This January, the United States Food and Drug Administration (FDA) announced the approval of a new drug for the symptoms of schizophrenia. Appointed KarXT but with the commercial name of Cobenfybrought an unprecedented revolution in nearly 75 years of psychiatric medicine. Its antipsychotic capacity is based on simulating the effects of a neurotransmitter, acetylcholineinstead of traditional treatment which blocks the dopamine. Today, this mechanism also opens up new possibilities against Alzheimer’s.
“For the first time since using chlorpromazine in 1952the indication in schizophrenia is given to a medication which does not act directly on dopamine receptors“, he appreciated Celso Arangohead of the Child and Adolescent Psychiatry Department and director of the Institute of Psychiatry and Mental Health of the Gregorio Marañón University General Hospital, in statements to Science Media Center. The new drug also reduces dopamine in psychotic hyperactivity, but it does so through muscarinic receptors.
This is an important difference because muscarinic receptors are located all over the body and its stimulation brings important side effects. The first compound that forms KarXT, xanomelinewas developed in the 1990s to specifically combat psychotic symptoms in patients with Alzheimer’s disease. However, its use declined because people who received the drug in trials were likely to suffer from nausea and vomitingincludes an article recently published in the magazine Nature.
However, a Boston-based pharmaceutical company, Karuna Therapeutics, successfully combined xanomeline with trospiumobtaining the KarXT-Cobenfy formula. This second compound does not cross the blood-brain barrier, but is able to block muscarinic receptors which would cause side effects in the rest of the body. Thus, during tests carried out on patients diagnosed with schizophrenia, it was possible to observe cognitive and antipsychotic benefitswith much milder side effects than in initial trials.
“Xanomeline was tested several decades ago and found to be effective, but it was abandoned due to peripheral muscarinic side effects,” explains Arango. “Now they have added a second substance (trospium) that blocks peripheral receptors to prevent these side effects.” Furthermore, “by not having a direct dopaminergic effect”, the “typical” effects of drugs used against schizophrenia do not appear or appear in an attenuated form, “as extrapyramidal symptoms (tremors, uncontrolled movements) or hyperprolactinemia (excess prolactin)”.
Following the success of the formula as an antipsychotic, Karuna Therapeutics was bought by Bristol giant Myers Squibb in a deal valued at $14 billion. The new owner of Cobenfy plans tests with a double aspect: first recovering its potential as a antipsychotic for patients with Alzheimer’s diseasehoping that easing the problems with xanomeline will make it more tolerable. A second course of action would consist of testing its effectiveness among patients diagnosed with bipolar disorder.
The key lies in xanomeline’s ability to stimulateYes five muscarinic receptors, classified from M1 to M5. Effects on M4 are linked to greater antipsychotic capacity, but M1 is strongly linked to cognitive capacity. As explained Naturetrials on mice engineered to suffer from a disease compatible with Alzheimer’s disease in humans have seen a slow down neurodegenerative processes when treated with a specific medication for M1.
However, long-term studies highlight potential difficulties for treatment. Two years after starting treatment for schizophrenia with KarXT and resume your life outside the hospital, between 11 and 18% of participants during the trial, there was stopped taking the medicine. Although they acknowledged seeing improvements, the side effects were still too unfavorable so they can tolerate it.
