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New depression drug related to ketamine recommended by FDA panel
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Download the PDF here
Download the PDF here
Experimental nasal spray is intended for people with severe depression who aren't helped by other treatments or therapies.
Feb. 12, 2019, 5:51 PM EST
By Reuters
An experimental nasal spray, which has a compound similar to the 'club drug' ketamine, has been recommended as a new depression treatment by an advisory panel to the Food and Drug Administration Tuesday.
The influential panel voted 14-2 in favor of Johnson & Johnson's drug esketamine, a treatment developed to treat major depression in patients who have not benefited from at least two different therapies. The panel said the benefits of the nasal spray outweighed the risks. Side effects include dizziness, nausea and an unpleasant feeling of dissociation, according to the company. One member in the panel abstained from voting.
Esketamine is a variation of the anesthetic ketamine, which is also abused as a recreational party drug with the street name, Special K. Intravenous infusions of ketamine have been shown to help people with severe depression who experience suicidal thoughts, but the researchers expect the nasal spray will take effect more quickly and be easier to use.
"I think esketamine has the potential to be a game-changer in the treatment of depression ... I use the term potential because the issues of cost and patient accessibility need to be addressed," said Walter Dunn, a panel member who voted in favor of the approval.
Major depressive disorder (MDD) affects over 300 million people globally, and attempted suicides in people with this condition is about 20-fold higher than that of the general population, according to the company.
However, depression is a tricky area of development. Patients in clinical trials often show a big placebo response, masking the efficacy of the drug being tested.
The FDA, although not mandated to follow the panel's recommendation, is expected to announce its decision on esketamine by March 4.
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"There are still a number of questions to resolve about the best dose, the mechanism, and the long-term efficacy and safety of ketamine."....."Where is the bar where they determine a patient is not appropriate for ketamine treatment if they can pay?"
Late last month, the FDA stepped in to offer some help. The agency released a draft guidance on developing new treatments for major depressive disorder that lays out the special considerations for clinical trials on rapid-acting antidepressants. The FDA is taking comments on it through Aug. 20 and then will finalize the document.
Pdf attached above
FDA Briefing Document:
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630970.pdf
J&J Briefing document:
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630971.pdf
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When ketamine is used as an anaesthetic or a hallucinogen, it blocks the NMDA receptor. This in turn stimulates the release of a glutamate burst, which is believed to be responsible for the drug's hallucinatory effects. The neurotransmitter then stimulates other receptors that control gene transcription to enable rapid rewiring of brain circuits. This rewiring, or plasticity, is thought to cause the antidepressant effect.Nature.com see full text below
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FDA panel backs J&J's ketamine-like depression drug
Feb 13, 2019 9:30am Firecebiotech.com
A FDA advisory committee has voted overwhelmingly in favor of Johnson & Johnson's depression drug esketamine. The panel's decision to back the ketamine-like drug despite the shortcomings of its clinical program tees J&J up to win approval for one of the most notable antidepressants in decades.
Esketamine is a form of ketamine, an illegal street drug that has developed a reputation as a novel way to treat depression over the past 20 years. The reputation is underpinned by evidence that the drug acts far faster than existing antidepressants, suggesting it could fill a gap in the toolkit physicians have to treat people with severe forms of the condition.
The advisory committee gave esketamine a big push toward real-world use this week when it voted 14-2 that the benefits of the drug outweigh the risks. The panel voted by the same margin that J&J had shown the nasal spray is effective in treatment-resistant depression.
With the panel also voting overwhelmingly in favor of the safety profile of the drug, J&J emerged from the meeting looking set to win FDA approval. J&J finds itself in that position despite the FDA and the advisory committee identifying shortcomings in the dataset it presented in support of the drug.
Two of the three pivotal trials J&J ran to assess the short-term effects of esketamine missed their primary endpoints. That meant results from one of the short-term studies-which assessed flexible doses of esketamine in people aged under 65-and data generated in a maintenance trial formed the backbone of J&J's case for the efficacy of the drug.
While the panelists questioned whether approving a drug that failed two out of three trials would set a bad precedent, they ultimately came down on the side that the benefits of esketamine outweigh the risks in the target population.
That view is partly underpinned by the unmet need. In recent years, physicians have resorted to using ketamine off-label as there is a lack of approved, fast-acting depression drugs. With a body of evidence beyond the esketamine trials suggesting ketamine works fast-and the maintenance trial finding positive effects are sustained-J&J's case was compelling enough to get it over the line.
The application will now advance to the FDA, which will decide whether to approve the drug. Given the frequency with which the FDA follows committee recommendations and the content of its briefing notes on esketamine, odds look good for the drug to get the green light from the agency.
Johnson & Johnson's nasal spray for depression wins FDA panel backing
(Reuters) - An advisory panel to the U.S. Food and Drug Administration on Tuesday voted in favor of Johnson & Johnson's experimental nasal spray, which has a compound similar to often-abused ketamine, bringing the drug closer to approval.
