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.
Genital Transplants: Is Science Going Too Far, Too Fast?
Thanks to the remarkable evolution of organ transplantation, it's now possible to replace genitals that don't work properly or have been injured. Surgeons have been transplanting ovarian tissue for more than a decade, and they're now successfully transplanting penises and wombs too.
Rules and regulations aren't keeping up with the rapid rise of genital transplants.
Earlier this year, an American soldier whose genitals were injured by a bomb in Afghanistan received the first-ever transplant of a penis and scrotum at Johns Hopkins Medicine.
Rules and regulations aren't keeping up with the rapid rise of genital transplants, however, and there's no consensus about how society should handle a long list of difficult and delicate questions.
Are these expensive transplants worth the risk when other alternatives exist? Should men, famously obsessed with their penises, be able to ask for a better model simply because they want one? And what happens when transplant technology further muddles the concept of biological parenthood?
"We need to remember that the human body is not a machine with interchangeable parts," says bioethicist Craig M. Klugman of DePaul University. "These are complicated, difficult and potentially dangerous surgeries. And they require deep consideration on a physical, psychological, spiritual, and financial level."
From Extra Testicles to Replacement Penises
Tinkering with human genitalia -- especially the male variety -- is hardly a new phenomenon. A French surgeon created artificial penises for injured soldiers in the 16th century. And a bizarre implant craze swept the U.S. in the 1930s when a quack physician convinced men that, quite literally, the more testicles the merrier – and if the human variety wasn't available, then ones from goats would have to do.
Now we're more sophisticated. Modern genital transplants are designed to do two things: Treat infertility (in women) and restore the appearance and function of genitals (in men).
In women, surgeons have successfully transplanted ovarian tissue from one woman to another since the mid-2000s, when an Alabama woman gave birth after getting a transplant from her identical twin sister. Last year, for the first time in the U.S., a young woman gave birth after getting a uterus transplant from a living donor.
"Where do you draw the line? Is pregnancy a privilege? Is it a right?"
As for men, surgeons in the U.S. and South Africa have successfully transplanted penises from dead men into four men whose genitals were injured by a botched circumcision, penile cancer or a wartime injury. One man reportedly fathered a child after the procedure.
The Johns Hopkins procedure was the first to include a scrotum. Testicles, however, were not transplanted due to ethical concerns. Surgeons have successfully transplanted testicles from man-to-man in the past, but this procedure isn't performed because the testes would produce sperm with the donor's DNA. As a result, the recipient could father a baby who is genetically related to the donor.
Are Transplants Worth the Expense and Risk?
Genital transplants are not simple procedures. They're extremely expensive, with a uterus transplant estimated to cost as much as $250,000. They're dangerous, since patients typically must take powerful drugs to keep their immune systems from rejecting their new organs. And they're not medically necessary. All have alternatives that are much less risky and costly.
Dr. Hiten D. Patel, a urologist at Johns Hopkins University, believes these types of factors make penis transplants unnecessary. As he wrote in a 2018 commentary in the journal European Urology, "What in the world are we doing?"
There are similar questions about female genital transplants, which allow infertile women to become pregnant instead of turning to alternatives like adoption or surrogacy. "This is not a life-saving transplant. A woman can very well live without a uterus," says McGill University's Dr. Jacques Balayla, who studies uterine transplantation. "Where do you draw the line? Is pregnancy a privilege? Is it a right? You don't want to cause harm to an individual unless there's an absolute need for the procedure."
But Johns Hopkins urologist Dr. Arthur L. Burnett II, who served on the surgical team that performed the penis-and-scrotum procedure, says penis transplants can be appropriate when other alternatives – like a "neophallus" created from forearm skin and tissue – aren't feasible.
It's also important to "restore normalcy," he says. "We want someone to be able to have sense of male adequacy and a normal sense of bodily well-being on both physical and psychological levels."
Surgical team members who performed the penis transplant, including W. P. Andrew Lee, director of the department of plastic and reconstructive surgery, center.
As for the anonymous recipient, he's reportedly doing "very well" five months after the transplant. An update on Johns Hopkins' website states that "he has normal urinary functions and is beginning to regain sensation in the transplanted tissues."
When the Organ Donors Do It Live
Some peculiar messages reached Burnett's desk after his institution announced it would begin performing penis transplants. Several men wanted to donate their own organs. But for now, transplanted penises are only coming from dead donors whose next of kin have approved the donation.
Burnett doesn't expect live donors to enter the penis transplant picture. But there are no guidelines or policies to stop surgeons from transplanting a penis from a live donor or, for that matter, a testicle.
