October 20, 2017 — Editor's note: This article has been updated from its previous versions.
The seemingly ever-expanding business of off-label ketamine infusion therapy for treatment-resistant depression (TRD), along with a host of other conditions, appears to be unchecked by any regulatory or legislative oversight ― raising both ethical and safety concerns among clinicians and medical organizations.
"It scares the hell out of me that this is still unregulated," Steve Levine, MD, a psychiatrist and the founder and CEO of Actify Neurotherapies, a 10-clinic network that offers ketamine infusions, told Medscape Medical News.
Although ketamine has only been approved by the US Food and Drug Administration (FDA) for use as an anesthetic, it has shown effectiveness in the research setting for TRD. However, off-label infusions are being promoted by some clinics almost as a cure-all with little risk.
Because the majority of ketamine infusions are not covered by insurance, vulnerable patients pay out of pocket, often handsomely, for a generic product that has been available for almost 50 years.
Increasingly, these clinics have no psychiatrist or mental health professional on staff. Ketamine infusion is being pitched through online courses as a way for any physician, nurse, nurse practitioner, or physician assistant to have an additional income stream.
In addition, some clinics offer inducements, such as cut-rate infusions, for referring other patients.
Potential for Abuse
Because off-label prescribing is permitted, the FDA has not taken a role in the oversight of ketamine treatment. The US Drug Enforcement Administration (DEA) has listed ketamine as a schedule III controlled substance, which means there is potential for abuse. However, the DEA has not prosecuted any clinics for diversion or the equivalent of running a "pill mill," according to a recent agency report.
Clinic operators are subject to medical or professional board supervision, but those organizations rely on consumer or peer complaints.
The apparent lack of clinic monitoring has led some US ketamine providers, as well as the American Psychiatric Association (APA), to call for stricter oversight.
Dr Levine has met with the Joint Commission and private insurers about standardizing practice parameters and instituting some form of accreditation for ketamine infusion therapy. His actions could be viewed as those of a self-interested business owner wanting to restrict competition, but business owners typically do not invite regulation.
Dr Levine also said he wants to create a registry to gather safety and efficacy data, especially long-term safety data.
Among those he's talked with is Rupert McShane, MD, RCPsych, a psychiatrist at the University of Oxford in the UK and leader of the ketamine treatment service at Oxford Health National Health Service Foundation Trust, United Kingdom.
In an article published online in April in Lancet Psychiatry, Dr McShane and colleagues called for better oversight. "We find that, based on current evidence, ketamine use for severe, treatment-resistant depression does not violate ethical principles," they write.
"However, clinicians and professional bodies must take steps to ensure that guidelines for good practice are enacted, that all experimental and trial data are made available through national registries, and that the risk potential of ketamine treatment continues to be monitored and modelled."
As reported by Medscape Medical News, the APA issued a consensus statement published in JAMA Psychiatry in April this year on the use of ketamine for the treatment of mood disorders in an attempt to provide some guardrails, said Charles Nemeroff, MD, chairman, Department of Psychiatry and Behavioral Sciences, Leonard M. Miller School of Medicine, University of Miami, Florida, who is a member of the consensus writing committee.
The statement, put together by the APA's Council of Research Task Force on Novel Biomarkers and Treatments, offers guidance on patient selection, clinician training, appropriate settings for administration, dosing, how to administer the infusion, and how to monitor for short- and long-term safety. One major concern is that patients with a history of substance use disorder could abuse ketamine, said Dr Nemeroff.
"There are a number of clinics that have sprung up around the country," he told Medscape Medical News. "They range from really following to the letter our recommendations to those that are fly by night ― anybody that walks through the door with any complaint can end up getting an infusion if you pay the requisite amount of money."
Dramatic Leap in Clinic Numbers
It is unclear how many clinics are operating in the United States, but Dr Levine estimates that it could number at least a thousand.
In a 2015 article in Anesthesiology News, Dennis Hartman, the founder of the Ketamine Advocacy Network (KAN), was quoted as saying that 60 private clinics were in operation.
Currently, the patient group lists 24 US ketamine providers on its Web site, but there may be more. For a variety of reasons, KAN won't list clinics. Among those reasons are what it considers to be bogus efficacy claims or fees that are out of the mainstream.
A Google search using the term "ketamine clinic" brings up hundreds of businesses, many with similar names.
Web sites such as Ketamineclinicsdirectory.com provide a state-by-state listing of infusion centers that offer ketamine for depression, pain, complex regional pain syndrome, posttraumatic stress disorder, obsessive-compulsive disorder, and other conditions.
Only 14 clinics are included in this directory. Prices are listed for infusions for depression, pain, and maintenance infusions. For depression, the per infusion price ranges from $400 to $1000.
