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New analysis claims the FDA rushed ketamine's approval for depression treatment
Clinical trials by Janssen Pharmaceuticals showed troubling results.
- A new analysis in The British Journal of Psychiatry claims the FDA approval process for ketamine was rushed.
- Only one of three clinical trials showed efficacy, while the discontinuation trial produced troubling outcomes.
- Ketamine's side effects include anxiety, poor appetite, delusions, hallucinations, paranoia, rage, and craving.
There was a lot of excitement when the FDA fast-tracked trials for ketamine as a depression treatment in 2016. The announcement marked a major turning point in our understanding of psychedelics, which were deemed a Schedule 1 substance as part of Richard Nixon's racist 1970 "War on Drugs." Ketamine was approved for use as an anesthetic that same year; due to increasing recreational usage in the 1990s, however, it was deemed Schedule III in America in 1999.
Though ketamine is not a traditional psychedelic—they have an agonist (or partial agonist) effect at brain serotonin 5-HT2A receptors—it falls into this class due to its hallucinogenic and dissociative effects. Recently it has been referred to as a "party psychedelic." Psychedelic therapy advocates were pleased when the FDA approved a nasal spray medication for treatment-resistant depression known as esketamine in 2019. Janssen Pharmaceuticals launched Spravato shortly after.
This move is exciting. Trials of two types of ketamine—racemic ketamine and esketamine—showed early positive results, even though researchers are not exactly sure how it functions in depression treatment. We do know antidepressants and antipsychotics are showing less efficacy and more chronic side effects than previously believed, however.
There is precedent in the psychedelic realm. Psilocybin, ayahuasca, ibogaine, MDMA, and LSD are showing early positive results in treating anxiety, depression, addiction, and PTSD. This does not mean we should rush blindly ahead, however.
That's the consensus reached by Mark Horowitz (writer) and Joanna Moncrieff (editor), whose recent analysis, published in The British Journal of Psychiatry, concludes that we're moving too fast in clinically adopting ketamine. As their data shows, caution is necessary.
Since its discovery in 1962, ketamine has been used broadly as a sedative and anesthetic; to aid in emergency surgeries in war zones; as a bronchodilator for severe asthmatics; to treat certain type of seizures; in postoperative pain management; and now, as a nasal spray to treat depression. Unlike SSRIs and SNRIs, esketamine works immediately—in as little as two hours—making it more attractive to patients and clinicians.
The Experimental Ketamine Cure for Depression
While treatment-resistant depression sounds extreme, Horowitz notes the definition: patients unsuccessful with two different antidepressants, a low bar for the term "resistant." The problem with trying esketamine, he writes, falls back on the FDA fast-tracking of the drug.
"Out of the three short-term trials conducted by Janssen only one showed a statistically significant difference between esketamine and placebo. These were even shorter than the 6–8 week trials the FDA usually requires for drug licensing."
Each trial lasted only four weeks. The FDA normally requires that two such trials show better results than the placebo; in this case, only one achieved this goal. The successful trial showed a four-point margin on a scale that goes to 60.
Failing to provide two effective trials, the FDA allowed Janssen to submit a discontinuation trial as evidence. This 16-week trial let patients either continue or stop treatment. The problem: side effects were treated as evidence of relapse, not withdrawal symptoms.
Ketamine users have a long history of withdrawal issues, including anxiety, poor appetite, delusions, hallucinations, paranoia, addiction, rage, and craving. The discontinuation trial considers such effects as proof of ketamine's efficacy, not as symptoms of withdrawal.
Science writer Peter Simons explains why this is worrisome:
"Perhaps even more concerning is the fact that, within the discontinuation trial, a single site in Poland drove the apparent finding of efficacy. Data from this site suggested that 100% of the placebo group supposedly relapsed (compared with about 33% of the placebo group in all the other sites)—an unlikely result. When data from this suspicious outlier was removed, the study analysis showed no evidence that esketamine was better than the placebo."
Add to this that six people in the esketamine group died during the trials, including three by suicide—two of whom had previously shown no signs of suicidal ideations—and a troubling picture emerges. The FDA accepted Janssen's explanation: the problem wasn't esketamine, but their underlying condition. This is possible, but the company did not provide conclusive evidence.
Jennifer Taubert, executive vice president and worldwide chairman of Janssen Pharmaceuticals, Johnson & Johnson, testifies before the Senate Finance Committee on "Drug Pricing in America: A Prescription for Change, Part II" February 26, 2019 in Washington, DC. The committee heard testimony from a panel of pharmaceutical company CEOs on the reasons for rising costs of prescription drugs.
