New Chapter in Antipsychotics and Schizophrenia Treatment

Antipsychotics haven’t had a straight-forward path in research, but recent efforts yielded a new FDA-approved drug to treat schizophrenia.

By Rebecca DeGiosio

Schizophrenia can be a challenging diagnosis, both to live with and to treat. Given its range of symptoms—including psychosis, depression-like symptoms, and cognitive impairments—it’s hardly surprising that schizophrenia represents one of the top 15 leading causes of disability worldwide.

It’s challenging to study, too. Schizophrenia was once known as the “graveyard of pathology” to scientists in the 1970s trying to understand its origins. Even its early treatments—like first-generation antipsychotics—were discovered by accident.

Researchers are still working constantly to better understand the brain circuitry that underpins schizophrenia. But in the meantime, another chance finding has led to a huge step forward in schizophrenia treatment. 

As of September 2024, Cobenfy (xanomeline and trospium chloride) is FDA-approved for the treatment of schizophrenia in adults. This twice-a-day pill represents the first schizophrenia drug with a new mechanism of action seen in decades. It targets a different set of receptors in the brain than other antipsychotics, offering a new option to those who don’t respond well to current treatments.

The research behind Cobenfy heralds a new era of antipsychotic drug development, a field of research with surprising origins. Here, we trace this history from its lucky beginnings to a promising future.

Chlorpromazine: The first antipsychotic

Just as they sound, antipsychotics aim to reduce symptoms of psychosis. These symptoms are found in not only schizophrenia but also bipolar disorder, some forms of depression, and other mental disorders.

Antipsychotic development kicked off in the 1950s with the release of chlorpromazine. But the company that made it—a French company called Rhône-Poulenc—didn’t intend to make a drug for psychosis or schizophrenia. They were looking for new antihistamines: drugs that are typically used to treat allergies.

At the time, French army surgeon Henri Laborit believed these drugs could suppress the nervous system and prevent surgical shock: forms of physical shock that arise in surgery. After Laborit’s research found some antihistamines that caused a noticeable mental relaxation in patients—some so strongly that others called it a “pharmacological lobotomy”—Rhône-Poulenc focused on making chemically similar drugs that enhanced these calming properties, inventing chlorpromazine in the process. Chlorpromazine was released to market in 1952.

Since chlorpromazine was so good at helping patients stay calm before and after surgery, Laborit and others wondered if the drug could help patients with psychiatric disorders. And in 1952, psychiatrists Jean Delay and Pierre Deniker would perform some of the first studies using chlorpromazine in psychotic or “agitated” patients, with notable success.

From there, more clinical studies across Europe would support the use of chlorpromazine as an antipsychotic, and its use by psychiatrists would rapidly grow.

First-generation antipsychotics

With the success of chlorpromazine, researchers jumped on the chance to develop similar compounds. This led to other so-called “first-generation antipsychotics.” 

Others were found unexpectedly. For example, another widely successful antipsychotic, haloperidol, was developed by Belgian company Janssen Pharmaceutica in 1958 after researching new pain-killing medications, noticing that some of these compounds had similar relaxing effects as chlorpromazine. 

But how do these substances work? Key insights first came in 1963, when Swedish scientists Arvid Carlsson and Margit Lindqvist found that both chlorpromazine and haloperidol could bind dopamine receptors in the brain, preventing dopamine release by neurons. Dopamine is a neurotransmitter in the brain that helps neurons communicate. It’s now well-known for its roles in motivation and reward, as well as body movement.

RELATED: Making Antipsychotics with Baker’s Yeast

More research in the ’60s and ’70s would show that antipsychotics share a common mechanism; they block a specific kind of dopamine receptor called D2 receptors. We now know that D2 receptor overactivation in a specific brain pathway called the mesolimbic pathway is a major cause of psychosis.

However, these drugs block all D2 receptors in the brain, not just in the mesolimbic pathway. This leads to some serious side effects, including movement disorders. Tardive dyskinesia, for example, can develop after first-generation antipsychotic use, causing involuntary movements in the face and body. These disorders can be irreversible, posing a major setback.

Second-generation antipsychotics 

Another huge step forward in schizophrenia treatment was marked by the approval of clozapine. Clozapine is the first of the “second-generation antipsychotics”: drugs with a different pharmacological and side effect profile than their first-generation cousins.

Clozapine was only FDA-approved to treat schizophrenia in 1990. But it was first discovered in 1959 by Janssen, as part of a screening for new antidepressants. Though it showed potent antipsychotic properties, trust among psychiatrists was slow to develop, due to its “atypical” profile relative to other antipsychotics of the time.

Yet clozapine is as effective—if not more so—than first-generation drugs in reducing psychosis. It also has a lower risk of causing tardive dyskinesia and other side effects. That quickly made it a first-line schizophrenia treatment, and it remains one today.

