After 70 years, a new class of drugs for schizophrenia

Antipsychotic drugs were discovered by accident. In the early 1950s, psychiatrists at the Sainte-Anne Hospital in Paris realized that chlorpromazine, a drug originally developed as an antihistamine, successfully treated patients suffering from hallucinations and delusions (1). This serendipitous discovery quickly led to an explosion of various antipsychotic drugs prescribed to treat schizophrenia around the word. Over the next two decades, researchers revealed that these drugs work primarily by acting on the dopamine 2 (D2) receptor to reduce dopamine in the brain (2).

A man with glasses in a suit on a blue background

As a psychiatrist and researcher involved in clinical trials to test new drugs for schizophrenia, Christoph Correll hopes that more treatment options will soon be available for patients.

Credit: Christoph Correll

More than 70 years later, all of the currently approved antipsychotic drugs still target D2 receptors. Unfortunately, these drugs cause a wide range of unpleasant and harmful side effects and do not treat the full range of schizophrenia symptoms. As a result, studies show that up to 70 percent of patients stop taking their antipsychotic medications (3,4). Despite a clear need for novel classes of antipsychotic drugs, no other options exist for patients.

That could finally change this year if the FDA approves KarXT, an antipsychotic drug developed by Karuna Therapeutics (now a Bristol Myers Squibb company), that mimics the neurotransmitter acetylcholine and binds to muscarinic acetylcholine receptors 1 (M1) and 4 (M4).

“September 26^th of this year, [KarXT] will be approved. I don't have any doubt about this because the efficacy and tolerability is established,” said Christoph Correll, a psychiatrist and psychopharmacologist at the Zucker School of Medicine at Hofstra/Northwell. Correll was involved in the placebo-controlled clinical trials that demonstrated KarXT’s safety, tolerability, and efficacy in patients with schizophrenia (5-7). “This is huge. It's the first time in seven decades, since the discovery of antipsychotics, that we have a different way into the brain to treat schizophrenia,” said Correll, who has consulted for Karuna Therapeutics.

The encouraging results of KarXT may have breathed new life into the field. Other non-D2 antipsychotics are also being tested in clinical trials, including additional drugs targeting muscarinic acetylcholine receptors. “If KarXT breaks through as expected, you wonder, would this be the first, and then a couple others come through once you break through that wall?” said Daniel Foster, a pharmacologist at the University of South Carolina who was not involved in the development of KarXT. “It's super exciting,”

“The idea that [KarXT] is going to be the first ever non-dopamine based treatment — hopefully — it's amazing to think about,” said Andrew Miller, the inventor of KarXT and now an advisor to Bristol Myers Squibb. “I hope that there's a bunch of other medicines that are launched behind this … People respond differently to different treatments for reasons that we perhaps don't really understand, and so there is just a benefit to having options that are available.”

Split of the mind

More than 100 years ago, schizophrenia got its name from merging the two greek roots “schizo” (split) and “phrene” (mind). Today, psychiatrists are quick to point out that people with schizophrenia do not have a split mind in the sense of split personality disorder. “It's one person,” said Correll, but “the feeling and the acting and the thinking are not in sync.”

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René Kahn, a psychiatrist and researcher at the Icahn School of Medicine at Mount Sinai, said that current D2 antipsychotics are not as effective at treating the non-psychosis symptoms of schizophrenia.

Credit: Mount Sinai Health System

Psychiatrists often break down schizophrenia symptoms into three domains: positive, negative, and cognitive. The positive symptoms get the most attention, including hallmark signs of psychosis like hallucinations, delusions, and disorganized speech and behaviors. Negative symptoms refer to the absence of a behavior, like flat affect, asociality, and anhedonia, while cognitive symptoms refer to impairments in memory, attention, reasoning, and processing speed.

So far, the antipsychotic medications that block dopamine are much better at treating the positive symptoms, but not the negative or cognitive ones. “The overall outcome hasn't really improved that much in the sense that can patients go back to work? Can they build a family? Can they live independently? In that regard, it's still disappointing,” said René Kahn, a psychiatrist and neurobiologist at the Icahn School of Medicine at Mount Sinai.