The panel voted 14-2 in favor of the drug esketamine, developed to treat major depression in patients who have not benefited from at least two different therapies, saying its benefits outweighed the risks. One panel member abstained from voting.
Esketamine is a chemical mirror image of anesthetic ketamine, which is also abused as a recreational party drug and goes by the street nickname "Special K".
"I think esketamine has the potential to be a game-changer in the treatment of depression ... I use the term potential because the issues of cost and patient accessibility need to be addressed," said Walter Dunn, who voted in favor of approval.
However, the panel members echoed concerns raised by FDA staffers on Friday regarding the increased risk of sedation, dissociation and higher blood pressure observed in the study.
The FDA recommended implementing a risk evaluation and mitigation strategy (REMS) program which included ensuring esketamine is only dispensed and administered under supervision.
"Ketamine is a nasty drug ... should (J&J's) drug get approved, I think a strong effort has to be given as part of REMS ... so that patients really know what they are getting themselves into," said Steven Meisel, another member who voted 'yes'.
Major depressive disorder affects over 300 million people globally. About 30 percent to 40 percent of these patients fail to respond to first-line treatments such as antidepressants, most of which take at least four weeks to show effect.
However, depression is a tricky area of development. Patients in clinical trials often show a big placebo response, masking the efficacy of the drug being tested.
Currently, Eli Lilly and Co's Symbyax is the only FDA-approved drug for treatment-resistant depression.
"There is a lot of potential for people that just want that quick fix. I really would be cautious," said Kim Witczak, a panel member who voted 'no'.
J&J's esketamine, used in combination with a newly prescribed antidepressant, works by restoring the nerve cell connections in the brain, leading to an improvement in depression symptoms.
The FDA, although not mandated to follow the panel's recommendation, is expected to announce its decision on esketamine by March 4.
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FDA Advisory Committee Recommends Approval of SPRAVATOTM (esketamine) Nasal Spray CIII for Adults with Treatment-Resistant Depression
https://www.jnj.com/fda-advisory-committee-recommends-approval-of-spravatotm-esketamine-nasal-spray-ciii-for-adults-with-treatment-resistant-depression
f approved, SPRAVATOTM will offer the first new mechanism of action in 30 years to treat this debilitating disease, continuing Janssen's 60-plus-year history and commitment to research that make a difference for people living with mental illnesses, including severe mood disorders
TITUSVILLE, N.J., February 12, 2019 - The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee jointly voted (14 yes, 2 no, 1 abstain) that data support the favorable benefit-risk profile of SPRAVATOTM (esketamine) nasal spray CIII for adults living with treatment-resistant depression. SPRAVATOTM is an investigational prescription treatment that is thought to work differently than currently approved therapies for major depressive disorder (MDD). Janssen announced on September 4, 2018 that it submitted a New Drug Application (NDA) to the FDA for the approval of SPRAVATOTM.1 If approved, SPRAVATOTM would provide the first new mechanism of action in 30 years to treat this debilitating mental illness.2,3
"We are pleased with the advisory committees' vote and their recommendation to approve SPRAVATOTM as a potential therapy for adults living with treatment-resistant depression," said Husseini K. Manji, M.D., Global Head, Neuroscience Therapeutic Area, Janssen Research & Development, LLC. "Our comprehensive research program for esketamine nasal spray supports a positive benefit-risk profile for adults with treatment-resistant depression."
The committees based their support on the safety and efficacy data from five Phase 3 studies in patients with treatment-resistant depression: three short-term studies; one maintenance of effect study; and one long-term safety study. In addition, the SPRAVATOTM research program provided supportive data from three Phase 2 studies and 19 Phase 1 studies in patients with treatment-resistant depression and healthy volunteers. Data from both a short-term Phase 3 study and a long-term Phase 3 study demonstrated that esketamine nasal spray plus a newly initiated oral antidepressant provided statistically significant, clinically meaningful, rapid, and sustained improvement of depressive symptoms in this difficult-to-treat population.4,5 All the patients who participated in the Phase 3 studies received esketamine or placebo in addition to a newly initiated oral antidepressant at the start of the treatment phase.
The long-term safety study showed that esketamine was generally tolerable, with no new safety signals with dosing up to 52 weeks compared to data from short-term (4-week) studies.6 Discontinuation rates due to esketamine-related adverse events were low and occurred typically in the first weeks. Most treatment-emergent adverse events, including dissociative symptoms, dizziness/vertigo, increased blood pressure, and sedation, occurred shortly after dosing while patients were under the supervision of a health care professional, were transient, and resolved the same day. In addition to the comprehensive clinical research program, the company proposed a robust Risk Evaluation and Mitigation Strategy (REMS).
While the FDA is not bound by the committees' recommendation, it does take its advice into consideration. The Prescription Drug User Fee Act (PDUFA) date for SPRAVATOTM is March 4, 2019.
About SPRAVATOTM
SPRAVATOTM (esketamine) nasal spray is an investigational product being studied by Janssen Research & Development, LLC as part of a global development program. Esketamine is a glutamate receptor modulator, thought to help restore synaptic connections in brain cells in people with major depressive disorder. It is believed to have a novel mechanism of action, meaning it is thought to work differently than currently available therapies for major depressive disorder.
