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Ketamine infusion: The new therapy for depression, explained
The treatment is here, but are we ready?
- Ketamine is the first hallucinogen approved for therapeutic use in the U.S.
- Research has shown ketamine is effective at treating depression.
- Though ketamine infusion therapy is now being offered at hundreds of North American clinics, there are unaddressed dangers in the current ketamine gold rush.
In March 2019, the FDA approved ketamine, under the trade name Spravato (esketamine), for clinical use in treatment-resistant depression therapy. Alongside racemic ketamine, which is commonly used in ketamine infusion therapy, ketamine is the first hallucinogen approved for therapeutic usage in the United States.
Technically, ketamine is not a psychedelic but rather a hallucinogen and dissociative. (While ketamine has psychedelic effects, traditional psychedelics bind to the 5-HT2B receptor.) Still, advocates for psychedelic therapy recognize ketamine as a gateway for traditional psychedelics, such as psilocybin and LSD, to be considered for therapeutic usage.
To understand the proliferation of ketamine clinics across North America, the origins of this peculiar substance — one that went from battlefields to veterinary clinics to dance clubs in the span of two decades — must be discussed.
History of ketamine
In 1962, chemistry professor Calvin Stevens synthesized ketamine while researching alpha-hydroxyimine rearrangements. The first human tests were conducted on prisoners in 1964. Ketamine soon replaced phencyclidine (PCP) as the go-to anesthetic in hospitals. It was initially used on soldiers during the Vietnam War following FDA approval in 1970. Thanks to its success on the battlefield, ketamine was placed on the World Health Organization's List of Essential Medicines.
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 types of seizures; and in postoperative pain management. Now, ketamine infusions and nasal sprays are being used for depression. Ketamine is also showing potential efficacy in treating chronic pain and suicidal ideation, though more research needs to be done.
Of all of those uses, ketamine has predominantly been used as an anesthetic in humans and animals. While it restricts breathing less than other similar medications, ketamine also produces hallucinations (thus, it's labeled as a dissociative anesthetic). The list of potential side effects from using ketamine is long, including nausea, double vision, breathing problems, impaired memory, liver enzyme abnormalities, urinary tract problems, and even increased depression — an alarming possibility given its growing use as an antidepressant replacement.
Small-scale studies on using ketamine to treat depression were conducted in 2000 and 2006. Further research confirmed its role in alleviating depressive symptoms, including the possibility that the antidepressant effects of a single dose can persist for weeks. In 2016, the FDA fast-tracked ketamine trials for depression.
A chair is seen in a therapy room at Field Trip, a psychedelic therapy clinic in Toronto, Ontario, Canada.Credit: Cole Burston/AFP via Getty Images
Ketamine infusion therapy
There has yet to be a consensus on how ketamine addresses depression. Antidepressants act on the body's serotonin and noradrenaline systems. Ketamine seems to interfere with an amino acid derivative, NMDA. As a 2017 study published in the journal Nature explains:
"Ketamine is responsible for blocking the N-methyl-D-aspartate (NMDA) receptor, which causes an immediate alleviation of depressive effects, while another metabolite in the drug helps the effects last for hours. This blockage is also what causes the hallucinogenic effects."
Small intravenous doses of esketamine — an enantiomer of ketamine and the substance actually approved by the FDA — seem to lift depressed patients out of their funk. So does Spravato, a nasal spray that can only be administered under supervision in a doctor's office or clinic.
Patients that have tried two different antidepressant medications with no success (the definition of treatment-resistant depression) can legally receive ketamine infusions or Spravato at clinics located all over the country. Since the therapy is generally not covered by insurance, treatments range from $300 to $2,000 per session; the Field Trip Treatment Program, which includes psychotherapy and six infusions, runs $4,700.
The process of ketamine infusion therapy is varied depending on which clinic you attend. Companies like Field Trip and organizations such as MAPS require psychotherapy sessions to coincide with infusions.
Unfortunately, therapeutic implementation has not always lived up to federal requirements. Reports of patients quitting antidepressants and psychotherapy to use esketamine as their primary source of treatment abound. Since medical professionals with no mental health training, such as nurse practitioners, anesthesiologists, and pain physicians, can legally administer ketamine, patients are left to process the drug's effects with little to no guidance.
Thus far, efficacy has been mixed. As STAT News editor Megan Thielking writes, people with minor depressive issues are likely better candidates for ketamine therapy than those with treatment-resistant depression, the very cohort the drug is purported to target.
"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. 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."
Was ketamine approved too quickly?
