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New schizophrenia drugs could treat Alzheimer's disease
Latest advances in psychiatry: A newly approved drug approach to treat schizophrenia shows potential against Alzheimer's disease.
New schizophrenia drugs could treat Alzheimer's disease
Since a new drug against schizophrenia, the first in several decades with an innovative mechanism of action, in September the approval of the US authorities received, some researchers have one new era in psychiatry exclaimed. Around half a dozen similar drugs - for schizophrenia, Alzheimer's and other brain diseases - are in various stages of development, most of them in early clinical trials. However, the success of these medications is not guaranteed. Last week, a clinical trial of a highly anticipated drug for schizophrenia reported disappointing results.
For decades, drugs for schizophrenia worked in essentially the same way. They regulated that Dopamine activity, a chemical that is involved in the disorder's characteristic symptoms, such as hallucinations and delusions. New to the market is KarXT, sold as Cobenfy. It aims at muscarinic receptors and offers antipsychotic and cognitive benefits. “I don't think I've ever experienced so much excitement and interest in a new approach to psychiatry in my career,” says Jeffrey Conn, a pharmacologist at Vanderbilt University in Nashville, Tennessee, who is one of the company's scientific co-founders.
KarXT's success in gaining US approval has reinvigorated interest in muscarinic medications. “Drug development is returning to psychiatry,” says Arthur Christopoulos, a molecular pharmacologist at Monash University in Melbourne, Australia, who helped develop KarXT.
However, developing new drugs is a hard and long road. On November 11, Abbvie, a pharmaceutical company in North Chicago, Illinois, announced that its muscarinic drug for schizophrenia, called emraclidine, performed no better than a placebo. What impact this will have on other muscarinic drugs in development remains to be seen, says Christopoulos. “It’s still early.”
New psychiatric medications
The path to developing KarXT was not easy. Xanomeline, one of the drug's active components, was developed in the 1990s and showed that it could reduce psychotic symptoms in people with Alzheimer's disease. However, broken down in a clinical trial 1 Many participants who took the drug discontinued treatment due to nausea, vomiting and other side effects. Muscarinic receptors are present throughout the brain and body, so drugs that target them can produce broad effects. The drug was scrapped along with others developed at the time. “Everyone, including me and my colleagues, believed that muscarinic agonists probably presented an impossible challenge,” says Conn.
In 2009, Karuna Therapeutics, based in Boston, Massachusetts, combined xanomeline with another compound, trospium, which blocks muscarinic receptors but cannot penetrate the brain, preventing unwanted side effects in the body. This combination became known as KarXT. In clinical trials, people with schizophrenia who took the combined drug experienced antipsychotic and cognitive benefits, with milder side effects than with xanomeline alone.
Mechanism of action
Xanomeline acts primarily on two of the five muscarinic receptors: the M1 and M4 receptors. Animal studies suggest that the M4 receptor is most strongly associated with antipsychotic effects during the M1 receptor is associated with cognition.
Many of the schizophrenia drugs currently being studied target only one of these receptors - a strategy that researchers hope will yield greater benefits with fewer side effects, says Andrew Tobin, a neuroscientist at the University of Glasgow, UK. (Tobin is co-founder and CEO of Keltic Pharma Therapeutics, a Dublin-based company working on developing muscarinic drugs.)
Because of the similarities in the binding site of all five muscarinic receptors, selectively targeting one type is challenging, Tobin says. To get around this, researchers are studying "allosteric modulators" of muscarinic receptors, which act through regions outside the binding site that are more distinct than the binding sites of the five muscarinic receptors.
Emraclidine, an allosteric modulator targeting the M4 receptor, was one of the most advanced muscarinic drugs in the pipeline. But its failure in Abbvie's Phase II trial raises questions, such as whether drugs need to target both the M1 and M4 receptors, the way KarXT does, says Brian Dean, a biochemist at the Florey Institute of Neuroscience and Mental Health in Parkville, Australia.
Alzheimer's, addiction and beyond
New York-based pharmaceutical giant Bristol Meyers Squibb (BMS), which acquired Karuna in March, is conducting a human trial to test whether KarXT can also help treat psychosis associated with Alzheimer's, and is also studying whether the drug could potentially benefit people with bipolar disorder.
Given the role of M1 receptors in cognition, researchers are also designing drugs that target this receptor to reduce cognitive decline in people with Alzheimer's. Tobin says researchers hope muscarinic drugs could also slow disease progression. In 2016, he and his colleagues reported that an M1-specific drug slowed neurodegeneration in mice with a disease similar to Alzheimer's disease in humans 2.
Muscarinic receptors are located in the brain's reward circuits, and studies have shown that blocking these pathways protects animals from addiction Opioids can protect. The receptors are also involved in movement, which has led some scientists to investigate whether blocking them could also help people with Parkinson's 3.
Test in practice
Although there is excitement surrounding KarXT, it remains to be seen how it performs in practice. During the clinical trials, participants remained hospitalized, where there were few opportunities for environmental factors to influence treatment, says Carol Tamminga, a psychiatrist and neuroscientist at UT Southwestern Medical Center in Dallas, Texas. (Tamminga is a scientific advisor for Karuna and was involved in the KarXT clinical trials).
Last month, BMS released data from two one-year follow-up studies of KarXT in people with schizophrenia who were treated as outpatients. Although they continued to make progress during this time, 11-18% of participants stopped taking the medication due to side effects. Stopping a medication is also a problem with other available therapeutics for schizophrenia. “We still have a lot to learn about these drugs,” says Tamminga.
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