The true story of how S-ketamine was authorized as an anti-depressant (or: How you can pay 100x more for less, thanks to the FDA)
Janssen’s Special K
Use of ketamine, a drug first approved by the FDA in 1970 as an anesthetic, has taken off in recent years with psychiatrists, psychologists, and others using it to treat people suffering from depression, obsessive-compulsive symptoms, trauma (PTSD), and more. Ketamine is also widely used as a recreational drug. Now Janssen Pharmaceuticals have grabbed their slice of the cake with their development of Spravato (esketamine), which is being heralded as a “game-changer” in some mental health circles. But which game has been changed?
According to Dr. Wesley Ryan, a Los Angeles-based psychiatrist, the game is the usual one pharmaceutical companies play and the change is for Janssen’s profit sheet.
This is one of the oldest tricks in the book.
Cut it in half and call it something new (and patentable)
“We see this all the time with pharmaceutical companies patenting isomers of generic drugs,” Dr. Ryan explains. The drug now being marketed as Spravato/esketamine — or rather, S-ketamine — is one of the two molecules that make up regular, or racemic ketamine. Like many chemical substances, ketamine is made up of mirror-image molecules that are related to one another approximately in the same way as a person’s left hand is related to his right hand. In other words, S-ketamine (and its mirror image R-ketamine) are basically the same, and also basically the same as ketamine itself.
Why go to all that expensive trouble of figuring out how to separate the molecules? The original work with ketamine was done over 50 years ago, and JHP Pharmaceuticals was the beneficiary of what was then called Ketalar. Ketalar’s patent has long since expired, leaving the field open for drug developers, to take advantage of ketamine’s properties with minimal outlay, as ketamine is relatively inexpensive.
Then — enter Janssen.
Six dead men and an FDA approval
Janssen has conducted a number of clinical trials on its creation, S-ketamine/Spravato. Six are known of. Janssen may have conducted many more, with no one the wiser, because the FDA does not require a drug manufacturer to submit all its clinical trial results when applying for approval. In an article published in the British Journal of Psychiatry, Dr. Mark Horowitz and Professor Joanna Moncrieff detail the six studies that have been published and stress that only one of them could in any way be called a success — and a very limited success at that.
The FDA approved Spravato anyway, for the treatment of “treatment-resistant depression.”
Spravato was approved on the basis of a single, four-week-long study when even the FDA usually requires at least two studies for approval, each of them lasting for over six to eight weeks.
Spravato was approved based on a four-point improvement on the 60-point MADRS (Montgomery Asberg Depression Rating Scale) in that single study, an improvement which was not clinically significant.
Spravato was approved even though there were six car accidents in the S-ketamine group, of which one was fatal. Another person in the S-ketamine group died of a heart attack, and another of heart-lung failure.
Most significantly, Spravato was approved even though three people in the S-ketamine arm of the trial committed suicide, of whom two had stated prior to the trial that they had never experienced suicidal thoughts. Janssen and the FDA dismissed the deaths as unrelated to the drug, claiming the number of suicides was “low” and that there was “no pattern” among them.
Death is forever but clinical trials only last four weeks
In an editorial published in Lancet Psychiatry, Dr. Erick H. Turner MD, a member of one of the FDA advisory committees that recommended approving Spravato, decried the decision.
“Accepting just one short-term trial as being enough is an historic break from precedent,” he told Medscape Medical News.
Turner was not alone among FDA board members to criticize the organization’s decision. Another, Steven Meisel, the system director of medication safety for Fairview Health Services, pointed out that most antidepressant drugs are used in the very long-term and that Janssen’s trials had failed to provide any illumination in this area. “I don't think that we really understand what happens when you take this week after week for weeks and months and years,” he said.
For some unstated reason, Meisel nonetheless voted in favor of approving Spravato.
Another “yes” vote was that of Dr. Matthew Rudorfer of the National Institute of Mental Health (the government-run NIMH). Rudorfer, unlike Meisel, Turner, and others, justified the FDA’s decision.
I think we're all agreeing on the very important, and sometimes life-or-death, risk of inadequately treated depression that factored into my equation.
Indeed, most existing antidepressants don’t work very well, if at all, and many have debilitating and even permanent side-effects. It has been decades since something “new” has been approved to treat depression, but that doesn't mean Spravato will be better.
