New drug for schizophrenia could meet desperate need for better treatments
Schizophrenia is a debilitating mental health condition that affects around 24 million people worldwide. Patients experience hallucinations and delusions when they develop schizophrenia, with experts referring to these new thoughts and behaviors as positive symptoms. They also suffer from negative symptoms in which they lose important functions, suffering from dulled emotions, lack of purpose and social withdrawal.
Currently available drugs can control only a portion of these symptoms but, on August 8th, Karuna Therapeutics announced its completion of a phase 3 clinical trial that found a new drug called KarXT could treat both positive and negative symptoms of schizophrenia. It could mean substantial progress against a problem that has stymied scientists for decades.
A long-standing problem
Since the 1950s, antipsychotics have been used to treat schizophrenia. People who suffer from it are thought to have too much of a brain chemical called dopamine, and antipsychotics work by blocking dopamine receptors in the brain. They can be effective in treating positive symptoms but have little impact on the negative ones, which can be devastating for a patient’s quality of life, making it difficult to maintain employment and have successful relationships. About 30 percent of schizophrenia patients don't actually respond to antipsychotics at all. Current drugs can also have adverse side effects including elevated cholesterol, high blood pressure, diabetes and movements that patients cannot control.
The recent clinical trial heralds a new treatment approach. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” says Andrew Miller, COO of Karuna.
Scientists have been looking to develop alternatives. However, “the field of drug treatment of schizophrenia is currently in the doldrums,” says Peter McKenna, a senior researcher at FIDMAG Research Foundation in Spain which specialises in mental health.
In the 2000s there was a major push to target a brain receptor for a chemical called glutamate. Evidence suggested that this receptor is abnormal in the brains of schizophrenia patients, but attempts to try glutamate failed in clinical trials.
After that, many pharmaceutical companies dropped out of the race for a more useful treatment. But some companies continued to search, such as Karuna Therapeutics, led by founder and Chief Operating Officer Andrew Miller and CEO Steve Paul. The recent clinical trial suggests their persistence has led to an important breakthrough with their drug, KarXT. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” Miller says.
How it works
Neurotransmitters are chemical messengers that pass signals between neurons. To work effectively, neurotransmitters need a receptor to bind to. A neurotransmitter called acetylcholine seems to be especially important in schizophrenia. It interacts with sites called muscarinic receptors, which are involved in the network of nerves that calm your body after a stressful event. Post mortem studies in people with schizophrenia have shown that two muscarinic receptors in the brain, the M1 and M4 receptors, are activated at unusually low levels because they don’t receive enough signals from acetylcholine.
The M4 receptor appears to play a role in psychosis. The M1 receptor is also associated with psychosis but is primarily thought to be involved in cognition. KarXT, taken orally, works by activating both of these receptors to signal properly. It is this twofold action that seems to explain its effectiveness. “[The drug’s] design enables the preferential stimulation of these muscarinic receptors in the brain,” Miller says.
How it developed
It all started in the early 1990s when Paul was at pharmaceutical company Eli Lilly. He discovered that Xanomeline, the drug they were testing on Alzheimer's patients, had antipsychotic effects. It worked by stimulating M1 and M4 receptors, so he and his colleagues decided to test Xanomeline on schizophrenia patients, supported by research on the connection between muscarinic receptors and psychosis. They found that Xanomeline reduced both positive and negative symptoms.
Unfortunately, it also caused significant side effects. The problem was that stimulating the M1 and M4 receptors in the brain also stimulated muscarinic receptors in the body that led to severe vomiting, diarrhea and even the temporary loss of consciousness.
In the end, Eli Lilly discontinued the clinical trials for the drug, but Miller set up Karuna Therapeutics to develop a solution. “I was determined to find a way to harness the therapeutic benefit demonstrated in studies of Xanomeline, while eliminating side effects that limited its development,” Miller says.
He analysed over 7,000 possible ways of mixing Xanomeline with other agents before settling on KarXT. It combines Xanomeline with a drug called Trospium Chloride, which blocks muscarinic receptors in the body – taking care of the side effects such as vomiting – but leaves them unblocked in the brain. Paul was so excited by Miller’s progress that he joined Karuna after leaving Eli Lilly and founding two previous startups.
“It's a very important approach,” says Rick Adams, Future Leaders Fellow in the Institute of Cognitive Neuroscience and Centre for Medical Image Computing at University College London. “We are in desperate need of alternative drug targets and this target is one of the best. There are other alternative targets, but not many are as close to being successful as the muscarinic receptor drug.”
Clinical Trial
Following a successful phase 2 clinical trial in 2019, the most recent trial involved 126 patients who were given KarXT, and 126 who were given a placebo. Compared to the placebo, patients taking KarXT had a significant 9.6 point reduction in the positive and negative syndrome scale (PANSS), the standard for rating schizophrenic symptoms.