The U.S. FDA has granted Breakthrough Therapy Designations for esketamine for treatment-resistant depression and for a second indication, major depressive disorder with imminent risk for suicide.7
About Treatment-Resistant Depression
Major depressive disorder affects nearly 300 million people of all ages globally and is the leading cause of disability worldwide. Individuals with depression, including major depressive disorder, experience continuous suffering from a serious, biologically based disease which has a significant negative impact on all aspects of life, including quality of life and function.8 Although currently available antidepressants are effective for many patients, about one-third of patients do not respond to treatment and are thought to have treatment-resistant depression.9
About the Janssen Pharmaceutical Companies of Johnson & Johnson
At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science.
We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenUS and www.twitter.com/JanssenGlobal. Janssen Research & Development, LLC is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.
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Ketamine gives hope to patients with severe depression. But some clinics stray from the science and hype its benefits
September 24, 2018
Walk into Kalypso Wellness Centers in San Antonio, Texas, and you might be treated with one of five "proprietary blends" of ketamine. They're not cheap - $495 per infusion - and not covered by insurance, but the company offers a "monthly" membership program to cut costs and advertises discounts for members of the military and first responders.
Kalypso promotes ketamine, long used as an anesthetic during surgery and more recently as a club drug, as a treatment for more than two dozen conditions, including depression, chronic pain, and migraines. "Congratulations on resetting your life!!!" it cheerily tells patients on a form they're handed after an infusion.
Starting with just one office 19 months ago, Kalypso has expanded rapidly to meet surging patient demand for ketamine and now oversees two other Texas clinics and offices in North Carolina and New York. It recruits customers through online ads and radio spots, and even by visiting support groups for pain patients, people with depression, first responders, and grieving parents who have lost children.
"You name it, we've done it," said clinic co-founder and anesthesiologist Dr. Bryan Clifton.
An investigation by STAT shows that Kalypso's sweeping claims are hardly uncommon in the booming ketamine treatment business. Dozens of free-standing clinics have opened across the U.S. in recent years to provide the drug to patients who are desperate for an effective therapy and hopeful ketamine can help. But the investigation found wide-ranging inconsistencies among clinics, from the screening of patients to the dose and frequency of infusions to the coordination with patients' mental health providers. A number of clinics stray from recommendations issued last year by the American Psychiatric Association.
STAT interviewed ketamine clinic owners, psychiatrists, and patients and reviewed online staff pages and screening protocols for dozens of ketamine clinics to gauge how patients are selected and treated. Among the findings:
• Some clinics don't thoroughly screen patients, and experts worry they're offering the drug to anyone who can afford it. Clinics can charge anywhere from $350 to close to $1,000 per infusion and many patients get at least six rounds of the treatment.
• In many cases, clinics don't have a psychiatrist or other mental health professional on staff, though they are working with challenging patients who haven't responded to other treatments and may have suicidal thoughts. And not all clinics collaborate closely with a patient's own mental health provider or even require patients to have one throughout treatment.
• Clinics sometimes overhype the efficacy of ketamine, offer it for uses that haven't been well-studied, and tout special blends that experts say aren't supported by published evidence.
Patients are "getting treatments they may not need or that don't work, or they're getting more than they needed," said Dr. Jeffrey Lieberman, psychiatrist-in-chief of Columbia University Medical Center. One of the biggest risks from the explosion in ketamine use, he added, is "people getting fleeced."
Clifton said Kalypso works closely with referring physicians or mental health providers and makes sure that anyone who seeks treatment for suicidal thoughts "has adequate mental health care." Other clinics told STAT that they try to work with a patient's mental health provider or another physician.
There's a clear need for new treatments for major depressive disorder, and experts agree that ketamine holds potential to rapidly treat depression and possibly other mental health conditions in some - though nowhere near all - patients. Drug companies are testing similar medications for depression, suicidality, and bipolar disorder, but it hasn't yet been approved for these conditions.
That fact hasn't diminished patients' desire to try ketamine. Actify Neurotherapies, which oversees 10 clinics that provide the drug, said it has received nearly 28,000 inquiries through a call center or online request form - just since January.
"Ketamine has become this phenomenon," said Lieberman. Continual media coverage has fueled the excitement, generating significant interest and optimism among patients and physicians alike.
Mental health specialists don't begrudge providers for opening their doors and offering a potentially beneficial treatment to patients eager for relief before it's approved by the Food and Drug Administration. But they say some clinics are going too far in their promises - and not caring appropriately for patients.
"This is not snake oil. It's not something that has to be stamped out," Lieberman said. "It's something that has to be reined in."
Seeing hope in an experimental therapy
Rory Basurto knows the date of his first ketamine treatment by heart: Oct. 17, 2017. For more than a decade, he had suffered from devastating depression and thick anxiety that felt "like walking around with a wet blanket on all the time." The 36-year-old can rattle off a laundry list of treatments he's tried: Paxil, Lexapro, Zoloft, Ritalin, klonopin, neurofeedback, psychotherapy.
