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.
Agriculture in the 21st century is not as simple as it once was. With a population seven billion strong, a climate in crisis, and sustainability in farming practices on everyone's radar, figuring out how to feed the masses without destroying the Earth is a pressing concern.
Tufts scientists argue that insect cells may be better suited to lab-created meat protein than traditional farm animal cells.
In addition to low-emission cows and drone pollinators, there's a promising new solution on the table. How does "lab-grown insect meat" grab you?
Writing in Frontiers in Sustainable Food Systems, researchers at Tufts University say insects that are fed plants and genetically modified for maximum growth, nutrition, and flavor could be the best, greenest alternative to our current livestock farming practices. This lab-grown protein source could produce high volume, nutritious food without the massive resources required for traditional animal agriculture.
"Due to the environmental, public health, and animal welfare concerns associated with our current livestock system, it is vital to develop more sustainable food production methods," says lead author Natalie Rubio. Could insect meat be the key?
Next Up
New sustainable food production includes what's called "cellular agriculture," an emerging industry and field of study in which meat and dairy are produced via cells in a lab instead of whole animals. So far, scientists have primarily focused on bovine, porcine, and avian cells to create this "cultured meat."
But the Tufts scientists argue that insect cells may be better suited to lab-created meat protein than traditional farm animal cells.
"Compared to cultured mammalian, avian, and other vertebrate cells, insect cell cultures require fewer resources and less energy-intensive environmental control, as they have lower glucose requirements and can thrive in a wider range of temperature, pH, oxygen, and osmolarity conditions," reports Rubio.
"Alterations necessary for large-scale production are also simpler to achieve with insect cells, which are currently used for biomanufacturing of insecticides, drugs, and vaccines," she adds.
They still have some details to hash out, however, including how to make cultured insect meat more like the steak and chicken we're all familiar with.
"Despite this immense potential, cultured insect meat isn't ready for consumption," says Rubio. "Research is ongoing to master two key processes: controlling development of insect cells into muscle and fat, and combining these in 3D cultures with a meat-like texture." They are currently experimenting with mushroom-derived fiber to tackle the latter.
People would still be able to eat meat—it would just come from a different source.
Open Questions
As the report points out, one thing that makes cellular agriculture an attractive alternative to high-density animal farming is that it doesn't require consumers to change their behaviors. People would still be able to eat meat—it would just come from a different source.
But the big question remains: How will lab-grown insect meat taste? Will the buggers really taste as good as burgers?
And, of course, there's the "ew" factor. Meat alternatives have proven to work for some people—Tofurky is still in business, after all—but it may be a hard sell to get the masses to jump on board with eating bugs. Consuming creepy crawlies sounds simply unpalatable to many, and the term "lab-grown, cellular insect meat" doesn't help much. Perhaps an entirely new nomenclature is in order.
Another question is whether or not folks will trust such scientifically-created food. People already use the term "frankenfood" to refer to genetic modification -- even though the vast majority of the corn and soybeans planted in the U.S. today are genetically engineered, and other major crops with GM varieties include potatoes, apples, squash, and papayas. Still, combining GM technology with eating insects may be a hard sell.
However, we're all going to have to get used to trying new things if we want to leave a habitable home for our children. If a lab-grown bug burger can save the planet, maybe it's worth a shot.
Six Reasons Why Humans Should Return to the Moon
"That's one small step for man; one giant leap for mankind."
This July 20th marks fifty years since Neil Armstrong, mission commander of NASA's Apollo 11, uttered those famous words. Much less discussed is how Project Apollo shifted lunar science into high gear, ultimately teaching scientists just how valuable the Moon could become.
A lunar-based solar power system would actually be cheaper than Earth-based solar power implemented on a global scale.
During the six missions that landed humans on the lunar surface from 1969 to 1972, Apollo astronauts collected some 842 pounds of lunar rocks and dirt. Analysis of these materials has provided us with major clues about the origin of Earth's celestial companion 4.51 billion years ago, but also has revealed the Moon is a treasure trove. Lunar rock contains a plethora of minerals with high industrial value. So let's take a look at some prime examples of how humanity's expected return to the lunar surface in the years to come could help life here on Earth.
24/7 solar energy for Earth
During the 1970s, scientists began examining the Apollo lunar samples to study how the lunar surface could be used as a resource. One such scientist was physicist David Criswell, who has since shown that a lunar-based solar power system would actually be cheaper than Earth-based solar power implemented on a global scale. Whoa! How is that possible, given the high cost of launching people and machines into space?
The key is that it would be enormously expensive to scale up enough Earth-based solar power to supply all of humanity's electrical needs, since solar power on such a scale would require a lot of metal, glass, and cement.
But the Moon's lack of atmosphere and weather means that photovoltaic cells built by robots from lunar materials can be paper thin, in contrast with the heavy structures needed in Earth-based solar arrays. Ringing the Moon, such a system would be in perpetual sunlight, making it cheaper to collect solar power there and beam it down to Earth in the form of microwaves.
A source of helium-3 for clean, safe nuclear fusion power and other uses
The gas helium-3 is extremely rare on Earth, but plentiful on the Moon, and could be used in advanced nuclear fusion reactors. Helium-3 also has anti-terrorism and medical uses, especially in the diagnosis of various pulmonary diseases.
A place to offload industrial pollution
Since there are minerals and oxygen in lunar rocks and dust, and frozen water in certain locations, the Moon is an ideal home for factories. Thus, billionaire Jeff Bezos has proposed relocating large segments of heavy industry there, reducing the amount of pollution that is produced on Earth.
The Moon could be a place for colonists to get their space legs before humans put down roots on more distant locations like Mars.
Radio Astronomy without interference from Earth
Constructed on the Moon's far side (the side of the Moon that always faces away from Earth), radio telescopes advancing human knowledge of the Cosmos, and searching for signals from extraterrestrial civilizations, could operate with increased sensitivity and efficiency.
Lunar Tourism
Using the Moon as a destination for tourists may not sound helpful initially, given that only the very wealthy would be able to afford such journeys in the foreseeable future. However, the economic payoff could be substantial in terms of jobs that lunar tourism could provide on Earth. Furthermore, short of actual tourism, companies are gearing up to provide lunar entertainment to fun-seekers here on Earth in the form of mini lunar rovers that people could control from their living rooms, just for fun.
Lunar Colonies
Similar to lunar tourism, lunar colonization sounds initially like a development that would help only those people who go. But, located just three-days' travel from Earth, the Moon would be an excellent place for humanity to become a multi-planet species. The Moon could be a place for colonists to get their space legs before humans put down roots on more distant locations like Mars. With hundreds or thousands of humans thriving on the Moon, Earthlings might find some level of peace of mind knowing that humanity is in a position to outlive a planetary catastrophe.