KarXT also led to statistically significant declines in positive and negative symptoms compared to the placebo. “The results suggest that KarXT could be a potentially game-changing option in the management of both positive and negative symptoms of schizophrenia,” Miller says.
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, is optimistic about the side effects but highlights the need for more safety trials.
McKenna, the researcher at FIDMAG Foundation, agrees about the drug’s potential. “The new [phase 3] study is positive,” he says. “It is reassuring that one is not dealing with a drug that works in one trial and then inexplicably fails in the next one.”
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, said the drug is an unprecedented step forward. “KarXT is one of the first drugs with a novel mechanism of action to show promise in clinical trials.”
Even though the drug blocks muscarine receptors in the body, some patients still suffered from adverse side effects like vomiting, dizziness and diarrhea. But in general, these effects were mild to moderate, especially compared to dopamine-blocking antipsychotics or Xanomeline on its own.
McCutcheon is optimistic about the side effects but highlights the need for more safety trials. “The trial results suggest that gastrointestinal side effects appear to be manageable,” he says. “We know, however, from previous antipsychotic drugs that the full picture regarding the extent of side effects can sometimes take longer to become apparent to clinicians and patients. Careful ongoing assessment during a longer period of treatment will therefore be important.”
The Future
The team is currently conducting three other trials to evaluate the efficacy and long-term safety of KarXT. Their goal is to receive FDA approval next year.
Karuna is also conducting trials to evaluate the effectiveness of KarXT in treating psychosis in patients suffering from Alzheimer’s.
The big hope is that they will soon be able to provide a radically different drug to help many patients with schizophrenia. “We are another step closer to potentially providing the first new class of medicine in more than 50 years to the millions of people worldwide living with schizophrenia,” says Miller.
Scientists experiment with burning iron as a fuel source
Story by Freethink
Try burning an iron metal ingot and you’ll have to wait a long time — but grind it into a powder and it will readily burst into flames. That’s how sparklers work: metal dust burning in a beautiful display of light and heat. But could we burn iron for more than fun? Could this simple material become a cheap, clean, carbon-free fuel?
In new experiments — conducted on rockets, in microgravity — Canadian and Dutch researchers are looking at ways of boosting the efficiency of burning iron, with a view to turning this abundant material — the fourth most common in the Earth’s crust, about about 5% of its mass — into an alternative energy source.
Iron as a fuel
Iron is abundantly available and cheap. More importantly, the byproduct of burning iron is rust (iron oxide), a solid material that is easy to collect and recycle. Neither burning iron nor converting its oxide back produces any carbon in the process.
Iron oxide is potentially renewable by reacting with electricity or hydrogen to become iron again.
Iron has a high energy density: it requires almost the same volume as gasoline to produce the same amount of energy. However, iron has poor specific energy: it’s a lot heavier than gas to produce the same amount of energy. (Think of picking up a jug of gasoline, and then imagine trying to pick up a similar sized chunk of iron.) Therefore, its weight is prohibitive for many applications. Burning iron to run a car isn’t very practical if the iron fuel weighs as much as the car itself.
In its powdered form, however, iron offers more promise as a high-density energy carrier or storage system. Iron-burning furnaces could provide direct heat for industry, home heating, or to generate electricity.
Plus, iron oxide is potentially renewable by reacting with electricity or hydrogen to become iron again (as long as you’ve got a source of clean electricity or green hydrogen). When there’s excess electricity available from renewables like solar and wind, for example, rust could be converted back into iron powder, and then burned on demand to release that energy again.
However, these methods of recycling rust are very energy intensive and inefficient, currently, so improvements to the efficiency of burning iron itself may be crucial to making such a circular system viable.
The science of discrete burning
Powdered particles have a high surface area to volume ratio, which means it is easier to ignite them. This is true for metals as well.
Under the right circumstances, powdered iron can burn in a manner known as discrete burning. In its most ideal form, the flame completely consumes one particle before the heat radiating from it combusts other particles in its vicinity. By studying this process, researchers can better understand and model how iron combusts, allowing them to design better iron-burning furnaces.
Discrete burning is difficult to achieve on Earth. Perfect discrete burning requires a specific particle density and oxygen concentration. When the particles are too close and compacted, the fire jumps to neighboring particles before fully consuming a particle, resulting in a more chaotic and less controlled burn.
Presently, the rate at which powdered iron particles burn or how they release heat in different conditions is poorly understood. This hinders the development of technologies to efficiently utilize iron as a large-scale fuel.