"It helped until it didn't. Until I completely broke down," said Basurto, who lives in Encinitas, Calif. That was last fall, when he had to quit his job working with a family business and attempted suicide.
Basurto, like many patients contending with major depression, needed another option. Many don't respond to conventional antidepressants, such as the SSRIs. And for others, the drugs just don't work quickly enough, taking weeks to kick in.
"Patients are getting more and more frustrated because the help that they're getting failed them," said Dr. Lori Calabrese, a psychiatrist who treats patients with ketamine at her clinic in South Windsor, Conn.
Ketamine has started to fill that breach. Since the early 2000s, small studies have suggested that it might have potential as a depression drug. Unlike traditional antidepressants that target the brain's serotonin and noradrenaline systems, ketamine appears to block a receptor called NMDA, which is activated by the neurotransmitter glutamate.
The evidence is promising: A dose much smaller than what's used for anesthesia - given through an IV - stems symptoms of severe depression in some patients with treatment-resistant depression, often within hours.
In Basurto's case, he read about ketamine online after his suicide attempt. He reached out to South Coast TMS and Ketamine, an Encinitas clinic opened in 2016 by Dr. Drew Belnap, an anesthesiologist. Belnap consulted with Basurto's therapist, who confirmed Basurto has anxiety and depression.
Since October, Basurto has undergone nearly two dozen ketamine infusions, paying between $450 and $500 per treatment. About once a month, he heads into the clinic, fills out a questionnaire about his symptoms, and settles into a zero-gravity chair. A staff member monitors Basurto as the ketamine drips into his bloodstream. He watches nature videos on a TV during the roughly 50-minute treatment.
"This is not snake oil. It's not something that has to be stamped out. It's something that has to be reined in."
Dr. Jeffrey Lieberman, psychiatrist-in-chief of Columbia University Medical Center
He said the drug has changed how he grapples with the everyday challenges that used to knock the wind out of him, often leaving him sad or angry.
"Before, something happened and it was the end of the world. I still go through that, but it's a lot quicker now," he said.
Drug companies are racing to create a rapid-acting antidepressant that can produce effects similar to ketamine. Janssen, a division of Johnson & Johnson, is testing a nasal spray of esketamine, a ketamine-derived drug. When combined with an oral antidepressant, it has shown promise in quickly curbing symptoms of serious depression, and is also being tested in patients at risk of suicide. Allergan is developing its own experimental rapid-acting antidepressant, rapastinel. Like ketamine, it works on the NMDA receptor, which is involved in learning and memory.
But there are clear limitations to the data on ketamine. There aren't data on long-term effects or potential risks down the road. There's no clear consensus between the providers currently offering it on optimal dosing, how to go about maintaining the drug's effects, or the best kind of care to complement ketamine treatment, such as cognitive behavioral therapy.
"The pace of ketamine treatment in real-world practices has outstripped what researchers are able to do and publish," Calabrese said.
Seeing an "urgent need for some guidance," an American Psychiatric Association task force issued a consensus statement in April 2017 that laid out the medical evidence on ketamine, the kind of training it thought physicians should have, and advice for thoroughly screening patients. Because ketamine can possibly affect heart rate or blood pressure in some patients, it recommended clinicians who provide treatment have advanced cardiac life support certification.
The panel said the screening process for every single patient should include a comprehensive diagnostic assessment, an in-depth look at a patient's history of depression treatments, a careful review of medical and psychiatric records, and a clear informed consent process that walks a patient through the risks and limitations of ketamine treatment.
It's clear that some clinics aren't sticking to those suggestions.
Minimal screening and untrained providers
Screening practices and the extent of collaboration with mental health providers vary wildly from one ketamine clinic to the next. That means some patients might not get the support they need, particularly if they don't respond to ketamine, experts said.
At Actify Neurotherapies, people first talk to a "patient care coordinator" who asks a few questions to make sure there aren't any big red flags, like psychosis. "It's intended to be a sieve with large holes," said the CEO, Dr. Steven Levine. A patient then has a consultation with a psychiatrist on staff.
At Calabrese's clinic, she requests records from each patient's psychiatrist and primary care doctor, then does a lengthy intake. But at other clinics, the intake process is quicker and leans heavily on a screening tool such as the PHQ-9 questionnaire, which is commonly used to diagnose symptoms of depression. That's fueled concern that any patient who can fork over hundreds of dollars for each infusion might be offered ketamine treatment, whether or not it's the right course of action.
"Where is the bar where they determine a patient is not appropriate for ketamine treatment if they can pay?" said Dr. Cristina Cusin, co-director of a ketamine clinic at Massachusetts General Hospital. Cusin, who is also a psychiatry professor at Harvard Medical School, has run several studies on ketamine for treatment-resistant mood disorders.
One patient, a 28-year-old graduate student in California who didn't want to be named out of concern being identified could affect her job hunt, told STAT said that since the start of this year, she has seen four different ketamine providers. All agreed to treat her with the drug for her severe depression, anxiety, and panic attacks, even though her response to the treatment varied and it didn't always help.