While ketamine therapy is certainly promising, the FDA-approved trials raise a number of red flags. A recent analysis in The British Journal of Psychiatry concludes that we're moving too fast. Author Mark Horowitz writes:
"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."
Trials usually last three months; the approved ketamine trials only lasted four weeks and barely showed efficacy above placebo. More concerning, the FDA allowed Janssen to submit a discontinuation trial with a study design flaw as evidence of efficacy — side effects were treated as evidence of relapse, not withdrawal symptoms. Even more alarmingly, six people in the esketamine group died during the trials, including three by suicide, two of which had previously shown no signs of suicidal ideation.
When Janssen stated that the problem wasn't esketamine but underlying conditions, the FDA accepted the reasoning even though no conclusive evidence was provided. This doesn't mean ketamine therapy isn't potentially therapeutic, though it does suggest that its approval by the FDA was rushed.
Psychiatrist Lori Calabrese, who offers ketamine infusion for depression and anxiety in her clinic, puts it best when stating, "The pace of ketamine treatment in real-world practices has outstripped what researchers are able to do and publish." Time will tell if this treatment proves more beneficial than dangerous in mental health treatments.
Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."
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So much for rest in peace.
- Australian scientists found that bodies kept moving for 17 months after being pronounced dead.
- Researchers used photography capture technology in 30-minute intervals every day to capture the movement.
- This study could help better identify time of death.
We're learning more new things about death everyday. Much has been said and theorized about the great divide between life and the Great Beyond. While everyone and every culture has their own philosophies and unique ideas on the subject, we're beginning to learn a lot of new scientific facts about the deceased corporeal form.
An Australian scientist has found that human bodies move for more than a year after being pronounced dead. These findings could have implications for fields as diverse as pathology to criminology.
Dead bodies keep moving
Researcher Alyson Wilson studied and photographed the movements of corpses over a 17 month timeframe. She recently told Agence France Presse about the shocking details of her discovery.
Reportedly, she and her team focused a camera for 17 months at the Australian Facility for Taphonomic Experimental Research (AFTER), taking images of a corpse every 30 minutes during the day. For the entire 17 month duration, the corpse continually moved.
"What we found was that the arms were significantly moving, so that arms that started off down beside the body ended up out to the side of the body," Wilson said.
The researchers mostly expected some kind of movement during the very early stages of decomposition, but Wilson further explained that their continual movement completely surprised the team:
"We think the movements relate to the process of decomposition, as the body mummifies and the ligaments dry out."
During one of the studies, arms that had been next to the body eventually ended up akimbo on their side.
The team's subject was one of the bodies stored at the "body farm," which sits on the outskirts of Sydney. (Wilson took a flight every month to check in on the cadaver.)Her findings were recently published in the journal, Forensic Science International: Synergy.
Implications of the study
The researchers believe that understanding these after death movements and decomposition rate could help better estimate the time of death. Police for example could benefit from this as they'd be able to give a timeframe to missing persons and link that up with an unidentified corpse. According to the team:
"Understanding decomposition rates for a human donor in the Australian environment is important for police, forensic anthropologists, and pathologists for the estimation of PMI to assist with the identification of unknown victims, as well as the investigation of criminal activity."
While scientists haven't found any evidence of necromancy. . . the discovery remains a curious new understanding about what happens with the body after we die.
Metal-like materials have been discovered in a very strange place.
- Bristle worms are odd-looking, spiky, segmented worms with super-strong jaws.
- Researchers have discovered that the jaws contain metal.
- It appears that biological processes could one day be used to manufacture metals.
The bristle worm, also known as polychaetes, has been around for an estimated 500 million years. Scientists believe that the super-resilient species has survived five mass extinctions, and there are some 10,000 species of them.
Be glad if you haven't encountered a bristle worm. Getting stung by one is an extremely itchy affair, as people who own saltwater aquariums can tell you after they've accidentally touched a bristle worm that hitchhiked into a tank aboard a live rock.
Bristle worms are typically one to six inches long when found in a tank, but capable of growing up to 24 inches long. All polychaetes have a segmented body, with each segment possessing a pair of legs, or parapodia, with tiny bristles. ("Polychaeate" is Greek for "much hair.") The parapodia and its bristles can shoot outward to snag prey, which is then transferred to a bristle worm's eversible mouth.
The jaws of one bristle worm — Platynereis dumerilii — are super-tough, virtually unbreakable. It turns out, according to a new study from researchers at the Technical University of Vienna, this strength is due to metal atoms.
Metals, not minerals
Fireworm, a type of bristle wormCredit: prilfish / Flickr
This is pretty unusual. The study's senior author Christian Hellmich explains: "The materials that vertebrates are made of are well researched. Bones, for example, are very hierarchically structured: There are organic and mineral parts, tiny structures are combined to form larger structures, which in turn form even larger structures."
