On December 11, 1951, in the labs of French pharmaceutical company Rhône-Poulenc, chemist Paul Charpentier concocted a drug that would change the field of psychiatry forever.
Charpentier hadn’t intended to spark a revolution; he was actually trying to make a better antihistamine. But by tweaking an existing drug called promazine, he ended up making a new compound called chlorpromazine. The drug was passed on to a surgeon by the name of Henri Laborit, who was on the hunt for a more effective anesthetic. He noticed it produced a calming effect in his patients, and in 1952 Laborit convinced colleagues at a military hospital in Paris to give the drug to a 24-year-old man suffering from psychosis. Twenty days of treatment later, the man was ready “to resume normal life.” Despite no one being sure how the drug worked, its popularity exploded across the United States and Europe as a treatment for psychosis, birthing antipsychotics as they’re known today.
Around the same time, it was found that drugs used to increase the release of the neurotransmitter dopamine, like amphetamines, can lead to the onset of psychotic symptoms. Researchers eventually discovered that drugs like chlorpromazine might work by dampening the transmission of dopamine. Fiddling with dopamine levels became the cornerstone of schizophrenia treatment, laying the foundation for the dopamine hypothesis of schizophrenia—the theory that a dysregulated dopamine system causes the condition’s symptoms.
Since this rush of discoveries in the middle of the 20th century, the field hasn’t progressed much. The dopamine focus has led to antipsychotics becoming the classic treatment for schizophrenia. The drugs currently on the market do achieve a degree of relief for many people living with the condition, but they have a poor effect for some patients, zero effect for others, and are notorious for triggering unwanted and sometimes overwhelming side effects.
Frustratingly, the antipsychotic that works best against schizophrenia’s symptoms—clozapine, which emerged in the late 1980s—can have the nastiest unwanted effects, including weight gain, diabetes, and excessive sleepiness. “It doesn’t work in everybody, but it’s about as effective and amazing as drugs get,” says Ragy Girgis, associate professor of clinical psychiatry at Columbia University. Overall, the weak efficacy and notorious side effects of the currently available drugs mean a big percentage of people with schizophrenia simply stop taking their medication.
But a new drug is bringing hope to the field. Xanomeline-trospium, or KarXT, has a novel way of diminishing dopamine transmission that’s showing promise at reducing symptoms while also limiting side effects. “The field has been waiting for something like this for far too long,” says Sameer Jauhar, a psychiatrist in London and a lecturer in affective disorders and psychosis at King’s College London. “I think it’s a breakthrough,” says Christoph U. Correll, professor of psychiatry at Hofstra University in New York. “For 70 years, we’ve been waiting for a new mechanism of action.”
While dopamine seems to be a key player, exactly what triggers schizophrenia, which affects about about 24 million people worldwide, remains elusive. But the need for better treatments is clear. The condition is one of the leading causes of disability worldwide: One in 20 people with schizophrenia takes their own life, about 80 percent leave employment, and it cuts its affected peoples’ lives short by one to two decades.
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