Experts also express concern about the coordination of care between clinics and a patient's usual providers. Some clinics say they'll work with a patient's mental health provider if he or she wants them to do so. Levine said each of Actify's clinics "engages the person's outside primary team" throughout the course of treatment. At Kalypso, co-founder Clifton said staff follow up with a referring provider if there is one or will work with a patient's primary care provider unless the patient specifically requests that they don't.
At Ketamine Clinics of Los Angeles, co-founder and anesthesiologist Dr. Steven Mandel said contact with a mental health provider "ranges from no contact to two or three times" a week. Sam Mandel, an entrepreneur who opened the clinic with his father, Steven, and now serves as chief operating officer, said the only reasons the clinic wouldn't stay in contact with patients' mental health provider is if they don't make themselves available or if a patient doesn't have one, in which case the staff works with the primary care provider.
Many clinics don't require patients to continue seeing a mental health provider, which means that ketamine becomes the sole source of mental health care for patients who can be among the most complicated to treat. "When there's no sort of collaborative involvement, that's worrisome," Lieberman said.
Dr. Nora Janeway, a primary care doctor in New Hampshire, recently found out that a young patient had just received a series of infusions at a ketamine clinic run by two nurse practitioners.
Her heart sank: This was a particularly complex patient who first came to Janeway's office a few months ago on a slew of psychiatric prescription drugs, including two benzodiazepines, an antipsychotic, a mood-stabilizing medication, and a stimulant. Janeway wanted the patient to connect to a psychiatrist to manage those medications, but that hadn't happened yet when the patient started receiving ketamine. Janeway said she was never contacted for records or notified of her patient's treatment.
"There's no sense of obligation [in regards to] continuity or follow-up of the patient," she said.
Basurto, the patient who has received nearly two dozen ketamine infusions since last October, hasn't seen a mental health provider in six months, he said. Belnap, the anesthesiologist who oversees Basurto's treatment, said he strongly encourages patients to see an outside mental health care provider, but he can't force them to do so. He noted that many patients taking traditional SSRI antidepressants for long periods aren't undergoing psychotherapy either.
In many cases, ketamine providers aren't qualified to provide mental health care on their own. They're often anesthesiologists or pain physicians, and in some cases, nurse practitioners. STAT's review of staffing found that many clinics have no mental health providers on staff. Clifton and his three co-founders are each in the San Antonio office one day a week - and on Tuesdays, a physician assistant staffs the office. Two of Kalypso's affiliated clinics are run by physician assistants, another is run by a primary care doctor, and the last by a pain physician. Clifton and his co-founders train those providers for a few days and then oversee the care at those clinics through a management service agreement, he said.
The APA says that whoever is providing ketamine treatment needs to be trained in how to address behavioral health problems, because ketamine can cause dissociative effects such as hallucinations. The organization also says it's critical that clinics have caregivers qualified to make sure patients aren't at risk for behavioral problems - including experiencing suicidal thoughts - before they're sent home.
Anesthesiologists, in turn, argue that psychiatrists aren't qualified to provide ketamine treatment on their own. They're not prepared the same way anesthesiologists are to deal with problems that could crop up during an infusion, such as an irregular heart rhythm or more serious cardiac issues.
Belnap noted that the safety information included in every box of ketamine says that the physician administering ketamine should be trained in using anesthetics and managing problems with a patient's airway.
"I'm not saying psychiatrists can't [administer ketamine], but they need to have someone in the room or in the clinic who knows ketamine - because they don't," Belnap said.
One thing is clear: Collaboration is critical.
"You don't treat an advanced disease with just an infusion and a 'see you next time,'" Cusin said. "If [doctors] replace your knee but don't do physical therapy, you don't walk again."
But in some clinics, that appears to be the case, experts said.
Even in her clinic at Mass. General, staffed with experts used to dealing with complicated mental health issues, Cusin won't allow a patient to receive ketamine if that person doesn't have a primary mental health provider. She and her colleagues can't provide both ketamine treatment and comprehensive psychiatric care themselves.
"It's hard. It's unrelenting. There's always someone relapsing," she said.
Studies vary but have found response rates to ketamine as high as 70 percent among people with major depression who have failed a few other antidepressants, Cusin said. But the rate is lower for patients with extremely treatment-resistant depression, and how long any improvement lasts varies from one patient to the next. Cusin carefully explains what patients can expect during the informed consent process, and also talks with their therapist. Not all clinics lay such a thorough foundation.
The stakes couldn't be higher for patients, Cusin said: "Imagine if you take out a loan for $5,000 or $6,000 for treatment, and it doesn't work. That could be heartbreaking."
'They're throwing bait in the water'
A number of clinics' websites pump up the promise of ketamine with the same four-year-old quote from Dr. Thomas Insel, the former director of the National Institute of Mental Health: "Recent data suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades."