Live women have already donated wombs and ovarian tissue, forcing them to face their own risks from transplant surgery. "You're putting the donor at risk because she has to undergo pretty expensive surgery for a procedure that is not technically lifesaving," McGill University's Balayla says.
When it comes to uterus transplants, the risk spreads even beyond donor and recipient. Balayla notes there's a third person in the equation: The fetus. "Immunosuppressant medication may harm the baby, and you're feeding the baby with a [uterine] blood vessel that's not natural, held together by stitches," he says.
It's up to each medical institution that performs the procedures to set its own policies.
Bioethicists are talking about other issues raised by genital transplants: How should operations for transgender people fit in? Should men be able to get penis transplants for purely cosmetic reasons? And then there's the looming question of genetic parenthood.
It's up to each medical institution that performs the procedures to set its own policies.
Let's say a woman gets a transplant of ovarian tissue, a man gets a testicle transplant, and they have a baby the old-fashioned way.* The child would be genetically linked to the donors, not the parents who conceived him or her.
Call this a full-employment act not just for bioethicists but theologians too. "Catholicism is generally against reproductive technologies because it removes God from the nature of the procreative act. This technology, though, could result in conception through the natural act. Would their concern remain?" DePaul University's Klugman asked. "Judaism is concerned with knowing a child's parentage, would a child from transplanted testes be the child of the donor or the recipient? Would an act of coitus with a transplanted penis be adultery?"
Yikes. Maybe it's time for the medical field or the law to step in to determine what genital transplants surgeons can and can't -- or shouldn't -- do.
So far, however, only uterus transplants have guidelines in place. Otherwise, it's up to each medical institution that performs the procedures to set its own policies.
"I don't know if the medical establishment is in the position to do the best job of self-regulation," says Lisa Campo-Engelstein, a bioethicist with Albany Medical College. "Reproductive medicine in this country is a huge for-profit industry. There's a possibility of exploitation if we leave this to for-profit fertility companies."
And, as bioethicist Klugman notes, guidelines "aren't laws, and people can and do violate them with no effect."
He doesn't think laws are the solution to the ethical issues raised by genital transplants either. Still, he says, "we do need a national conversation on these topics to help provide guidance for doctors and patients."
[Correction: The following sentence has been updated: "Let's say a woman gets a transplant of ovarian tissue, a man gets a testicle transplant, and they have a baby the old-fashioned way." The original sentence mistakenly read "uterus transplant" instead of "ovarian tissue."]
Carl Zimmer: Genetically Editing Humans Should Not Be Our Biggest Worry
Carl Zimmer, the award-winning New York Times science writer, recently published a stellar book about human heredity called "She Has Her Mother's Laugh." Truly a magnum opus, the book delves into the cultural and scientific evolution of genetics, the field's outsize impact on society, and the new ways we might fundamentally alter our species and our planet.
"I was only prepared to write about how someday we would cross this line, and actually, we've already crossed it."
Zimmer spoke last week with editor-in-chief Kira Peikoff about the international race to edit the genes of human embryos, the biggest danger he sees for society (hint: it's not super geniuses created by CRISPR), and some outlandish possibilities for how we might reproduce in the future. This interview has been edited and condensed for clarity.
I was struck by the number of surprises you uncovered while researching human heredity, like how fetal cells can endure for a lifetime in a mother's body and brain. What was one of the biggest surprises for you?
Something that really jumped out for me was for the section on genetically modifying people. It does seem incredibly hypothetical. But then I started looking into mitochondrial replacement therapy, so-called "three parent babies." I was really surprised to discover that almost by accident, a number of genetically modified people were created this way [in the late 90s and early 2000s]. They walk among us, and they're actually fine as far as anyone can tell. I was only prepared to write about how someday we would cross this line, and actually, we've already crossed it.
And now we have the current arms race between the U.S. and China to edit diseases out of human embryos, with China being much more willing and the U.S. more reluctant. Do you think it's more important to get ahead or to proceed as ethically as possible?
I would prefer a middle road. I think that rushing into tinkering with the features of human heredity could be a disastrous mistake for a lot of reasons. On the other hand, if we completely retreat from it out of some vague fear, I think that we won't take advantage of the actual benefits that this technology might have that are totally ethically sound.
I think the United Kingdom is actually showing how you can go the middle route with mitochondrial replacement therapy. The United States has just said nope, you can't do it at all, and you have Congressmen talking about how it's just playing God or Frankenstein. And then there are countries like Mexico or the Ukraine where people are doing mitochondrial replacement therapy because there are no regulations at all. It's a wild west situation, and that's not a good idea either.
