When federal regulators approved the nasal spray esketamine as a choice for treatment-resistant depression in March 2019, it was the first approval of an antidepressant with a unique treatment mechanism since the debut of Prozac 31 years earlier.
But esketamine — a derivative of the chemical mixture known as ketamine, a dissociative anesthetic with a long history in clubbing culture and the operating room alike — could not be taken on its own. It needed to be prescribed in combination with a traditional oral antidepressant. That changed on Jan. 17, when the Food and Drug Administration (FDA) increased its confidence in esketamine by approving the drug for standalone use.
That’s one regulatory hurdle cleared for the drug, which is used to treat people who have a history of not responding to existing antidepressants. But Dr. Linda Carpenter, a professor of psychiatry in the Warren Alpert Medical School of Brown University and chief of the mood disorders program at Butler Hospital in Providence, said increased permissiveness for prescribers might not lead to immediate changes for patients.
“I think the logistics are the big story for so many patients,” said Carpenter, who was a principal investigator in a clinical study funded by Janssen, a subsidiary of Johnson & Johnson which manufactures esketamine in the U.S. as Spravato. From November 2020 through January 2024, Carpenter was one of over 50 researchers working across the country to determine if the still-novel antidepressant could fly solo.
In Rhode Island, most people have esketamine coverage, even Medicare and Medicaid recipients, Carpenter said. But clinics like Butler aren’t always reimbursed well enough by insurers to cover the administrative costs incurred by the drug’s dosing procedures. Esketamine follows a special set of FDA-specified rules to be dispensed to patients, including a two-hour monitoring period in a clinical setting after the drug is inhaled. After all, the parent drug ketamine is used recreationally in beyond-clinical doses to induce psychedelic-like trips — a possibility with esketamine as well, and something clinicians must consider.
“But a number of patients in Rhode Island can’t get it because the way their insurance covers it is as an outpatient medication prescription benefit,” Carpenter said. “It feels uncomfortable, because when people say, ‘Oh, I have coverage,’ and it’s like, ‘Oh, actually, yeah, you do. But in order to get it here, you’re going to have to have this or that insurance policy, and not the one you have.’”
Carpenter estimated that a third of Butler patients receive behavioral health benefits through Optum, a subsidiary of UnitedHealth, and identified the company’s plans as a common problem for esketamine hopefuls. In Rhode Island, Optum also partners with Neighborhood Health Plan, which served approximately 220,000 members last year, with 82% of those enrollees eligible for Medicaid.
A spokesperson for United said the expanded approval was currently under review. Documents from 2024 for both Medicaid and non-Medicaid United plans label the drug as medical benefit coverage.
As for Neighborhood Health Plan, spokesperson Tyler McCollum said in an email, “We would prefer not to comment on member coverage without context.” Esketamine does not appear in Neighborhood’s 2025 formularies, or lists of covered medicines, for people with Medicaid or non-Medicaid plans.
Richard Salit, a spokesperson for Blue Cross Blue Shield of Rhode Island, said in an email that the company is reviewing its approvals for esketamine.
“Our health plans currently provide coverage of esketamine in accordance with FDA requirements, including that patients also receive an oral antidepressant and that it be administered under direct supervision of a healthcare provider,” Salit wrote via email. “We are reviewing our coverage policies in response to the FDA’s decision on Jan. 21 to approve esketamine as a monotherapy, clearing its use as a standalone treatment for depression.”
“It takes a while for the FDA to get around to its approvals, and it’ll take a little while for the insurance companies to catch up and change their coverage policies, too,” Carpenter said.
Drugs with similar names, but different rules
“Insurance and prior authorization are a whole other topic we could probably talk about for a really long time,” said Dr. Rachel Wightman, a Rhode Island Department of Health consultant medical director and Brown Emergency Medicine toxicologist who worked on a study published in the October 2024 issue of the Rhode Island Medical Journal.
The study did not focus on clinics like the one at Butler, or esketamine in a clinical setting. Instead, it examined prescribing rates. The authors found that esketamine prescribing rates in Rhode Island have skyrocketed by 1,289% since the initial approval in 2019 — and 80% of these scripts were paid for by insurance.
