater is one of them. During a visit to the ED in February for a mental health crisis, the 48-year-old was offered two options: hospitalization or esketamine. Chater had heard about the growing movement to repurpose psychoactive drugs for depression and was wary of the reaction she might have. But she had tried almost every other treatment imaginable, including other antidepressants and electroconvulsive therapy; she even had a device surgically implanted into her brain as part of an experimental Dartmouth-Hitchcock Medical Center study probing the merits of deep brain stimulation. Nothing worked. Desperate, she gave the esketamine nasal spray a shot.

Three months later, Chater has undergone a dozen treatments. Beyond a floating, out-of-body sensation she felt during her first treatment in the ED, the side effects have been pretty mild, she said. Meanwhile, she's feeling far better than she was back in the winter, when she could barely get out of bed some days.

"I feel like I come out of the treatments a different person," Chater said. "I'm calm. I'm relaxed. I'm more hopeful."

Withers, the Middlebury primary care doc, said she will start with a single patient, then will likely open treatment to the rest of the practice's patients before determining whether to accept referrals from other UVM-affiliated clinics. "We want to be thoughtful about it," she said.

Her nursing colleagues, who learned about her plan to offer esketamine at an all-staff meeting last fall, say they wish they had been consulted earlier. If they had, they said, they would have told her that they don't think a primary care clinic is a good place for the treatment.

"We are already not serving our patient base [well]," said nurse Hilary Hatch, noting that the practice has a sizable wait list for routine care such as annual physicals. "And now we're taking five or 10 [appointment slots] away a week for a single esketamine patient."

The nurses also worry that, as part of the two-hour monitoring requirement, they and their less experienced medical assistant colleagues will be asked to check in and perhaps even intervene with patients who are in altered states of mind — something most of them have not been trained to do. "We don't want to do a half-ass job," Reiss said.

Asked about her staff's concerns, Withers said she has spent a lot of time hearing them out and "providing the education that they have asked for."

"They've been part of this along the way and have been able to raise concerns, ask questions, contribute to the workflows and that kind of thing, and we will continue to do that," she said.

Providers experienced with esketamine confirmed that dissociation, or the feeling of being disconnected from reality, is a common side effect. But they said they've never encountered a situation that could not be handled with some gentle verbal directions.

"'This is time-limited, you are safe, and I am here if you need me,'" said Ellen Munger, a nurse at Treatment Associates, describing her typical mantra for people experiencing dissociation.

At Brattleboro Retreat, patients who reported out-of-body sensations often said they were "drifting through tunnels of light or across the universe," Thigpen said, although some have told him that they think they've died. His advice: Listen to music, ideally something in another language or without a story. "As long as you hear the music," he tells them, "you know you're alive and fine."

Dr. Fuerstman, who has provided esketamine to about two dozen patients since 2020, said the role of the provider is mostly one of "babysitting." The UVM nurses will probably find it boring, he said, "because it's so un-interactive."

One major unanswered question about esketamine is whether patients who do experience symptom relief will need treatments indefinitely to continue reaping benefits.

Stone, in Montpelier, said his esketamine patients typically get significantly less depressed over the first three months. Many have remained stable for up to a year or more afterward using just traditional antidepressants.

"Occasionally people need to come back in for kind of a 'tune-up,'" he said, "and then we let them go on their way until they need another."

Dr. G. Caleb Alexander, a researcher from the Center for Drug Safety & Effectiveness at Johns Hopkins University, reviewed dozens of studies involving ketamine and esketamine as part of a literature review he coauthored last year that concluded neither drug has been proven to be safe for extended clinical use to treat depression. Alexander and his colleagues described the expanded use of the drugs to treat psychiatric disorders as "a significant risk to the public" and urged policy makers to reassess this burgeoning niche of medicine.

"A central but unanswered question is the cumulative effects of repeatedly inducing this altered state of consciousness," Alexander told Seven Days.

Vermont providers say they must weigh the unknown risks against the very real danger of living with untreated depression.

"We would love to study everything until we know everything about it, but at what point do you say the data is good enough? That it's safe enough?" said Thigpen, the Brattleboro Retreat doctor.

"If there's a chance that it works," he added, "I feel like we owe it to them."