They neglect to include another line that appears a few paragraphs down in Insel's 2014 blog post about ketamine: "There are still a number of questions to resolve about the best dose, the mechanism, and the long-term efficacy and safety of ketamine."
Asked recently by STAT whether he was concerned about the use of his truncated quote in the promotional material, Insel responded by noting many caveats when it comes to ketamine treatment for mental health conditions, but said he had "no regrets'' about the post.
Insel, now president of Mindstrong Health, a medical technology company based in Palo Alto, Calif., said "optimal care for someone with a depressive disorder requires careful diagnosis and comprehensive treatment."
"I suspect that does not happen in every ketamine clinic," he added.
The use of Insel's quote is a prime example of the way some clinics aggressively promote the potential of ketamine while underselling its risks and limitations. Victory Medical, a ketamine provider in Texas, for example, says on its site that "the path to happiness begins with the first session." The website for Sierra Ketamine Clinics in Nevada proclaims that "patients who have lost hope and thought they would remain in the grips of chronic pain and mental illness for the rest of their lives have emerged across the country with renewed spirit and joy."
Mental health specialists said they're troubled by the way such glowing language might appeal to patients in need of help.
"They're fishing. They're throwing bait in the water and trying to lure people in," Lieberman said.
Like Kalypso, some clinics offer special blends they say can curb side effects. But without published data, experts said there isn't robust evidence to support those claims. Others make statements that similarly aren't supported by strong, published evidence, including that their treatment plans work better than protocols published in scientific journals or that they can treat a slew of conditions with ketamine.
"Where is the bar where they determine a patient is not appropriate for ketamine treatment if they can pay?"
Dr. Cristina Cusin, co-director of a ketamine clinic at Massachusetts General Hospital
On its website, Kalypso says that it has a 91 percent success rate. Clifton told STAT the company offers ketamine for 32 conditions, including lupus and cancer-related pain. When asked whether there was evidence to support each of those uses, Clifton said "absolutely" and said the company is "compiling all of our data to be able to publish it all."
At the top of its website, the company also prominently highlights its $199 genetic testing services to determine the "right formulation" of ketamine. But experts said genetic testing hasn't been proven to offer any meaningful information about ketamine treatment at this point.
"We are currently still researching how to best use this test for patient therapy," Clifton said.
Many clinics use social media to reach patients. To mark National Suicide Prevention Awareness Month, Rocky Mountain Mind & Body clinic in Colorado tweeted to its followers that it was offering a "special": After patients finish an initial infusion series, they'll get their first maintenance infusion free.
Some patients said they felt pressured to try ketamine, despite being unsure whether it was the right treatment for them. Alexia Taylor, a 41-year-old who has depression, called the New England Center for Healthy Minds in Acton, Mass., in February to ask about ketamine treatment.
She was floored to find out it would cost thousands and said she wasn't interested.
"They didn't want me to get off the phone," she said. "They said, wouldn't you like to feel better?"
The New England Center for Healthy Minds said that the screening and scheduling of patients is handled by an outside company called Neuragain, a network of ketamine providers. Julie Lassner, who works with patient and provider services at Neuragain, said the company's receptionists only collect basic formation needed to secure an appointment, and then formal screening is conducted by the the Center for Health Minds.
All the providers STAT interviewed were quick to say they're not prescribing ketamine to get rich. Clinics charge anywhere from $350 to upward of $1,000 for a single treatment - with a generic drug. Much of that money covers the significant overhead of running a clinic, providers said.
Most clinics offer a series of six infusions over two to three weeks, and many offer "boosters" as patients feel their symptoms creep back. It's not clear whether all these infusions are necessary. According to the APA's review of the research, the evidence is limited on the benefits and risks of longer-term treatment, such as monthly booster infusions.
Some patients scrimp and save for months to afford the treatments. Others ask friends and family to help them, put it on credit cards, or dip into their savings.
Insurers don't yet cover ketamine treatment for major depressive disorder, because it hasn't been approved by the FDA for a psychiatric indication. Levine, the Actify Neurotherapies CEO, said an estimated 40 percent of people who contact the company don't end up scheduling an appointment due to cost. That, critics say, points to another possible issue: the high price will exacerbate health care disparities.
"The problem is, the patients who most need the treatment are the patients who can't afford it," Cusin said.
'Whose job is it to rein this in?'
So what will it take to rein in rogue practices?
Mental health experts called for professional societies to follow in the APA's footsteps and issue recommendations outlining training requirements and screening protocols for providers who treat mood disorders with ketamine.
The APA also strongly recommended that every clinic come up with standard operating procedures based on the best evidence available. That plan should outline clear steps for screening and obtaining informed consent; assessment of a patient's physical and mental status before, during, and after infusions; and a plan for managing problems that crop up during or after treatment.
Another idea: create a registry to collect data on every patient who receives ketamine treatment for mood disorders. That will help provide more evidence on outcomes, both in the short-term and the long run.
Experts have pinned some hope - but not too much - on the FDA approving one of the new treatments in the works. A drug approval would mean clear information on dosing, treatment protocol, and indications for which a treatment is approved. And it could clear the path for insurance coverage; if insurers are involved, screening might be more stringent and more people would be able to afford treatments.