Because regular ketamine lacks FDA approval for depression, prescriptions for it rose a more modest 55.8% since 2017, and it’s subsidized by patients’ with nearly 84% of ketamine prescribed in Rhode Island in 2023 paid for out-of-pocket.
“Off-label ketamine use has been ongoing for quite some time,” Wightman said, noting that the drug has been OK’d as a general anesthetic for decades. “I’m an emergency doctor in the hospital, and so in that acute care environment, we’ve been using ketamine off-label in clinical care for pain, procedural sedation and other indications for years.”
The study noted that ketamine infusions can be pricey, costing around $3,000, while an uninsured person might pay $240 out-of-pocket for esketamine spray. While esketamine “is covered by many public and private third-party payers,” the study said, some patients find it cheaper to get ketamine prescribed and compounded at a pharmacy out of state. That cost-friendliness may have influenced a 22% increase in ketamine prescriptions filled at out-of-state compound pharmacies since 2022.
“While insurance coverage plays an important factor in the accessibility of esketamine, there are limited clinics that can administer the medication,” the authors wrote. For patients in lower-income areas, “ketamine may be the more affordable option if paying out-of-pocket, even factoring in the cost share of a physician office visit to receive the medication.”
Out of the nightclub, into the hospital
Massive spikes in illicit ketamine trafficking — there was a 349% increase in seizures by the Drug Enforcement Administration from 2017 to 2022 — have been matched by considerable interest in the drugs for people who feel they have tried but not succeeded in escaping the clutches of depressive illness.
Questions about providers, insurance and pricing abound on Reddit’s r/TherapeuticKetamine, a forum dedicated to discussing the medicinal use of the drug and its derivatives. One thread stuck at the top is titled, “Who is your provider and how much are you paying?” When patients do find a way to access the drug, some claim they have powerful results. In a post to another Reddit forum on Spravato, the child of a patient writes that their mother was “urged” by a psychiatrist to try the drug as a last resort.
“She’s sitting up straighter, she’s able to hold a conversation, she’s eating, she smiled a few times, and even laughed for a second or two!” the poster wrote in their thread titled, “This stuff is amazing and so is everyone here.”
“It can work miracles for some of us,” another user replied, claiming that the drug helped alleviate their suicidal thoughts and a lack of emotion.
Clinical experience shows less raving enthusiasm for ketamine-based drugs, with some data suggesting they are at best mildly successful as antidepressants. At the Ketamine Clinic at Mass General Hospital — which sees about 16 patients a day, compared to around six at Carpenter’s Butler Hospital clinic — there’s about a 20% response rate among patients, said Dr. Cristina Cusin, the clinic’s director, at a panel during a 2024 conference of the American Psychiatric Association.
The clinic opened in 2018 and delivers primarily ketamine infusions. About a third of patients show better outcomes on the Quick Inventory of Depressive Symptomatology, a diagnostic tool used to gauge a patient’s response to a drug.
“In clinical trials, they report a 60% to 70% response rate. We don’t see that,” Cusin was quoted in Psychiatric News.
Carpenter pointed to Cusin’s findings and described the drugs’ successes and failures as a chicken-or-the-egg situation: “Maybe the type of patients that make their way to Spravato have a disease that’s just not getting better and staying better with other treatments,” she said. The drug’s dosing and efficacy are inconsistent and can differ vastly from patient to patient. She recalled one woman at the Butler clinic who received monthly esketamine doses — then got divorced, and upped her number of visits. Other patients may get one dose and not come back for six months.
“I can’t say that’s entirely a function of the drug or or (sic) the type of patient that ends up getting it,” Carpenter said.
The doctor compared esketamine to methadone: If it works, you might be on it for life. Not every patient makes the commitment to stay on the drug. Of the patients who come to Butler, maybe half stick with the treatment on a regular basis.
“But others,” Carpenter said, “They’re just living from one dose to the next, and that’s good enough, because that’s the best they’ve ever felt.”
This story was originally published by the Rhode Island Current.
