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On December 11, 1951, in the laboratories of the French pharmaceutical company Rhône-Poulenc, the chemist Paul Charpentier invented a medicine that would forever change the field of psychiatry. The scholar had no intention of starting a revolution; he actually he was trying to enhance the effects of an antihistamine. However, by modifying an existing drug called promazine, he ended up creating a new compound, the 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 for “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 themodern use of antipsychotics.
Around the same time it was discovered that drugs used to increase 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 by dampening dopamine transmission. Manipulating the levels of this molecule has become a cornerstone of health care schizophreniaand laid the foundations for thedopaminergic hypothesisthe theory that the symptoms of the disease are the result of a 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 they have a limited or no effect in some patients and they can cause unwanted side effectssometimes very heavy. 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 is 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 schizophrenia drugs mean that a large percentage of people with the disease stop taking them.
Possible breakthrough
Today, a new drug has revived hopes in the industry. There 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 are at one breakthrough. We have been waiting for a new mechanism of action for seventy years“, says Christoph U. Correll, professor of psychiatry at Hofstra University in New York. Although dopamine appears to be a key element, it is still unclear what exactly triggers schizophrenia, which affects about 24 million people all over the world. But the need for better therapies is clear: the disease shortens the life of the people who are affected by it one or two decades and is one of the leading causes of disability worldwide; one in twenty people suffering from schizophrenia, moreover, she takes her own life, and about 80 percent leaves the world of work, and the v, reduces the lives of those affected
The symptoms of the disease are divided into three categories: the 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 disturbances in working memory and executive functions. 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 adds 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’ve always proven themselves in the end hole in the water. 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.
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