None of those are surefire fixes. Ketamine can still be offered off-label to patients with a range of conditions. As clinics continue to crop up, experts are skeptical that use of ketamine will become standardized any time soon.
"Whose job is it to rein this in?" Lieberman said. "Nobody's gonna come down on them unless something happens."
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'Party drug' turned antidepressant approaches approval
Nature Reviews Drug Discovery volume 17, pages 773-775 (2018) | Download Citation
Johnson & Johnson has submitted its esketamine for regulatory approval, but researchers still don't understand how the fast-acting antidepressant lifts moods.
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When researchers showed in 2006 that the anaesthetic ketamine - also known as the club drug Special K - was a rapid and potent antidepressant, big pharmaceutical companies quickly jumped into the game. Extensive efforts to improve on decades-old antidepressants had floundered, but ketamine finally promised a novel mechanism of action and the potential to help treatment-resistant patients.
Because ketamine is an old drug and difficult to commercialize for a new indication, early entrants into this space set out to build ketamine mimetics that could replicate the anaesthetic's effect, ideally without its hallucinatory side effects. A few of these ketamine-inspired drugs are now nearing the finish line (Table 1). In September, Johnson & Johnson (J&J) filed for FDA approval of a nasal spray containing esketamine - an isomer of ketamine that the company has patented. Despite some lingering questions about its efficacy compared with ketamine, experts in the field expect the drug will be approved, providing the first antidepressant breakthrough in decades.
"What's exciting is not that there's going to be a new drug approved, but that we're going to have a whole new class of drug approved"
"What's exciting is not that there's going to be a new drug approved, but that we're going to have a whole new class of drug approved," says psychiatrist James Murrough at Mount Sinai Hospital. "Everyone's waiting with bated breath."
This is fostering high hopes that psychiatric drug development - which has seen an exodus of major pharma companies owing to continuing failures - could be poised for a renaissance. The number of ketamine trials has skyrocketed, not only in depression but also for obsessive-compulsive disorder, post-traumatic stress disorder and even chronic pain. "If ketamine works and we understand the effects of ketamine on these different disorders, it could really open the way for drug discovery," says Lisa Monteggia, a neuroscientist at Vanderbilt University.
Yet it is far from clear how this work will play out. Whereas early evidence suggested that ketamine acted through the NMDA receptor, many of the first-generation ketamine mimetics that were designed to act on this target failed in clinical trials (Table 1). Accumulating evidence now suggests that ketamine's antidepressant activity may be more complicated.
As a result, some companies are quietly going back to the drawing board. "My sense is that NMDA-receptor blocking studies are diminishing quite quickly and people are looking at other mechanisms," says psychiatrist Carlos Zarate at the National Institute of Mental Health (NIMH). While NMDA blockers haven't been abandoned, he says, "companies are just giving a second thought to whether they want to continue pursuing these programmes." Until a clearer picture of the mechanism is worked out, the field may be doomed to a trial and error hunt for better-than-ketamine mimetics.
Novel antidepressant activity
The most commonly used antidepressants target signalling by the monoamine neurotransmitters serotonin, dopamine and noradrenaline. But starting in the 1950s, researchers using the antibiotic D-cycloserine to treat tuberculosis found that the drug alleviated patient melancholy. Researchers later learned that the antibiotic, at low doses, blocks the NMDA receptor, a glutamate receptor. Then in the late 1990s, when psychiatrist John Krystal of Yale University was curious about whether the neurotransmitter glutamate contributed to schizophrenia, he decided to test the known NMDA receptor antagonist ketamine in nine depressed patients.
At the time, glutamate had mostly been studied for its role in learning and memory. But Krystal's group found that ketamine induced a rapid improvement in mood in patients.
Zarate and Husseini Manji, who is now head neuroscience researcher at J&J, set out to replicate the surprising findings at the NIMH in a larger trial, enrolling 18 subjects with major depression. The results from this small study suggested that ketamine was a miracle drug - lifting a person's mood almost immediately. Reporting in the Archives of General Psychiatry, they showed that 70% of depressed patients responded to ketamine within 24 hours. By contrast, in one of the largest studies of people with depression, only one-third of patients responded to selective serotonin reuptake inhibitors (SSRIs) after 8 weeks.
Ketamine also appears to reduce suicidal thoughts - something that no other drug is known to do - and its effects last for weeks to months.
"Ketamine works so well it would be hard to do better"
"Ketamine works so well it would be hard to do better," says neuroscientist Todd Gould of the University of Maryland. Some clinics have taken this conclusion to heart, and are already offering ketamine to depressed patients on an off-label basis (Box 1). Drug developers have meanwhile been working hard to make next-generation alternatives, armed with a preliminary hypothesis for how the drug lifts moods.
When ketamine is used as an anaesthetic or a hallucinogen, it blocks the NMDA receptor. This in turn stimulates the release of a glutamate burst, which is believed to be responsible for the drug's hallucinatory effects. The neurotransmitter then stimulates other receptors that control gene transcription to enable rapid rewiring of brain circuits. This rewiring, or plasticity, is thought to cause the antidepressant effect.
