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Drug Discovery

New schizophrenia medications could signal a comeback for psychiatric drugs

Muscarinic agonists may reignite Big Pharma’s interest in psychiatry

by Sarah Braner
March 4, 2024 | A version of this story appeared in Volume 102, Issue 7


A colored positron-emission tomography scan of the brain of a person with schizophrenia.
Credit: Wellcome/Science Source
A colored positron-emission tomography scan of the brain of a person with schizophrenia

In November, the Boston-based biotech firm Karuna Therapeutics submitted its new schizophrenia medication, called KarXT, to the US Food and Drug Administration for approval. If the agency gives KarXT the green light, the drug will be the first truly new treatment for schizophrenia in decades.

Regulatory success for KarXT might also pave the way for more new psychiatric drugs in a landscape plagued by failed trials—but challenges remain in one of drug discovery’s most difficult arenas.

In 2022, the World Health Organization estimated that about 24 million people across the planet have schizophrenia; the National Institutes of Health puts the prevalence of schizophrenia and related psychotic disorders in the US between 0.25% and 0.64%. Schizophrenia is associated with one of the highest mortality risks across all psychiatric disorders, and it’s estimated that people with schizophrenia might live 15 to 20 years less than other groups (World Psychiatry 2022, DOI: 10.1002/wps.20994).

We get locked in to the same classes of drugs, and we iterate on them, and we incrementally innovate on them, but it’s really challenging to introduce something that’s fundamentally different.
Andrew Miller, founder, Karuna Therapeutics

But researchers don’t know what causes the disorder; in fact, schizophrenia is best understood as a syndrome, or set of symptoms. Joshua Kantrowitz, a psychiatrist at Columbia University and the New York State Psychiatric Institute, likens schizophrenia to a cough, which is the outward expression of something wrong with one’s upper respiratory tract. The cough could have any of several causes, like allergies, asthma, or the flu or another virus, but the cough is the perceivable effect of any of these causes.

“Schizophrenia is kind of like that but a little more complicated in that we’re dealing with the brain and not the lungs,” Kantrowitz says.

People with schizophrenia experience three broad categories of symptoms: positive symptoms that are additive to the person’s condition, negative symptoms that represent functional deficits, and cognitive impairment. The positive symptoms are the most well known and include hallucinating and hearing voices; the negative symptoms are often depression-like, such as social withdrawal and inability to feel pleasure. Many individuals with schizophrenia also display cognitive impairment (Schizophr. Res. 2011, DOI: 10.1016/j.schres.2010.09.015).

For many people with schizophrenia, antipsychotic medications help reduce symptoms. But the drugs don’t work for everyone. About a third of those with the disorder exhibit what’s called treatment-resistant schizophrenia, and even when the drugs do alleviate schizophrenia symptoms, their side effects can be debilitating (Schizophrenia 2020, DOI: 10.1038/s41537-019-0090-z).

All available antipsychotics for schizophrenia antagonize neuronal D2 dopamine receptors. But a problem with D2 receptor antagonists is that dopamine is required across multiple parts of the brain, not just the parts linked to psychosis. Inhibiting how much dopamine is available in the brain can cause side effects like tremors or stiffness, weight gain, and hyperprolactinemia (J. Psychopharmacol. 2008, DOI: 10.1177/0269216307087148).

“As you can imagine, this can have a significant impact on people’s self-identity as well as desire to take these medications,” says Ann Shinn, the director of the Schizophrenia and Bipolar Disorder Research Program at Mass General Brigham’s McLean Hospital.

If people can’t or won’t take their medications because of the side effects, the medications can’t help with psychosis—and patients with schizophrenia don’t have another class of drugs they can turn to. “For the past 20 years, the field has been releasing similar, slightly different D2 antagonists, which are not moving the needle,” Kantrowitz says.

Enter muscarinic agonists.

Muscarinic mechanism
Karuna Therapeutics says its drug to treat schizophrenia works by activating muscarinic receptors and thereby decreasing dopamine availability in the brain.
Proposed mechanism for how xanomeline in KarXT works in the brain.
Credit: Yang H. Ku/C&EN/Shutterstock
Chemical structure of xanomeline.

In the 1990s, the big drugmaker Eli Lilly and Company was testing a new molecule, xanomeline, as a possible treatment for Alzheimer’s disease. While the molecule was in trials, researchers observed that it alleviated the psychosis that can sometimes stem from Alzheimer’s disease (Arch. Neurol. 1997, DOI: 10.1001/archneur.1997.00550160091022).

Chemical structure for trospium.

Lilly conducted a small trial to evaluate xanomeline’s potential in treating psychosis. The company decided the molecule caused too many gastrointestinal side effects to justify its use and shelved it.

But Andrew Miller, then a vice president at the biotech company PureTech Health, saw potential in the molecule, a muscarinic agonist, as a first-in-class therapy. So Miller licensed xanomeline from Lilly in 2012 and established Karuna to develop it.