On top of not effectively treating the negative and cognitive symptoms, these drugs also have undesirable side effects. Depending on the drug, these include weight gain that can lead to diabetes, brain fog, sexual dysfunction, motor impairments that can turn into tardive dyskinesia, and depression. “Patients are really looking for something else,” said Correll. “We need novel mechanisms of action because we have all these unaddressed needs of patients.”

The magic ingredient

Like its antipsychotic drug predecessors, KarXT also has a serendipitous past. Eli Lilly developed xanomeline, the muscarinic agonist component of KarXT, to improve cognition in Alzheimer’s disease (AD). When they ran a clinical trial with the drug in the late 1990s, they discovered that the drug had antipsychotic effects for patients with hallucinations and delusions associated with AD (8). However, xanomeline also caused side effects like diarrhea, vomiting, and sweating because the drug binds to acetylcholine receptors outside of the brain too. Despite its positive antipsychotic effects, Eli Lilly shelved it and moved on.

Andrew Miller came up with the idea to add trospium to xanomeline to create KarXT, which could become the first drug in a new class of antipyschotics for treating schizophrenia.

Credit: Karuna Therapeutics

About ten years later, a novel idea for xanomeline took root in Miller’s mind. He thought of blocking the cholinergic side effects in the rest of the body using trospium, an antimuscarinic drug for treating overactive bladder already on the market. KarXT, which combines xanomeline and trospium, was born. Since trospium does not cross the blood brain barrier, KarXT has one medication that targets the seat of psychosis in the brain and one that controls unwanted side effects in the body.

At first, the concept for KarXT was just an idea on a piece of paper, Miller recalled. Now, the results of the clinical trials demonstrate its efficacy as a novel antipsychotic that appears to be tolerated well and may potentially treat the negative and cognitive symptoms better than prior medicines, although further studies will be needed (5-7). In terms of side effects, the addition of trospium to KarXT appears to mitigate the intolerable cholinergic side effects seen with Eli Lilly’s previous drug. Researchers still observed gastrointestinal side effects, but Miller noted that these were usually mild and often resolved after about two weeks of treatment. They did not see the side effects associated with other dopamine-blocking antipsychotic drugs.

“Our data suggest that it has a very robust and potentially broad efficacy profile, and importantly, a side effect profile that is very different than existing treatments,” said Miller. “We're optimistic that this could present KarXT as a unique class of medicine, the first in the unique class that doesn't interact directly with dopamine and is focused on this muscarinic agonist pharmacology.”

If KarXT is approved in September, psychiatrists will finally have another option to prescribe to patients. “It is obviously nice to have something different than the classical dopamine 2 antagonists or a partial dopamine agonist. But on the other hand, since I've been in this business for a while, … let's see how the drug will do once it's on the market,” said Kahn.

Activating acetylcholine

After researchers discovered that the early antipsychotic drugs like chlorpromazine work through lowering dopamine, the dopamine hypothesis of schizophrenia took hold in 1966 (9). The hypothesis posits that schizophrenia is caused by overactive dopamine pathways, and it’s had a strong influence on the field of schizophrenia research ever since. “That locked us into the idea that schizophrenia is a dopamine excess condition, and we need to block dopamine in order to treat it,” said Anthony Grace, a neuroscientist at the University of Pittsburgh. “[KarXT] points to the idea that you don't need to block dopamine in order to get an effective drug.”

Rather than blocking D2 receptors to lower dopamine levels in the brain, KarXT targets the muscarinic receptors that bind acetylcholine. Of the five muscarinic acetycholine receptors, KarXT targets M1 and M4. Based on studies so far, Miller explained that KarXT’s modulation of the M1 receptor, which boosts acetylcholine signaling, seems to confer cognitive benefits due to M1 receptor expression in the regions of the brain important to learning and memory like the hippocampus and executive function in the prefrontal cortex. On the other hand, Miller said that modulation of the M4 receptors results in the antipsychotic effects because of their expression in brain areas related to perception.

A man in a blue suit smiling in an office

Anthony Grace uses animal models to study the neurobiology of schizophrenia and the mechanisms of action of antipsychotic drugs.