Breakthrough therapy – therapy that breaks through all the rules
The supposed novelty of S-ketamine was exciting for Janssen as it could be patented. For the FDA, the novelty was similarly enticing. In 2013, Janssen persuaded the FDA to designate S-ketamine a “breakthrough therapy” for its apparent ability to reverse depression rapidly and offer a solution to people who were seriously suicidal. The potential was assessed based on a study lasting just two days with only 30 people enrolled.
Once the FDA assigned “breakthrough” status to S-ketamine, it was on a fast-track to approval, meaning that the FDA actively participated in the entire approval process rather than merely assessing trial results when submitted. According to Medscape, this meant that the FDA together with Janssen decided how to define “treatment-resistant depression,” as well as how many successful trial results would be needed for S-ketamine to clear the approval bar.
Dr. Turner is highly critical of the way the FDA handled Spravato’s approval from the outset, citing “breakthrough bias” as one reason why the drug, which operates in a totally different way to existing antidepressants, was given preferential treatment.
If you showed them the same data for an SSRI, they would ask, “What's good about this?
Turner stresses that Spravato’s preferential treatment turned out to be unwarranted, given that the trial results showed S-ketamine to be inferior to other methods of treating “treatment-resistant depression” (TRD). One drug combination that is often used for TRD is olanzapine-fluoxetine, which seems to be just as effective as Spravato. Another combo is aripiprazole plus quetiapine, whose trial results are actually better than S-ketamine’s.
Failed trials or failed patients?
It’s important to stress that Spravato has only been FDA-approved for TRD and not for “regular” depression. While that may sound impressive — according to Janssen, Spravato can go where no drug has gone before — here too the FDA lowered the bar to let S-ketamine through.
According to Professor Glen Spielmans of Metropolitan State University in Saint Paul, Minnesota, the patients enrolled in Janssen’s trials “were not necessarily highly treatment-resistant.”
Based on the evidence provided in Janssen's application, the FDA should not have approved the drug.
Janssen’s only “successful” clinical trial for S-ketamine had 227 people enrolled. 49 of them had only failed one class of oral antidepressants. That would have ruled them out as “treatment-resistant” had the FDA not altered its definition from failing two classes of antidepressants to two different antidepressant drugs, even from the same class.
Dr. Turner also points out that trial participants were not required to have “failed” with psychotherapy, which skewed the trials because they therefore did not reflect the “real world” of depressed patients.
Can a placebo give you a trip?
Prof. Spielmans notes another problem with the clinical trials. Although they were technically double-blinded (neither participants nor researchers knew which group people were in), the very nature of S-ketamine meant that the blinding was imperfect.
[S-ketamine] is not subtle. It has characteristic properties. For example, it causes high rates of sedation and dissociation. People are going to notice if they [take it or] stop taking it, which erases the “blindness” of the study.
A further problem was bound up in the nature of the studies themselves. S-ketamine was not tested directly against placebo, or another anti-depressant. Rather, S-ketamine plus a newly-initiated antidepressant was tested against placebo plus a newly-prescribed antidepressant. Before the trial commenced, participants were abruptly taken off any antidepressant drug they had been taking beforehand, which is likely to have resulted in withdrawal effects for many of them which could potentially make their depression feel worse — and using an anesthetic-psychedelic drug to counter withdrawal effects could potentially appear much more effective than it would otherwise.
Yet even with the decks stacked in its favor, S-ketamine still performed poorly in most of the trials published. In one trial, only about ten percent of patients in the treatment arm had a “rapid clinical response.” In another of the failed trials, the results were even worse — just eight percent had a rapid response, compared to five percent for the placebo arm.
Relapse, or just coming down from a high?
As noted, the FDA relied on a single trial for approval. It did, however, add another “successful” trial to its records — this was a withdrawal trial. Turner is similarly dismissive of the results here, even though the trial found that “Esketamine and antidepressant treatment decreased the risk of relapse by 51%...”
Turner explains that those included in the withdrawal trial were taken from the previous “successful” trial — but only those who had responded well to S-ketamine. Those who hadn’t responded well were “weeded out.”
You're testing whether the drug works within a subset of known esketamine responders. It’s like conducting a poll on the popularity of our fine president within a sample of people who you know already voted for him.
Spielmans points out another troubling aspect of the withdrawal study: the fact that people switched from Spravato, whose depression had supposedly been alleviated by the drug, to placebo, relapsed so fast.