A new wave of drug development followed in clozapine’s footsteps, giving rise to other second-generation antipsychotics. Further research would show that, while these drugs block D2 receptors like the first-generation drugs, they also interact with brain receptors for serotonin and norepinephrine: other neurotransmitters known for roles in mood and the fight-or-flight response, respectively. 

RELATED: Brains and Play Behavior in Rats

Most block a specific serotonin receptor, 5HT2A, that can indirectly promote dopamine release. This receptor also influences the functions of the neurotransmitter glutamate, which may also be altered in schizophrenia.

In all, this more complex mechanism reduces psychosis while minimizing serious side effects. Still, second-generation antipsychotics come with side effects of their own. Clozapine, for example, often causes weight gain and increases risk of seizures. 

On top of that, neither first- nor second-generation drugs are very effective against the depression-like symptoms of the disorder. They also have mixed effects on cognitive function. Plus, up to 34 percent of people with schizophrenia are treatment resistant, meaning they still have symptoms even after trying 2 different medications. That leaves a lot of room for improvement…a void that researchers behind Cobenfy hope to fill.

Xanomeline: The next generation of antipsychotics?

Xanomeline (Cobenfy) will be the first drug for schizophrenia that doesn’t modulate dopamine at all. Instead, it activates a specific type of receptor for acetylcholine: a neurotransmitter that helps relay signals between the brain and organs/muscles in the body. Acetylcholine tells our muscles to contract and sends signals to our gut to aid digestion, among other things.

This might seem an unexpected target for the treatment of schizophrenia. And in fact, not unlike chlorpromazine, xanomeline wasn’t initially developed to treat schizophrenia; it was developed for Alzheimer’s disease. 

A drug that prevents the breakdown of acetylcholine is already used to treat dementia. So, other pro-acetylcholine drugs have been developed to try to improve cognition in the disorder. However, some patients with Alzheimer’s also have psychotic symptoms…and it was noted that xanomeline was especially effective in relieving these symptoms.

Despite promising results, xanomeline also had a host of nasty side effects that caused many subjects to discontinue treatment. These were mainly gastrointestinal, due to activation of acetylcholine receptors in the digestive system. 

However, activating receptors in the brain was probably sufficient to prevent psychosis. This thought inspired then–PureTech Health vice president Andrew Miller to combine it with a second medicine called trospium chloride. This drug blocks gastrointestinal acetylcholine receptors, but it doesn’t enter the brain, so receptors there can still be activated.

The result? A more tolerable treatment that yields significant improvement not only in psychotic symptoms of schizophrenia, but also in the depression-like symptoms, like apathy and lack of motivation. Though it has its own side effects like nausea and constipation, these promise to be even less severe than those of second-generation medicines.

A leap forward

And so, the development of Cobenfy marks another leap forward in antipsychotic medications. It offers a whole new mechanism of action, focused on acetylcholine rather than dopamine.

Decades of research have hinted at the importance of acetylcholine receptors in schizophrenia… specifically the subtype called muscarinic receptors, which xanomeline targets. Some studies have suggested that subjects with schizophrenia have fewer of these receptors in certain brain areas, for instance.

But there’s a lot left to be learned about how exactly these receptors contribute to psychosis and other symptoms. They might act on the dopamine system, or affect other relevant pathways not yet known.

A deeper understanding of the link between muscarinic receptors and schizophrenia could launch a whole new wave of pharmaceutical research. And in the future, Cobenfy and similar drugs might treat psychosis in Alzheimer’s or bipolar disorder, too. 

With hard work—and a bit of luck—a new generation of drugs could raise patient outcomes to new heights.

References

Bodick, N. C., Offen, W. W., Shannon, H. E., Satterwhite, J., Lucas, R., van Lier, R., & Paul, S. M. (1997). The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer disease and associated disorders, 11, S16–22.

Dean, B., Crook, J. M., Opeskin, K., Hill, C., Keks, N., & Copolov, D. L. (1996). The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Molecular Psychiatry, 1(1), 54–58.

Lally, J., Ajnakina, O., Di Forti, M., Trotta, A., Demjaha, A., Kolliakou, A., … & Murray, R. M. (2016). Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychological Medicine, 46(15), 3231–3240.

López-Muñoz, F., & Álamo, C. (2009). The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice. Brain Research Bulletin, 79(2), 130–141.

López-Muñoz, F., Álamo, C., Cuenca, E., Shen, W. W., Clervoy, P., & Rubio, G. (2005). History of the discovery and clinical introduction of chlorpromazine. Annals of Clinical Psychiatry, 17(3), 113–135. 

Vos, T., Abajobir, A. A., Abate, K. H., Abbafati, C., Abbas, K. M., Abd-Allah, F., … & Murray, C. J. L. (2017). Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet, 390(10100), 1211–1259.