“We get locked in to the same classes of drugs, and we iterate on them, and we incrementally innovate on them, but it’s really challenging to introduce something that’s fundamentally different,” Miller says. “So what I saw in xanomeline, and what others saw, was that this could represent a new class.”

But the side effect challenge remained. The solution that Miller and the Karuna team found was to add trospium, a muscarinic antagonist, to combat the systemic gastrointestinal side effects. Trospium, critically, does not cross the blood-brain barrier, and “it allows us to ameliorate, or block, the activation of muscarinic receptors in peripheral tissues like the gastrointestinal tract, where the side effects were being generated, but leave that central brain-based therapeutic benefit unchanged,” Miller says. The combination of trospium and xanomeline became KarXT.

While xanomeline is likely to be the first of this new class of antipsychotics to be approved, it is not the only one. Emraclidine, a schizophrenia-targeting molecule from the biotech firm Cerevel Therapeutics, also acts on muscarinic receptors. But while xanomeline acts on both M1 and M4 receptors, emraclidine acts on just M4 receptors, which theoretically negates the need for another molecule like trospium to dampen side effects. Other firms working on muscarinic agonists for the treatment of schizophrenia include Sosei Heptares and Anavex Life Sciences.

Experts say these molecules present a compelling new option. “It’s really exciting that we potentially have this new class of medications that can be really helpful for symptoms and not have these adverse effects that patients find really intolerable,” Shinn says.

Researchers have not directly compared KarXT with conventional D2 antagonists to see which is better at controlling psychosis. Miller says a reduction in positive and negative symptoms has been the focus so far, and Karuna submitted its data to the FDA on that strength. But the therapy has shown promise in reducing cognitive impairment as well, he adds.

While the exact mechanism of action for muscarinic agonists has yet to be determined, researchers think that they still affect the amount of dopamine signaling in the brain, just through an indirect approach.

Miller’s team at Karuna hypothesizes that in the brain, xanomeline acts on the M1 receptor present on γ-aminobutyric-acid-ergic interneurons in the prefrontal cortex (Am. J. Psychiatry 2022, DOI: 10.1176/appi.ajp.21101083). Through a series of steps, this activity reduces the production of dopamine. But M1 and M4, along with the similar receptors M2 and M3, are present throughout the peripheral nervous system and the gastrointestinal system as well, which is likely why xanomeline on its own causes gastrointestinal side effects like nausea, vomiting, and diarrhea.

Chemical structure of emraclidine.

Emraclidine acts on M4 receptors similarly to how xanomeline acts on M1 receptors in that it eventually leads to reduced amounts of dopamine molecules released. But it does this by activating a pathway that uses acetylcholine-producing neurons.

By not dampening D2 receptors directly, xanomeline and emraclidine avoid the pitfalls of movement-related side effects that plague D2 antagonists.

Bristol Myers Squibb and AbbVie acquired Karuna and Cerevel, respectively, in December, in multibillion-dollar deals that analysts at the investment firm Stifel described in a note at the time as “validating that novel mechanisms in psychiatry have blockbuster potential.” Industry observers have suggested that these deals could signal that Big Pharma is ready to try its luckin psychiatry again after backing offin response to trial failures in the 2010s.

But it may be too soon to proclaim a new golden age of psychiatric drugs.

Psychiatric drug discovery is exceedingly difficult, and many roadblocks stand in the way of developing new therapies for the brain, according to Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Not only is the brain the most complex organ in the body, which alone makes drug discovery difficult, but neurological researchers can’t take brain-tissue samples for experiments in the way that a cancer researcher might be able to take a biopsy of a tumor.

Researchers face a dearth of animal models available for psychiatric disorders—and there is no animal model for schizophrenia. In addition, the field doesn’t have access to biomarkers for a disorder such as schizophrenia. Thus, trials must be performed with a heterogeneous group of people who have been diagnosed with schizophrenia. “That means that the power to detect a signal in a clinical trial is very diluted,” Hyman says. He concludes that “it may not be easy to replicate the success” of Karuna and Cerevel.

But Karuna’s Miller is optimistic that the field is getting better at developing new drugs by taking advantage of serendipitous discoveries such as the one the Lilly researchers first made. “A substantial source of innovation in psychiatry [is] these unexpected effects,” he says. “That’s how antidepressants were discovered. It’s how antipsychotics were discovered. It’s how anxiolytics were discovered as well. And so there are sources of innovation and insight. And I think we’re much better at translating those.”

Miller is hopeful that KarXT will be approved by the FDA soon. And Karuna is starting to send KarXT back where it began: the firm is testing the compound’s effectiveness in treating psychosis in people with Alzheimer’s disease, and it may begin testing the treatment's effectiveness for Alzheimer's-related cognitive impairment.


This story was updated on March 6, 2024, to add that Karuna Therapeutics is testing KarXT for treating psychosis in people with Alzheimer's disease.


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