"Since 2016, things have picked up," said Dr Levine, adding that ketamine infusion clinics were few and far between initially. "More recently, there's been this burst of people making a grab."
For example, the Ketamine Infusion Academy, which offers online training and education, notes on its Web site that the program will "guide you step-by-step on how to open your own cashed [sic] based clinic capable of generating gross revenues of over $1,000,000." It promises to help students "achieve freedom from their current J.O.B. by creating their own private ketamine practice."
The upsurge in ketamine clinics may not be entirely about getting rich quick. Kaiser Permanente of Northern California considers ketamine a valuable treatment and offers it at five sites as a covered benefit to eligible health plan members with TRD, said Mason Turner, MD, the organization's director of outpatient mental health and addiction medicine.
The clinics have treated more than 200 patients, and "our results with our program have been outstanding," Dr Turner told Medscape Medical News.
"We've seen response rates as high as 75%," he said. About three quarters of patients experience an immediate reduction in symptoms, he said. Dr Levine said he has seen similar success in the 1500 patients he's treated in the past 6 years.
But it's not clear how long the effects last. "The durability of response is a lot tougher to sort out," said Dr Turner.
Gerard Sanacora, MD, PhD, professor of psychiatry and director of the Yale Depression Research Program, New Haven, Connecticut, along with Dr Levine and several other colleagues surveyed ketamine providers in late 2016 and early 2017 to get a snapshot of how these infusions are being offered and by whom. Fifty-seven providers participated in the survey, which was published in July in the American Journal of Psychiatry.
About three quarters of the participants were in private practice, and one third were based on the West Coast. Sixty-seven percent were psychiatrists, 23% were trained in anesthesiology, 3% were trained in emergency medicine, and 3% were in family medicine.
The most common reason for treatment was major depressive disorder (73%), and intravenous administration was the most common route. Overall, most providers monitored heart rate, pulse oximetry, and blood pressure at a regular interval during the infusion. This is crucial, because it is thought that ketamine can have ill effects on heart rate and blood pressure for some patients.
Almost all providers said they offered ketamine on a maintenance basis, either monthly (29.8%), every 3 weeks (21.1%), every 2 weeks (12.3%), or less (15.8%).
Kaiser limits treatment duration "to about a year," said Dr Turner. "We want to make sure that we don't extend the treatments too long, because we don't know a lot about the long-term effects yet."
Although Kaiser and other organizations debate whether ketamine can be safely administered for extended periods, some clinics seem to offer open-ended maintenance treatment, at least in the materials provided on their Web sites.
Other clinics employ questionable practices. Gainesville-based Georgia Ketamine has sent out electronic flyers offering a reduced-rate $200 booster infusion for patients who have completed 10 infusions, and a "free infusion for anyone sending in [a] referral patient receiving five infusions." The clinic also offers patients nasal and sublingual ketamine.
Allowing patients to self-administer flies in the face of APA recommendations, because patients who self-administer cannot be monitored for cardiac side effects or potential hallucinations. Dr Nemeroff said one of his patients had received intranasal ketamine from a California practitioner to use at will. "That is beyond irresponsible," he said.
Georgia Ketamine declined to discuss its inducements or other practices.
California has a growing number of ketamine clinics, but Chris Valine, a spokeswoman for the Medical Board of California, said the organization is not able to say whether complaints have risen and that the board is not allowed to divulge complaints about specific physicians.
The board urges physicians to document the legitimacy of off-label prescribing by providing references to scientific studies that support that use and by documenting informed consent, said Valine.
Will Patients Win or Lose?
Ketamine is providing hope to people with depression who otherwise have not had relief, and the infusion clinics are proliferating "because there's a real need for it," said Dr Turner.
Dr Nemeroff agreed, noting that clinics have sprung up "for a combination of altruistic and financial reasons." But, he said, "I wish it could be regulated."
Because of the number of clinics operating in a questionable fashion and the fact that many have similar names, Dr Levine decided to change the name of his business to distance himself from the other providers.
When Ketamine Treatment Centers became Actify Neurotherapies, it was also a nod to the future. "We do not want to be seen as just a ketamine clinic," said Dr Levine, adding that he views ketamine as a tool for discovery in the neuroscience of depression.
The use of ketamine infusions could possibly be supplanted by use of an intranasal form of the drug developed by Johnson & Johnson that is currently under review at the FDA.
In the meantime, in the absence of oversight, Dr Levine is "nervous that there are going to be some bad outcomes, especially with a population that's so vulnerable," he said.
"For a few bad actors to ruin this would be just horrible and cost a lot of lives."
Medscape Medical News © 2017
Cite this: US Ketamine Clinics Continue to Mushroom With No Regulation - Medscape - Oct 09, 2017.