Schizophrenia, there is a promising new drug
Schizophrenia
On December 11, 1951, in the laboratories of the French pharmaceutical company Rhône-Poulenc, chemist Paul Charpentier invented a medicine that would change the field of psychiatry forever. The scholar had no intention of starting a revolution; he was actually trying to enhance the effects of an antihistamine. However, by modifying an existing drug called promazine, he ended up creating a new compound, chlorpromazine. The drug came to the attention of Henri Laborit, a surgeon searching for effective anesthetics. The doctor noticed that chlorpromazine produced a calming effect on his patients, and in 1952 he persuaded colleagues at a military hospital in Paris to give it to a 24-year-old man suffering from psychosis. After about twenty days the patient was ready to “go back to his life”. Although no one was sure how it worked, the drug became very popular in the United States and Europe as a treatment for psychosis, giving rise to the modern use of antipsychotics.Around the same time, it was discovered that the drugs used to increasing the release of the neurotransmitter dopamine, such as amphetamines, can lead to the onset of psychotic symptoms. Researchers realized that substances such as chlorpromazine can dampen dopamine transmission. Manipulating levels of this molecule has become a cornerstone in the treatment of schizophrenia, and laid the foundations for the dopaminergic hypothesis, the theory that disease symptoms are the result of dopaminergic dysfunction in the brain.
Since this wave of discoveries in the second half of the twentieth century, the field has not progressed much. The focus on dopamine has led antipsychotics to become the gold standard therapy for schizophrenia. The drugs currently on the market are able to give relief to many people suffering from this pathology, but have a limited or no effect in some patients and can cause unwanted side effects, sometimes very serious. Unfortunately clozapine, the most effective antipsychotic against the symptoms of schizophrenia introduced in the late 1980s, can lead to the most serious side effects, including weight gain, diabetes and excessive sleepiness. "It doesn't work for everyone, but it's the most effective of the drugs," says Ragy Girgis, associate professor of clinical psychiatry at Columbia University. Overall, the poor efficacy and side effects of currently available medications for schizophrenia mean that a large percentage of people with the disease stop taking them.
Possible Breakthrough
Today, a new drug has rekindled hopes in the industry. Xanomelin-trospium or KarXT, which uses a novel way to decrease dopamine transmission, is showing promise for reducing symptoms and side effects. “ We've been waiting for something like this for too long ” comments Sameer Jauhar, London psychiatrist and lecturer specializing in affective disorders and psychosis at King's College London; "I think we're at a turning point. We've been waiting for a new mechanism of action for seventy years," says Christoph U. Correll, a professor of psychiatry at Hofstra University in New York. While dopamine appears to be a key contributor, it is still unclear what exactly triggers schizophrenia, which affects an estimated 24 million people worldwide. But the need for better therapies is clear: the disease shortens the lives of people who are affected by one or two decades and is one of the leading causes of disability worldwide; moreover, one in twenty people suffering from schizophrenia takes their own life, and about 80 percent leave the world of work, and v, reduces the lives of those affectedThe symptoms of the disease are divided into three categories: so-called positive symptoms, such as hallucinations or delusions; negative ones, such as social isolation or an inability to show emotion; and cognitive symptoms, which include impaired working memory and executive function. Current drugs have limited effect on the last two categories. Some patients, then, do not derive any benefit: it is estimated that in 30 percent of cases the therapies are not effective, which is added to the many other people for whom the medicines only partially work. Over the past three decades, researchers have examined dozens of drugs that target neurotransmitters other than dopamine in the hopes that they prove more effective. While many of these therapies showed promise in animal experiments, they always proved to be a failure in the end. A 2019 analysis looked at two hundred and fifty studies that tested alternative neurotransmitters, dating back to the 1970s: once they get to the experimental phase and patient tests they have always failed.
KarXT brings the attention back to the dopaminergic system , which however he manipulates in a new way . The drug targets one part of the brain, the muscarinic-acetylcholine system, by using a molecule, xanomeline, which stimulates parts of the surface of neurons called M1 and M4 receptors to reduce dopamine transmission. Xanomeline has long been known to be effective in relieving psychotic symptoms, but it also came with some unwanted side effects, such as nausea and vomiting. Now the biotechnology company Karuna Therapeutics claims to have solved the problem by adding trospium, a drug useful for controlling the common side effects that xanomeline produces when administered alone.