Burning metal in microgravity
In April, the European Space Agency (ESA) launched a suborbital “sounding” rocket, carrying three experimental setups. As the rocket traced its parabolic trajectory through the atmosphere, the experiments got a few minutes in free fall, simulating microgravity.
One of the experiments on this mission studied how iron powder burns in the absence of gravity.
In microgravity, particles float in a more uniformly distributed cloud. This allows researchers to model the flow of iron particles and how a flame propagates through a cloud of iron particles in different oxygen concentrations.
Existing fossil fuel power plants could potentially be retrofitted to run on iron fuel.
Insights into how flames propagate through iron powder under different conditions could help design much more efficient iron-burning furnaces.
Clean and carbon-free energy on Earth
Various businesses are looking at ways to incorporate iron fuels into their processes. In particular, it could serve as a cleaner way to supply industrial heat by burning iron to heat water.
For example, Dutch brewery Swinkels Family Brewers, in collaboration with the Eindhoven University of Technology, switched to iron fuel as the heat source to power its brewing process, accounting for 15 million glasses of beer annually. Dutch startup RIFT is running proof-of-concept iron fuel power plants in Helmond and Arnhem.
As researchers continue to improve the efficiency of burning iron, its applicability will extend to other use cases as well. But is the infrastructure in place for this transition?
Often, the transition to new energy sources is slowed by the need to create new infrastructure to utilize them. Fortunately, this isn’t the case with switching from fossil fuels to iron. Since the ideal temperature to burn iron is similar to that for hydrocarbons, existing fossil fuel power plants could potentially be retrofitted to run on iron fuel.
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
How to Use Thoughts to Control Computers with Dr. Tom Oxley
Tom Oxley is building what he calls a “natural highway into the brain” that lets people use their minds to control their phones and computers. The device, called the Stentrode, could improve the lives of hundreds of thousands of people living with spinal cord paralysis, ALS and other neurodegenerative diseases.
Leaps.org talked with Dr. Oxley for today’s podcast. A fascinating thing about the Stentrode is that it works very differently from other “brain computer interfaces” you may be familiar with, like Elon Musk’s Neuralink. Some BCIs are implanted by surgeons directly into a person’s brain, but the Stentrode is much less invasive. Dr. Oxley’s company, Synchron, opts for a “natural” approach, using stents in blood vessels to access the brain. This offers some major advantages to the handful of people who’ve already started to use the Stentrode.
The audio improves about 10 minutes into the episode. (There was a minor headset issue early on, but everything is audible throughout.) Dr. Oxley’s work creates game-changing opportunities for patients desperate for new options. His take on where we're headed with BCIs is must listening for anyone who cares about the future of health and technology.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
In our conversation, Dr. Oxley talks about “Bluetooth brain”; the critical role of AI in the present and future of BCIs; how BCIs compare to voice command technology; regulatory frameworks for revolutionary technologies; specific people with paralysis who’ve been able to regain some independence thanks to the Stentrode; what it means to be a neurointerventionist; how to scale BCIs for more people to use them; the risks of BCIs malfunctioning; organic implants; and how BCIs help us understand the brain, among other topics.
Dr. Oxley received his PhD in neuro engineering from the University of Melbourne in Australia. He is the founding CEO of Synchron and an associate professor and the head of the vascular bionics laboratory at the University of Melbourne. He’s also a clinical instructor in the Deepartment of Neurosurgery at Mount Sinai Hospital. Dr. Oxley has completed more than 1,600 endovascular neurosurgical procedures on patients, including people with aneurysms and strokes, and has authored over 100 peer reviewed articles.
Links:
Synchron website - https://synchron.com/
Assessment of Safety of a Fully Implanted Endovascular Brain-Computer Interface for Severe Paralysis in 4 Patients (paper co-authored by Tom Oxley) - https://jamanetwork.com/journals/jamaneurology/art...
More research related to Synchron's work - https://synchron.com/research
Tom Oxley on LinkedIn - https://www.linkedin.com/in/tomoxl
Tom Oxley on Twitter - https://twitter.com/tomoxl?lang=en
Tom Oxley TED - https://www.ted.com/talks/tom_oxley_a_brain_implant_that_turns_your_thoughts_into_text?language=en
Tom Oxley website - https://tomoxl.com/
Novel brain implant helps paralyzed woman speak using digital avatar - https://engineering.berkeley.edu/news/2023/08/novel-brain-implant-helps-paralyzed-woman-speak-using-a-digital-avatar/
Edward Chang lab - https://changlab.ucsf.edu/
BCIs convert brain activity into text at 62 words per minute - https://med.stanford.edu/neurosurgery/news/2023/he...
Leaps.org: The Mind-Blowing Promise of Neural Implants - https://leaps.org/the-mind-blowing-promise-of-neural-implants/
Tom Oxley