But in the UK, they said alright, well let's talk about this, let's have a debate in Parliament, and they did, and then the government came up with a well thought-through policy. They decided that they were going to allow for this, but only in places that applied for a license, and would be monitored, and would keep track of the procedure and the health of these children and actually have real data going forward. I would imagine that they're going to very soon have their first patients.
As you mentioned, one researcher recently traveled to Mexico from New York to carry out the so-called "three-parent baby" procedure in order to escape the FDA's rules. What's your take on scientists having to leave their own jurisdictions to advance their research programs under less scrutiny?
I think it's a problem when people who have a real medical need have to leave their own country to get truly effective treatment for it. On the other hand, we're seeing lots of people going abroad to countries that don't monitor all the claims that clinics are making about their treatments. So you have stem cell clinics in all sorts of places that are making all sorts of ridiculous promises. They're not delivering those results, and in some cases, they're doing harm.
"Advances in stem cell biology and reproductive biology are a much bigger challenge to our conventional ideas about heredity than CRISPR is."
It's a tricky tension for sure. Speaking of gene editing humans, you mention in the book that one of the CRISPR pioneers, Jennifer Doudna, now has recurring nightmares about Hitler. Do you think that her fears about eugenics being revived with gene editing are justified?
The word "eugenics" has a long history and it's meant different things to different people. So we have to do a better job of talking about it in the future if we really want to talk about the risks and the promises of technology like CRISPR. Eugenics in its most toxic form was an ideology that let governments, including the United States, sterilize their own citizens by the tens of thousands. Then Nazi Germany also used eugenics as a justification to exterminate many more people.
Nobody's talking about that with CRISPR. Now, are people concerned that we are going to wipe out lots of human genetic diversity with it? That would be a bad thing, but I'm skeptical that would actually ever happen. You would have to have some sort of science fiction one-world government that required every new child to be born with IVF. It's not something that keeps me up at night. Honestly, I think we have much bigger problems to worry about.
What is the biggest danger relating to genetics that we should be aware of?
Part of what made eugenics such a toxic ideology was that it was used as a justification for indifference. In other words, if there are problems in society, like a large swath of people who are living in poverty, well, there's nothing you can do about it because it must be due to genetics.
If you look at genetics as being the sole place where you can solve humanity's problems, then you're going to say well, there's no point in trying to clean up the environment or trying to improve human welfare.
A major theme in your book is that we should not narrow our focus on genes as the only type of heredity. We also may inherit some epigenetic marks, some of our mother's microbiome and mitochondria, and importantly, our culture and our environment. Why does an expanded view of heredity matter?
We should think about the world that our children are going to inherit, and their children, and their children. They're going to inherit our genes, but they're also going to inherit this planet and we're doing things that are going to have an incredibly long-lasting impact on it. I think global warming is one of the biggest. When you put carbon dioxide into the air, it stays there for a very, very long time. If we stopped emitting carbon dioxide now, the Earth would stay warm for many centuries. We should think about tinkering with the future of genetic heredity, but I think we should also be doing that with our environmental heredity and our cultural heredity.
At the end of the book, you discuss some very bizarre possibilities for inheritance that could be made possible through induced pluripotent stem cell technology and IVF -- like four-parent babies, men producing eggs, and children with 8-celled embryos as their parents. If this is where reproductive medicine is headed, how can ethics keep up?
I'm not sure actually. I think that these advances in stem cell biology and reproductive biology are a much bigger challenge to our conventional ideas about heredity than CRISPR is. With CRISPR, you might be tweaking a gene here and there, but they're still genes in an embryo which then becomes a person, who would then have children -- the process our species has been familiar with for a long time.
"We have to recognize that we need a new language that fits with the science of heredity in the 21st century."
We all assume that there's no way to find a fundamentally different way of passing down genes, but it turns out that it's not really that hard to turn a skin cell from a cheek scraping into an egg or sperm. There are some challenges that still have to be worked out to make this something that could be carried out a lot in labs, but I don't see any huge barriers to it. Ethics doesn't even have the language to discuss the possibilities. Like for example, one person producing both male and female sex cells, which are then fertilized to produce embryos so that you have a child who only has one parent. How do we even talk about that? I don't know. But that's coming up fast.
We haven't developed our language as quickly as the technology itself. So how do we move forward?
We have to recognize that we need a new language that fits with the science of heredity in the 21st century. I think one of the biggest problems we have as a society is that most of our understanding about these issues largely comes from what we learned in grade school and high school in biology class. A high school biology class, even now, gets up to Mendel and then stops. Gregor Mendel is a great place to start, but it's a really bad place to stop talking about heredity.
[Ed. Note: Zimmer's book can be purchased through your retailer of choice here.]
The cover of Zimmer's new book about genetics.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.