Photo by Win McNamee/Getty Images
According to Horowitz, this is a chronic problem with clinical trials and governing agencies.
"It would seem that themes from history are repeating: a known drug of misuse, associated with significant harm, is increasingly promoted despite scant evidence of efficacy and without adequate longterm safety studies."
He also notes that half of the patients experienced disassociation and one-third experienced dizziness. On this point, allow me to break the fourth wall. I've been experimenting with psychedelics since 1994 and am writing a book on psychedelics in ritual and therapy. I ingested a range of substances during my college years. By far, the most troublesome was ketamine. While I'm now aware of Parecelsus's dictum—what is beneficial in small doses is toxic in large doses—I wasn't measuring it out in the 1990s.
Administered doses in Janssen's trials were considered similar to recreational usage. I recall that a bump provided an energetic lift, yet when I'd occasionally snort a line, all bets were off. After a hearty dose one evening, I laid down, sat up, and stood in succession. I couldn't tell the difference between those three physical positions. Ketamine is the most dissociative substance I've ever taken, and I stopped shortly after that last instance.
Psychedelics are the next wave of mental health treatments—call it a continuation, given their role in traditional rituals. We came to rely on pharmacology too much in the twentieth century; hopefully we're learning from those mistakes. As Horowitz points out, however, it appears we're not.
The important word in psychedelic therapy is ritual. There are environmental and social factors entwined with our health. In the right context, psychedelics have tremendous healing power. And to be fair, some ketamine clinics are taking proper right safety precautions as well as designing treatment rooms to be more conducive to healing than sterile white rooms. Patients are anecdotally reporting success in depression treatment with ketamine. This isn't an either-or situation.
But we cannot make the same mistake we've made with CBD and believe these substances are cure-alls. We also can't afford to designate ketamine under the umbrella term "psychedelics." As Alan Watts wrote, hallucinogen is not a proper definition of the psychedelic experience, though it's fitting when describing ketamine. Conflating substances will only further confusion during a time when we need clarity. If the addictive properties and dangerous side effects of ketamine play out widely, it endangers the entire psychedelic therapy model.
We can hope for a clinically-effective dosage and delivery mechanism of ketamine. We can't, as Horowitz's analysis shows, make the same mistakes over. Pharmacological intervention has a place in psychiatry, but it's come to dominate the industry, often no better than placebo and psychotherapy. We need healing, not more side effects.
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The father of all giant sea bugs was recently discovered off the coast of Java.
- A new species of isopod with a resemblance to a certain Sith lord was just discovered.
- It is the first known giant isopod from the Indian Ocean.
- The finding extends the list of giant isopods even further.
Humanity knows surprisingly little about the ocean depths. An often-repeated bit of evidence for this is the fact that humanity has done a better job mapping the surface of Mars than the bottom of the sea. The creatures we find lurking in the watery abyss often surprise even the most dedicated researchers with their unique features and bizarre behavior.
A recent expedition off the coast of Java discovered a new isopod species remarkable for its size and resemblance to Darth Vader.
The ocean depths are home to many creatures that some consider to be unnatural.
According to LiveScience, the Bathynomus genus is sometimes referred to as "Darth Vader of the Seas" because the crustaceans are shaped like the character's menacing helmet. Deemed Bathynomus raksasa ("raksasa" meaning "giant" in Indonesian), this cockroach-like creature can grow to over 30 cm (12 inches). It is one of several known species of giant ocean-going isopod. Like the other members of its order, it has compound eyes, seven body segments, two pairs of antennae, and four sets of jaws.
The incredible size of this species is likely a result of deep-sea gigantism. This is the tendency for creatures that inhabit deeper parts of the ocean to be much larger than closely related species that live in shallower waters. B. raksasa appears to make its home between 950 and 1,260 meters (3,117 and 4,134 ft) below sea level.
Perhaps fittingly for a creature so creepy looking, that is the lower sections of what is commonly called The Twilight Zone, named for the lack of light available at such depths.
It isn't the only giant isopod, far from it. Other species of ocean-going isopod can get up to 50 cm long (20 inches) and also look like they came out of a nightmare. These are the unusual ones, though. Most of the time, isopods stay at much more reasonable sizes.
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During an expedition, there are some animals which you find unexpectedly, while there are others that you hope to find. One of the animal that we hoped to find was a deep sea cockroach affectionately known as Darth Vader Isopod. The staff on our expedition team could not contain their excitement when they finally saw one, holding it triumphantly in the air! #SJADES2018
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What benefit does this find have for science? And is it as evil as it looks?