Credit: University of Pittsburgh Public Relations Department

Even though muscarinic agonists like KarXT do not block dopamine receptors directly, researchers believe that the beneficial effects result from their ability to regulate dopamine levels. “Muscarinic receptors do have some downstream effects in the prefrontal cortex dopamine circuitry, but you don't see muscarinic receptors expressed in the dopamine pathway to the motor cortex,” said Miller. “We don't have effects in that pathway. We don't have effects in the pituitary gland, which is another dopamine pathway that leads to, for instance, the prolactin and hormonal changes associated with existing treatments.” Thus, the ability to selectively modulate dopamine levels in some regions of the brain but not others, especially in areas where dopamine may be too low, could play a role in the improved side effect profile of KarXT.

Muscarinic agonists may also regulate dopamine in a way that’s more efficacious for treating schizophrenia. “The deficits in the hyperactivity of dopamine in schizophrenia are thought to be in the release side of things. And so, by changing the release of dopamine, you might have different effects than blocking the receptors later that are postsynaptic to the release,” said Foster.

After KarXT, additional drugs targeting muscarinic acetylcholine receptors to treat schizophrenia could be on their way to FDA approval. The companies Cerevel, Neumora, and Neurocrine Biosciences all have clinical trials ongoing with drugs that target the M4 receptor (10-12). Though all these drugs act on M4, their mechanisms differ; KarXT and Neurocrine Biosciences’ drugs are agonists, while Cerevel and Neumora’s versions are positive allosteric modulators. “An agonist has the foot on the gas pedal the whole time … whereas an allosteric modulator fits there and amplifies the signal,” said Correll, who added that the amount of amplification depends on the biological availability of muscarinic receptors, but it preserves the naturally occurring signal temporally and spatially.

Different mechanisms could mean more options for patients. In addition, Correll emphasized that these drugs may work better for at least some patients than traditional D2 antipsychotics because of their influence on multiple neurotransmitters. Muscarinic acetylcholine receptors regulate dopamine levels not only through acetylcholine, but also through the interactions of acetylcholine with the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate (13). “This neural network finetuning is a novel approach that hopefully will really give us outcomes that we haven't seen for some patients,” said Correll.

Schizophrenia drugs of the future

Besides drugs targeting muscarinic acetylcholine receptors, other classes of antipsychotic drugs that go beyond the classic D2 receptor approach have also entered clinical trials. Trace amine-associated receptor 1 (TAAR1) agonists are thought to act inside neurons to decrease the synthesis and release of dopamine and potentially decrease the firing rate of dopamine neurons (14,15). In 2020, Sunovion Pharmaceuticals, now part of Sumitomo Pharma, ran a Phase 2 trial showing positive results with a TAAR1 agonist (16). But in 2023, results from two Phase 3 clinical trials from Sumitomo Pharma and Otsuka Pharmaceutical showed that the TAAR1 agonist did not perform better than placebo, although the placebo effect was also high (17).

Correll hopes that they decide to run one more trial. “We need more drugs with novel and different mechanisms of action for schizophrenia, and this is so safe,” he said. “It would be wonderful if they just did one more study and did it right, controlling for the placebo effect and maybe also finding the right dose.”

We're optimistic that this could present KarXT as a unique class of medicine, the first in the unique class that doesn't interact directly with dopamine and is focused on this muscarinic agonist pharmacology.
– Andrew Miller, advisor to Bristol Myers Squibb

As another example, Merck has a Phase 2b clinical trial ongoing to test a phosphodiesterase 10A (PDE10A) inhibitor, which works to normalize activity of the nigrostriatal dopaminergic pathway (18). Yet, past PDE10A inhibitors failed in clinical trials, which has been a common outcome for schizophrenia drugs and psychiatric drugs more generally.

“A big issue in the field now is how so many pharmaceutical companies have dropped psychiatric drug development because of so many failures,” said Grace. “[KarXT] is going to give them an outline of how they can get back into the field without all of the issues that they had before.”

“We faced a very high level of skepticism from investors and potential partners,” said Miller. “I really do hope that one of the things that we can be a part of is a resurgence in activity and interest because the need has always been there.”

Correll is now getting emails from patients asking when KarXT will be available since they have not responded well to current therapies. “At least for subgroups of patients, this can be foundational and really not just incremental,” he said.

As for the future of drug development for schizophrenia, Miller said that the field should learn from its often-accidental past discoveries. “This field of developing new treatments has been guided by these serendipitous human findings,” he said. “We really need to embrace that from a research perspective and look for things that also may tell us where new treatments might lie.”