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.
Gene Editing of Embryos Is Both Ethical and Prudent
BIG QUESTION OF THE MONTH: Should we use CRISPR, the new technique that enables precise DNA editing, to change the genes of human embryos to eradicate disease--or even to enhance desirable traits? LeapsMag invited three leading experts to weigh in.
Now that researchers around the world have begun to edit the genes of human embryos with CRISPR, the ethical debate has become more timely than ever: Should this kind of research be on the table or categorically ruled out?
All of us need gene editing to be pursued, and if possible, made safe enough to use in humans. Not only to pave the way for effective procedures on adults, but more importantly, to keep open the possibility of using gene editing to protect embryos from susceptibility to major diseases and to prevent other debilitating genetic conditions from being passed on through them to future generations.
Objections to gene editing in embryos rest on three fallacious arguments:
- Gene editing is wrong because it affects future generations, the argument being that the human germline is sacred and inviolable.
- It constitutes an unknown and therefore unacceptable risk to future generations.
- The inability to obtain the consent of those future generations means we must not use gene editing.
We should be clear that there is no precautionary approach; just as justice delayed is justice denied, so therapy delayed is therapy denied.
Regarding the first point, many objections to germline interventions emphasize that such interventions are objectionable in that they affect "generations down the line". But this is true, not only of all assisted reproductive technologies, but of all reproduction of any kind.
Sexual reproduction would never have been licensed by regulators
As for the second point, every year an estimated 7.9 million children - 6% of total births worldwide - are born with a serious birth defect of genetic or partially genetic origin. Had sexual reproduction been invented by scientists rather than resulting from our evolved biology, it would never have been licensed by regulators - far too inefficient and dangerous!
If the appropriate benchmark for permissible risk of harm to future generations is sexual reproduction, other germline-changing techniques would need to demonstrate severe foreseeable dangers to fail.
Raising the third point in his statement on gene-editing in human embryos, Francis S. Collins, director of the National Institutes of Health, stated: "The strong arguments against engaging in this activity remain … These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent."
"Serious and unquantifiable" safety issues feature in all new technologies but consent is simply irrelevant for the simple and sufficient reason that there are no relevant people in existence capable of either giving or withholding consent to these sorts of changes in their own germline.
We all have to make decisions for future people without considering their inevitably absent consent. All would-be/might-be parents make numerous decisions about issues that might affect their future children. They do this all the time without thinking about consent of the children.
George Bernard Shaw and Isadora Duncan were possibly apocryphal exceptions. She, apparently, said to him something like: "Why don't we have a child? With my looks and your brains it cannot fail," and received Shaw's more rational assessment: "Yes, but what if it has my looks and your brains?"
If there is a discernible duty here, it is surely to try to create the best possible child, a child who will be the healthiest, most intelligent and most resilient to disease reasonably possible given the parents' other priorities. This is why we educate and vaccinate our children and give them a good diet if we can. That is what it is to act for the best, all things considered. This we have moral reasons to do; but they are not necessarily overriding reasons.
"There is no morally significant line between therapy and enhancement."
There is no morally significant line that can be drawn between therapy and enhancement. As I write these words in my London apartment, I am bathed in synthetic sunshine, one of the oldest and most amazing enhancement technologies. Before its invention, our ancestors had to rest or hide in the dark. With the advent of synthetic sunshine--firelight, candlelight, lamplight and electric light--we could work and play as long as we wished.Steven Hawking initially predicted that we might have about 7.6 billion years to go before the Earth gives up on us; he recently revised his position in relation to the Earth's continuing habitability as opposed to its physical survival: "We must also continue to go into space for the future of humanity," he said recently. "I don't think we will survive another thousand years without escaping beyond our fragile planet."
We will at some point have to escape both beyond our fragile planet and our fragile nature. One way to enhance our capacity to do both these things is by improving on human nature where we can do so in ways that are "safe enough." What we all have an inescapable moral duty to do is to continue with scientific investigation of gene editing techniques to the point at which we can make a rational choice. We must certainly not stop now.
At the end of a 2015 summit where I spoke about this issue, the renowned Harvard geneticist George Church noted that gene editing "opens up the possibility of not just transplantation from pigs to humans but the whole idea that a pig organ is perfectible…Gene editing could ensure the organs are very clean, available on demand and healthy, so they could be superior to human donor organs."
"We know for sure that in the future there will be no more human beings and no more planet Earth."
We know for sure that in the future there will be no more human beings and no more planet Earth. Either we will have been wiped out by our own foolishness or by brute forces of nature, or we will have further evolved by a process more rational and much quicker than Darwinian evolution--a process I described in my book Enhancing Evolution. Even more certain is that there will be no more planet Earth. Our sun will die, and with it, all possibility of life on this planet.As I say in my recent book How to Be Good:
By the time this happens, we may hope that our better evolved successors will have developed the science and the technology needed to survive and to enable us (them) to find and colonize another planet or perhaps even to build another planet; and in the meanwhile, to cope better with the problems presented by living on this planet.
Editor's Note: Check out the viewpoints expressing condemnation and mild curiosity.
Would You Want to Know a Decade Early If You Were Getting Alzheimer's?