The discovery of a new species is always a cause for celebration in zoology. That this is the discovery of an animal that inhabits the deeps of the sea, one of the least explored areas humans can get to, is the icing on the cake.
Helen Wong of the National University of Singapore, who co-authored the species' description, explained the importance of the discovery:
"The identification of this new species is an indication of just how little we know about the oceans. There is certainly more for us to explore in terms of biodiversity in the deep sea of our region."
The animal's visual similarity to Darth Vader is a result of its compound eyes and the curious shape of its head. However, given the location of its discovery, the bottom of the remote seas, it may be associated with all manner of horrifically evil Elder Things and Great Old Ones.
If computers can beat us at chess, maybe they could beat us at math, too.
- Most everyone fears that they will be replaced by robots or AI someday.
- A field like mathematics, which is governed solely by rules that computers thrive on, seems to be ripe for a robot revolution.
- AI may not replace mathematicians but will instead help us ask better questions.
The following is an excerpt adapted from the book Shape. It is reprinted with permission of the author.
Will machines replace us? Since the origin of artificial intelligence (AI), people have worried that computers eventually (or even imminently!) will surpass the human cognitive capacity in every respect.
Artificial intelligence pioneer Oliver Selfridge, in a television interview from the early 1960s, said, "I am convinced that machines can and will think in our lifetime" — though with the proviso, "I don't think my daughter will ever marry a computer." (Apparently, there is no technical advance so abstract that people can't feel sexual anxiety about it.)
Let's make the relevant question more personal: will machines replace me? I'm a mathematician; my profession is often seen from the outside as a very complicated but ultimately purely mechanical game played with fixed rules, like checkers, chess, or Go. These are activities in which machines have already demonstrated superhuman ability.
Some people imagine a world where computers give us all the answers. I dream bigger. I want them to ask good questions.
But for me, math is different: it is a creative pursuit that calls on our intuition as much as our ability to compute. (To be fair, chess players probably feel the same way.) Henri Poincaré, the mathematician who re-envisioned the whole subject of geometry at the beginning of the 20th century, insisted it would be hopeless
"to attempt to replace the mathematician's free initiative by a mechanical process of any kind. In order to obtain a result having any real value, it is not enough to grind out calculations, or to have a machine for putting things in order: it is not order only, but unexpected order, that has a value. A machine can take hold of the bare fact, but the soul of the fact will always escape it."
But machines can make deep changes in mathematical practice without shouldering humans aside. Peter Scholze, winner of a 2018 Fields Medal (sometimes called the "Nobel Prize of math") is deeply involved in an ambitious program at the frontiers of algebra and geometry called "condensed mathematics" — and no, there is no chance that I'm going to try to explain what that is in this space.
Meet AI, your new research assistant
What I am going to tell you is the result of what Scholze called the "Liquid Tensor Experiment." A community called Lean, started by Leonardo de Moura of Microsoft Research and now open-source and worldwide, has the ambitious goal of developing a computer language with the expressive capacity to capture the entirety of contemporary mathematics. A proposed proof of a new theorem, formalized by translation into this language, could be checked for correctness automatically, rather than staking its reputation on fallible human referees.
Scholze asked last December whether the ideas of condensed mathematics could be formalized in this way. He also wanted to know whether it could express the ideas of a particularly knotty proof that was crucial to the project — a proof that he was pretty sure was right.
When I first heard about Lean, I thought it would probably work well for some easy problems and theorems. I underestimated it. So did Scholze. In a May 2021 blog post, he writes, "[T]he Experiment has verified the entire part of the argument that I was unsure about. I find it absolutely insane that interactive proof assistants are now at the level that within a very reasonable time span they can formally verify difficult original research."
And the contribution of the machine wasn't just to certify that Scholze was right to think his proof was sound; he reports that the work of putting the proof in a form that a machine could read improved his own human understanding of the argument!
The Liquid Tensor Experiment points to a future where machines, rather than replacing human mathematicians, become our indispensable partners. Whether or not they can take hold of the soul of the fact, they can extend our grasp as we reach for the soul.
Slicing up a knotty problem
That can take the form of "proof assistance," as it did for Scholze, or it can go deeper. In 2018, Lisa Piccirillo, then a PhD student at the University of Texas, solved a long-standing geometry problem about a shape called the Conway knot. She proved the knot was "non-slice" — this is a fact about what the knot looks like from the perspective of four-dimensional beings. (Did you get that? Probably not, but it doesn't matter.) The point is this was a famously difficult problem.