When developing a pharmaceutical version of ketamine, companies have generally decided to target the start of this pathway. J&J, for instance, chose to develop the S-enantiomer of ketamine because it is four times as potent at blocking the NMDA receptor as regular ketamine, which is a mix of R and S-enantiomers. J&J's Manji says that the company has no plans to compare its product directly with ketamine in a clinical trial. But overall, esketamine's side effects - including hallucinations - seem similar to the original drug.
The company recently published results from two phase III studies on depression, and will conclude a suicidal ideation trial next year. Clinical trial results were mixed, however. In one study of 223 participants, esketamine significantly reduced depression at 28 days. But the results were not as strong as the company had anticipated, and esketamine took longer to take effect than ketamine and missed its secondary end point of lifting mood within 24 hours. In the second study in 138 people over 65 years old, the drug missed its primary end point.
Nevertheless, these results have buoyed hopes for glutamate-based antidepressants. Whereas Pfizer, AstraZeneca, Roche and others terminated development of NMDA receptor modulators for mood disorder in recent years owing to failed trials or severe side effects, researchers hope that success for J&J will lift all boats.
"I think once esketamine is approved, and it becomes likely a multibillion-dollar drug, you'll see big pharma coming back"
"I think once esketamine is approved, and it becomes likely a multibillion-dollar drug, you'll see big pharma coming back," says drug researcher Ronald Duman at Yale University.
Upping the AMPA?
Basic research on ketamine's mechanism of action complicates future ketamine-mimetic discovery plans, however. In 2016, Gould and Zarate published a startling paper in Nature, proposing that a metabolic byproduct of ketamine - not the drug itself - was responsible for the mood altering activity in mice. The metabolite (2R,6R)-hydroxynorketamine, or HNK, didn't seem to interact with the NMDA receptor at all. Nor did it appear to cause the hallucinatory side effects of esketamine, even at doses nearly 40 times greater than the normal dose of ketamine.
The result suggested that drug developers may have been going after the wrong target all along. "It definitely created a stir," says Murrough. "It contributed to a realization that we don't really know how ketamine is working, and whatever the mechanism is, it's not simple."
Others aren't ready to give up on NMDA inhibition just yet. Monteggia reported earlier this year in Neuropsychopharmacology that when she repeated a similar experiment, she found that very high levels of HNK could indirectly block the NMDA receptor through an as-yet-unknown mechanism.
J&J's Manji is also skeptical about reading too much into the effect of HNK in mice. If the NMDA receptor is uninvolved, the company's esketamine nasal spray should not work as well as it has, Manji says. He suspects that previous NMDA antagonist failures can largely be chalked up to dosing problems and side effect profiles, rather than a problem with the target itself.
Researchers are trying to reconcile these various results. For instance, ketamine might quickly reverse depression by blocking the NMDA receptor, but perhaps HNK is responsible for maintaining the effect over time, says Monteggia. Zarate and Gould are planning to file for FDA permission later this year to start clinical trials with HNK in 2019, which they say should be able to answer some of these questions.
Other studies add further complications. In August, a twelve-patient study led by Alan Schatzberg of Stanford University suggested that ketamine might be acting through the opioid system and not the glutamatergic system at all. The researchers gave depressed patients naltrexone to block the opioid receptor before administering ketamine, and found that this eliminated ketamine's antidepressant effects but not its hallucinatory side effects.
Promising data from Allergan's lead antidepressant rapastinel, an intravenous drug in phase III trials for depression and suicidality, adds another wrinkle. Whereas ketamine and esketamine block the NMDA receptor, rapastinel is a partial agonist of the NMDA receptor. Phase II data suggest that the drug relieves depression quickly and that its effects last for several weeks. Phase III trials are currently underway, with first pivotal results expected next year.
And Allergan is doubling down on the mechanism. In May, the company bought rights to an experimental oral drug AGN-241751, which targets the NMDA receptor and is currently in phase II trials for depression.
"It's really hard to reconcile all those different studies into a unified model," says Gerard Sanacora, a psychiatrist at Yale University.
But he, Gould and others believe that studies are beginning to home in on one convergent mechanism: a glutamate receptor known as AMPA, which is activated when glutamate levels increase and that stimulates brain rewiring. Ketamine, HNK and rapastinel all activate AMPA receptors, and animal studies have shownthat directly blocking AMPA receptors eliminates the antidepressant effects of these drugs. Yet targeting AMPA receptors directly tends to raise the risk of seizures, Sanacora cautions, making it unlikely that AMPA receptor agonists could be turned into therapeutics.
Allergan's chief R&D officer David Nicholson, meanwhile, remains unfazed by the lingering uncertainty about the mechanism of action of ketamine-inspired drugs - as long as the drugs work. "We didn't know really how tricyclic [antidepressants] were working, or how SSRIs were working," he says. "You can debate if we really know that today, to be frank."
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