Melting schizophrenia treatment barriers

A few years ago, while wandering around Chicago with no plans, I found myself at the International Museum of Surgical Science. It was both fascinating and terrifying.  

The museum houses an extensive collection of jarring surgical instruments, artifacts and exhibits that tell the story of how surgery has evolved, from ancient practices to modern techniques.  

There are detailed displays on the history of anesthesia, the development of X-rays and even recreations of early operating rooms and procedures. The museum provides a gripping glimpse into the surgical field's past, underlining both the incredible innovations and the often-gruesome reality of early scientific progress. 

Lessons learned? Well to start, visit more medical museums. Also, it became very evident that when you begin looking into early treatments for almost any disorder, you're bound to find some shocking stuff.  

When it comes to psychological disorders, history can be especially unsettling. 

First coined by Swiss psychiatrist Eugen Bleuler in 1908, ‘schizophreniegruppe’ as a term — which translates to ‘split mind’ — represented the fragmented thinking and emotional disturbances characteristic of the illness. Early treatments were often harsh to say the least, including insulin coma therapy, electroconvulsive therapy and lobotomies. With the introduction of chlorpromazine, an antipsychotic, in the 1950s, schizophrenia treatment was revolutionized, providing symptom relief and paving the way for modern antipsychotic medications and more humane therapeutic approaches. 

Despite advancements, current schizophrenia treatments are far from perfect. They often fail to address the negative symptoms and cognitive deficits of the disorder, such as social withdrawal and memory problems, which significantly impact patients' lives. Moreover, many struggle with medication adherence due to drug side effects and the chronic nature of the disorder.  

After decades of being frozen in time, schizophrenia treatment barriers are beginning to melt. New drugs are looking to target different neurotransmitter systems, and research into prodrugs and formulations for once-daily dosing or long-acting injectables promise effective treatment with fewer side effects and improved adherence.

Treatment evolution 

The first symptoms of schizophrenia often include subtle changes in behavior, such as social withdrawal and unusual thoughts. Individuals may also experience mild hallucinations or delusions, along with increased difficulty in concentrating and maintaining focus. 

Diagnosing the disorder involves ruling out other conditions and ensuring symptoms aren't due to substance misuse or medical issues. This process includes a physical exam, tests and screenings for similar conditions and substance use, and possibly imaging studies like MRI or CT scans.  

Current treatment mainly involves antipsychotic medications, divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). The older FGAs, developed in the 1950s, target dopamine receptors and reduce symptoms like hallucinations and delusions but can often cause serious side effects, including severe motor dysfunction. 

The newer SGAs, introduced in the 1990s, target both dopamine and serotonin receptors and generally have fewer motor side effects, though they can still lead to issues like weight gain and diabetes.

Schizophrenia often involves overactive dopamine pathways, particularly in the mesolimbic pathway, which is responsible for controlling feelings and actions through dopamine signals. This overactivity leads to symptoms like hallucinations and delusions, so to counter this, many antipsychotic drugs block dopamine D2 receptors, reducing the overactivity in the mesolimbic pathway and alleviating these positive symptoms. 

Over the past 30 years, numerous medications have been approved for treating schizophrenia, but many use the same mechanisms of action: 

• Janssen Pharmaceuticals’ Risperdal (risperidone): First approved in 1993, serotonin-dopamine antagonist. Targets the serotonin 5-HT2A and dopamine D2 receptors. 
• Eli Lilly’s Zyprexa (olanzapine): First approved in 1996, antagonizes multiple receptors. Targets the dopamine D2 and serotonin 5-HT2A receptors. 
• AstraZeneca’s Seroquel (quetiapine): First approved in 1997, targets the serotonin 5-HT2A, dopamine D2, histamine H1, and adrenergic alpha1 receptors. 
• Otsuka Pharmaceutical’s Abilify (aripiprazole): First approved in 2002, targets the dopamine D2 and serotonin 5-HT1A receptors. 
• Janssen’s Invega (paliperidone): First approved in 2006, antagonist that targets the dopamine D2 and serotonin 5-HT2A receptors. 
  
  

Bristol Myers Squibb acquired Karuna in December 2023 for $14 billion, securing KarXT. With a regulatory action date of September 26, 2024, the drug is a blockbuster-hopeful. 

“The second issue is patient compliance,” says Clark. “We need medications that patients can take regularly. With schizophrenia, medication compliance is a major issue. And you want medications that don't have to be dosed as frequently, so that patients don't have a medication burden to take.”  

While revolutionary and undeniably impactful, Clark says that KarXT does present limitations. “The problem with KarXT is that it's twice daily, oral. Now, the gold standard for oral antipsychotics is once daily. Having to have a patient with schizophrenia take twice daily represents an additional hurdle.”  

A few medications offering a long-acting alternative have been approved but they still rely on traditional mechanisms of action.  

“At Terran, we developed prodrugs of both xanomeline and trospium to improve both molecules. This marks the first improvement of trospium since the 1960s and xanomeline since the 1990s,” Clark says. “This allows us to create a once-daily drug and a long-acting injectable, providing the same benefits without the need for twice-daily dosing.”  

A prodrug is developed by attaching a small side chain to the side of the molecule so that you improve the pharmacokinetics and absorption. Once taken, the side chain falls off in the body, allowing the original main molecule to exert its therapeutic effect. The method can help the drug work better, reduce side effects, improve how it's absorbed and processed, or target specific areas in the body more effectively. 

“Prodrugging antipsychotics is not new; many on the market have already been improved this way. However, this usually happens 10 to 15 years after the original antipsychotic is released,” says Clark.  "We believe patients shouldn't have to wait for the best technology, so we decided to make prodrug versions of KarXT (xanomeline and trospium) now prior to its (approval),  rather than a decade later."*

 With their novel combination of prodrugs of xanomeline and trospium called 'TerXT,' hopes to enable once-daily oral dose forms and long-acting injections with multi-month duration and pursue accelerated development and regulatory pathways.  

Where we are headed 

Looking ahead, researchers are focusing on developing drugs with novel mechanisms of action to improve symptom management and reduce side effects, especially for patients with treatment-resistant schizophrenia. 

Cerevel Therapeutics’ emraclidine, acquired by AbbVie back in December, acts as an M4 positive allosteric modulator. It has shown significant improvements in schizophrenia symptoms in early trials without targeting dopamine receptors directly. 

Iclepertin from Boehringer Ingelheim is another promising candidate targeting cognitive impairments in schizophrenia. It acts as a glycine transporter-1 (GlyT1) inhibitor, enhancing NMDA receptor function and showing promise in improving cognitive deficits associated with schizophrenia.

While treatments for neurological disorders have lagged behind other indications, change is on the horizon. 

"Neuroscience has been largely overlooked because it's difficult to tackle and less understood than fields like oncology," Clark says. "For a while, big pharma left neuroscience altogether due to profitability issues, shuttering many neuroscience departments about 20 years ago. But now we're seeing a resurgence, and we're glad it's getting more focus." 

*KarXT is comprised of two old molecules xanomeline (invented in the 1990s) and trospium (invented in the 1960s) the composition of matter has expired. Terran’s prodrugs contain structural modifications to the original xanomeline and trospium and thus represent new composition of matter. The US patent office has granted Terran a notice of allowance for the composition of matter for the prodrugs so they will be protected by a new composition of matter patent for 20 years.