A few years before Piccirillo's breakthrough, a topologist named Mark Hughes at Brigham Young had tried to get a neural network to make good guesses about which knots were slice. He gave it a long list of knots where the answer was known, just as an image-processing neural net would be given a long list of pictures of cats and pictures of non-cats.
Hughes's neural net learned to assign a number to every knot; if the knot were slice, the number was supposed to be 0, while if the knot were non-slice, the net was supposed to return a whole number bigger than 0. In fact, the neural net predicted a value very close to 1 — that is, it predicted the knot was non-slice — for every one of the knots Hughes tested, except for one. That was the Conway knot.
For the Conway knot, Hughes's neural net returned a number very close to 1/2, its way of saying that it was deeply unsure whether to answer 0 or 1. This is fascinating! The neural net correctly identified the knot that posed a really hard and mathematically rich problem (in this case, reproducing an intuition that topologists already had).
Some people imagine a world where computers give us all the answers. I dream bigger. I want them to ask good questions.
Dr. Jordan Ellenberg is a professor of mathematics at the University of Wisconsin and a number theorist whose popular articles about mathematics have appeared in the New York Times, the Wall Street Journal, Wired, and Slate. His most recent book is Shape: The Hidden Geometry of Information, Biology, Strategy, Democracy, and Everything Else.
Laughing gas may be far more effective for some than antidepressants.
- Standard antidepressant medications don't work for many people who need them.
- With ketamine showing potential as an antidepressant, researchers investigate another anesthetic: nitrous oxide, commonly called "laughing gas."
- Researchers observe that just a light mixture of nitrous oxide for an hour alleviates depression symptoms for two weeks.
The usual antidepressants don't work for everyone. That's what makes a new study of the antidepressant properties of nitrous oxide so intriguing. It looks like just a single low dose of what your dentist may call "laughing gas" can help alleviate symptoms of depression for weeks afterward.
The study, from researchers at University of Chicago and Washington University-St. Louis, is published in the journal Science Translational Medicine.
Resistance to anti-depression medications
Nitrous oxide: two atoms of nitrogen, one of oxygenCredit: Big Think
According to the senior author of the study, Charles Conway, "A significant percentage — we think around 15 percent — of people who suffer from depression don't respond to standard antidepressant treatment."
"These 'treatment-resistant depression' patients," Conway says, "often suffer for years, even decades, with life-debilitating depression. We don't really know why standard treatments don't work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals."
"There is a huge unmet need," says lead author Peter Nagele. "There are millions of depressed patients who don't have good treatment options, especially those who are dealing with suicidality."
If ketamine can help, can nitrous oxide?
Credit: sudok1 / Adobe Stock
The researchers wondered if some of the anti-depression properties seen in ketamine might also apply to nitrous oxide. Nagele explains, "Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression."
The researchers conducted a one-hour session — they describe it as a "proof-of-principle" trial — in which 20 individuals with depression were administered an air mixture with 50 percent nitrous oxide. Twenty-four hours later, the researchers found a significant reduction in the participants' symptoms of depression versus a control group.
However, the individuals also suffered the unpleasant side effects that laughing gas often causes in dental patients: headache, nausea, and vomiting.
Smaller dose, longer effect
Credit: sudok1 / Adobe Stock
"We wondered if our past concentration of 50 percent had been too high," recalls Nagele. "Maybe by lowering the dose, we could find the 'Goldilocks spot' that would maximize clinical benefit and minimize negative side effects."
In a new trial, 20 people with depression were given a lighter nitrous oxide mix, just 25 percent, and the individuals tested reported a 75 percent reduction in side effects compared to the a control group given an air/oxygen placebo. This time, the researchers also tracked the effect of nitrous oxide on symptoms of depression for a far longer period, two weeks instead of just 24 hours.
"The reduction in side effects was unexpected and quite drastic," reports Nagele, "but even more excitingly, the effects after a single administration lasted for a whole two weeks. This has never been shown before. It's a very cool finding."
Nagele also notes that, despite its popular renown as laughing gas, even a light 25 percent mix of nitrous actually causes people to nod off. "They're not getting high or euphoric; they get sedated."
Delivering help to people with depression
Nagele cautions, "These have just been pilot studies. But we need acceptance by the larger medical community for this to become a treatment that's actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we'll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice."
After all, Nagele adds, "If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that's a very gratifying line of research."