Depression should not naturally return so rapidly after discontinuing successful treatment.
Which is possibly his cautious way of suggesting that perhaps the depression never went away at all?
We researched Spravato, so it must be better, regardless of trial results…
Ketamine users, meanwhile, are often extremely enthusiastic about the drug’s impact on their depression or other emotional distress. Many admit its addictive properties, the damage it can cause to the bladder, the dangers of falling into a “K-hole” (a bad trip), and other downsides. But unlike Spravato, ketamine is at least cheap. S-ketamine is extremely expensive, around $550 per (low) dose, and multiple doses are needed.
Patients aren’t paying for the drug itself, of course. They’re paying for all the accoutrements, such as the clinic where, as per the FDA approval, the drug must be administered and the patient supervised for two hours afterward. This is, of course, what gives what is essentially a psychedelic drug its respectability.
According to Dr. Lisa Harding, former vice president of the American Society of Ketamine Physicians and assistant clinical professor of psychiatry at Yale School of Medicine, this is an unfair way of portraying Spravato. She insists that S-ketamine and racemic ketamine are “very distinct” in their chemical composition, without elaborating — not surprisingly, as she would be hard-pressed to distinguish clearly between the two.
She then adds that other key differences between off-label ketamine and Janssen’s Spravato are the FDA approval of the latter, plus the dosing and the method of administration. Regular ketamine is usually taken orally, whereas S-ketamine is a nasal preparation.
Discounting the experiences of probably hundreds of thousands of people, Harding insists that “there is no evidence to support treating patients” with ketamine lozenges, whereas Spravato has been properly studied.
Even the mainstream Kaiser Family Foundation admits the obvious flaw in Harding’s argument: The reason ketamine has not been properly studied is that nobody stands to gain financially from doing so:
Although ketamine has been used off-label for years to treat depression and post-traumatic stress disorder, drugmakers saw little profit in doing the studies to prove to the FDA that it worked for that purpose.
Ketamine is dangerous; Spravato is “safe and effective”
Harding is not alone in singing Spravato’s praises. Many healthcare professionals have expressed their relief that, finally, ketamine is being given a run for its money by something “demonstrably safe and effective.”
“People who decide to use ketamine recreationally need to be educated about potential risks,” said Dr. Joseph Palamar of New York University Grossman School of Medicine, New York City.
Samuel Wilkinson, MD, assistant professor of psychiatry and associate director of the Yale Depression Research Program, told Medscape Medical News of his relief that S-ketamine is now FDA-approved.
For a long time, we've been worried about the lack of regulation and coordination among clinics that provide ketamine as an off-label therapy for mental illness.
Wilkinson then added,
The opioid epidemic is another example [of the dangers of poorly regulated drugs]. Hopefully, [with ketamine], we can do a better job of erring on the side of safety.
Dr. Horowitz and Professor Moncrieff draw very different conclusions.
It is not clear how drug-induced euphoria and antidepressant effects can be distinguished ... The esketamine trials do not confirm that a clinically relevant effect occurs...
We [wish to] communicate our concern that the public might be exposed to a pharmacological agent for which robust efficacy and safety have not yet been demonstrated.
Postscript:
While the FDA approved Spravato based on just one allegedly successful trial, in China, researchers are already examining the use of S-ketamine for postpartum depression. One study, in which 364 women were enrolled, was hailed as successful despite a variety of adverse events.
Researchers reported a 74% reduction in the risk for postpartum depression in the group that received Spravato (6.7% vs 25.4%). Depression scores on the Edinburgh Postnatal Depression Scale were found to be lower in the Spravato cohort — a median difference of 3 on a 30-point scale.
The trial revealed various adverse effects in the Spravato group. Just over a quarter of new mothers receiving S-ketamine experienced dizziness. Almost five percent had double vision. Just over three percent had hallucinations or nightmares. Researchers reported that these adverse events “spontaneously” resolved within a day. They do not detail how the welfare of the newborn infants was safeguarded while their mothers were tripping.
The information contained in this article is for educational and information purposes only and is not intended as health, medical, financial or legal advice. Always consult a physician, lawyer or other qualified professional regarding any questions you may have about a medical condition, health objectives or legal or financial issues. If you are struggling with suicidal thoughts, you can call a qualified free mental health helpline or seek help from a qualified therapist.