Editor's Note: A team of researchers in Italy recently used artificial intelligence and machine learning to diagnose Alzheimer's disease on a brain scan an entire decade before symptoms show up in the patient. While some people argue that early detection is critical, others believe the knowledge would do more harm than good. LeapsMag invited contributors with opposite opinions to share their perspectives.
I first realized something was wrong with my dad when I came home for Thanksgiving 20 years ago.
I hadn't seen my family for more than a year after moving from New York to California. My father was meticulous, a multi-shower a day man, a regular Beau Brummell. He was never officially diagnosed with dementia, but it was easy to figure out after he stopped leaving the house, stopped reading, stopped being himself. My mother knew, but she never sought help. After his illness showed itself, I asked her if she considered a nursing home. "Never," she told me. "I can take care of him." And she did.
She gave herself a break once to visit me, and it was the first time she traveled separately from him since they eloped at seventeen. My brother watched my father, and it was not smooth. Dad was angry, hallucinating, and demanding his gun, which had been disposed of long ago. While Mom was visiting me in California, we played some board games. One demanded honest answers. The card read, What are you most afraid of? "Dementia," she said.
My father never saw this coming, none of us did.
Dementia ran on my mother's side. Her mother, my Nana, was senile, the popular diagnosis for older folks back then. My grandfather tried his hardest to take care of her, but she kept escaping their tidy 6th floor apartment to run away. My mother would go over every day to take care of them, but once my grandfather became ill, she took her mother into our apartment. She had two small children, Nana, and her husband in a two-bedroom flat. Nana talked to people under plates, wore tissues on her head, and tried to escape. We were on the first floor, so she could run into traffic if all eyes weren't on her. Soon, it was too much, even for my Wonder Woman mom. Nana was placed in a nursing home and died soon after.
My mother dropped dead on a NYC sidewalk two years after my father started to deteriorate. She was probably going to the store to buy milk and cigarettes. A kind stranger called 911, and a cop came to my parent's door soon after to tell my dad the news. My father cried for death, raged and ranted, then calmed down enough to come back as the dad we remembered for the week of mourning. He even ordered a Manhattan at dinner. His death came exactly a week and an hour after my mother's. He died of a broken heart. My husband cried with all his body after we left the cemetery, weeping, "Poor Buck. Poor Buck." I never saw him cry before.
Now, 18 years later, I sit here with my husband, 59 years old, as he suffers from the same hideous disease.
He is talking to someone I can't see, even laughing with him. He holds a Ph.D. in literature, taught college, had a single handicap golf game, and ate well. We never saw this coming. One day he went to type and jumbled letters came on the screen. He would show up late or early for his classes, wondering what was wrong with the students. He started running red lights. He was graciously counseled to retire, and he did, at 55. His doctor told him it was depression. The second opinion agreed. He was told to do nothing for a year, and he did. He played golf a bit, then one day he couldn't speak or think clearly. I came home from work to find him roaming the neighborhood, eyes ablaze, muttering to himself. I went on family leave. Many tests later we got the working diagnosis, but it meant nothing to him. He never reacted to the words Primary Progressive Aphasia or dementia. I was glad. If he was lucid, I knew what he would talk about doing. He told me after my dad's death that he did not want that life for himself.
I worry I may get it, too. It almost seems inescapable. Dementia has no cure, and the treatments for the symptoms are hit and miss. I thought about getting the full flight of predictive tests, but I know myself, and I scare myself into bracing for the worst. Others scare me, too, when I read their online statements about ending their lives if they learn they have it: I told my children to take me to a state where assisted suicide is legal; it's easy to overdose; I don't want to be a burden on my children. These are caregivers on social media forums. They live with the terror, eyes wide open. We have no children, but who would I burden? My sisters? My brother? Do I stay or do I go? This disease invites pandemonium. Assisted murder-suicides with caregiver spouses of those with dementia don't merit headlines, but their stories are on the sidebars. No thanks. I work on God's timeline.
There are no survivors – yet.
A diagnosis today would paralyze me and create melancholy for all who know me. I would second guess everything, I would read everything, I would cry, I would hardly live. I would be tempted to pick up that first drink after 20 plus years sober. I would even think about ending my life. It would be difficult not to consider. As a high school English teacher, I talk about suicide when I teach Hamlet. I tell the students suicide is a permanent solution to a temporary problem. Dementia isn't temporary. There are no survivors – yet.
I often think what my relatives would have done with an advance diagnosis. My grandmother was a classic worrier. She would have been beyond distraught. My father might have found that gun. My husband would have taken the right number of pills.
An advance diagnosis would paralyze me.
I appreciate the arguments for early diagnosis. Some people are made of sterner stuff. They have the mindset I lack. I admire so many who are contributing to the current conversation about dementia and are active advocates for a cure. They have found a purpose in their fate.
I don't need a test to get my ducks in a row. Loving those with dementia has prompted me to be prepared. I have a different type of bucket list: reset my priorities, slow down, be present, educate others, and make my legal plans. If and when it happens, there will be time for toast and tea and a walk along the shore. There will be time to plan for the inevitable and unenviable end. I am morbid enough to know I will recognize the purple elephant in the room. I don't want the shock and awe now. I can wait. My sisters agree. We will keep our elbows out.
Editor's Note: Consider the other side of the argument here.