The bristle worm jaw, by contrast, replaces the minerals from which other creatures' bones are built with atoms of magnesium and zinc arranged in a super-strong structure. It's this structure that is key. "On its own," he says, "the fact that there are metal atoms in the bristle worm jaw does not explain its excellent material properties."
Just deformable enough
Credit: by-studio / Adobe Stock
What makes conventional metal so strong is not just its atoms but the interactions between the atoms and the ways in which they slide against each other. The sliding allows for a small amount of elastoplastic deformation when pressure is applied, endowing metals with just enough malleability not to break, crack, or shatter.
Co-author Florian Raible of Max Perutz Labs surmises, "The construction principle that has made bristle worm jaws so successful apparently originated about 500 million years ago."
Raible explains, "The metal ions are incorporated directly into the protein chains and then ensure that different protein chains are held together." This leads to the creation of three-dimensional shapes the bristle worm can pack together into a structure that's just malleable enough to withstand a significant amount of force.
"It is precisely this combination," says the study's lead author Luis Zelaya-Lainez, "of high strength and deformability that is normally characteristic of metals.
So the bristle worm jaw is both metal-like and yet not. As Zelaya-Lainez puts it, "Here we are dealing with a completely different material, but interestingly, the metal atoms still provide strength and deformability there, just like in a piece of metal."
Observing the creation of a metal-like material from biological processes is a bit of a surprise and may suggest new approaches to materials development. "Biology could serve as inspiration here," says Hellmich, "for completely new kinds of materials. Perhaps it is even possible to produce high-performance materials in a biological way — much more efficiently and environmentally friendly than we manage today."
Dealing with rudeness can nudge you toward cognitive errors.
- Anchoring is a common bias that makes people fixate on one piece of data.
- A study showed that those who experienced rudeness were more likely to anchor themselves to bad data.
- In some simulations with medical students, this effect led to higher mortality rates.
Cognitive biases are funny little things. Everyone has them, nobody likes to admit it, and they can range from minor to severe depending on the situation. Biases can be influenced by factors as subtle as our mood or various personality traits.
A new study soon to be published in the Journal of Applied Psychology suggests that experiencing rudeness can be added to the list. More disturbingly, the study's findings suggest that it is a strong enough effect to impact how medical professionals diagnose patients.
Life hack: don't be rude to your doctor
The team of researchers behind the project tested to see if participants could be influenced by the common anchoring bias, defined by the researchers as "the tendency to rely too heavily or fixate on one piece of information when making judgments and decisions." Most people have experienced it. One of its more common forms involves being given a particular value, say in negotiations on price, which then becomes the center of reasoning even when reason would suggest that number should be ignored.
It can also pop up in medicine. As co-author Dr. Trevor Foulk explains, "If you go into the doctor and say 'I think I'm having a heart attack,' that can become an anchor and the doctor may get fixated on that diagnosis, even if you're just having indigestion. If doctors don't move off anchors enough, they'll start treating the wrong thing."
Lots of things can make somebody more or less likely to anchor themselves to an idea. The authors of the study, who have several papers on the effects of rudeness, decided to see if that could also cause people to stumble into cognitive errors. Past research suggested that exposure to rudeness can limit people's perspective — perhaps anchoring them.
In the first version of the study, medical students were given a hypothetical patient to treat and access to information on their condition alongside an (incorrect) suggestion on what the condition was. This served as the anchor. In some versions of the tests, the students overheard two doctors arguing rudely before diagnosing the patient. Later variations switched the diagnosis test for business negotiations or workplace tasks while maintaining the exposure to rudeness.
Across all iterations of the test, those exposed to rudeness were more likely to anchor themselves to the initial, incorrect suggestion despite the availability of evidence against it. This was less significant for study participants who scored higher on a test of how wide of a perspective they tended to have. The disposition of these participants, who answered in the affirmative to questions like, "Before criticizing somebody, I try to imagine how I would feel if I were in his/her place," was able to effectively negate the narrowing effects of rudeness.
What this means for you and your healthcare
The effects of anchoring when a medical diagnosis is on the line can be substantial. Dr. Foulk explains that, in some simulations, exposure to rudeness can raise the mortality rate as doctors fixate on the wrong problems.
The authors of the study suggest that managers take a keener interest in ensuring civility in workplaces and giving employees the tools they need to avoid judgment errors after dealing with rudeness. These steps could help prevent anchoring.
Also, you might consider being nicer to people.