Big hopes for schizophrenia treatment rely on a deep pipeline of new approaches

Like many drug discoveries throughout history, one of the medications still used today to treat schizophrenia came about accidentally. 

In 1951, a scientist at a French pharmaceutical company created chlorpromazine, a drug he hoped would boost the effects of general anesthesia. What he produced was a calming, non-sedating treatment that drew the eye of a French army surgeon, Henri Laborit, who saw its potential for treating psychiatric conditions. 

Thanks to this accidental discovery, chlorpromazine became the first in a new class of antipsychotic treatments for schizophrenia, a debilitating brain disorder marked by hallucinations, delusions, cognitive problems and functional challenges that affects about 24 million people worldwide.

While chlorpromazine marked a step forward for the field, scientific and clinical trial-related challenges such as slow recruitment and high drop-out rates have limited progress over the last 72 years. All of the current treatments for schizophrenia still act on the same dopamine D2 receptor as that first medication, said Andrew Miller, founder and president of research and development at Karuna Therapeutics. The pharmacology of chlorpromazine? differs slightly from more recently approved schizophrenia treatments — some of them also modulate serotonin — but they all stick to the same basic playbook.  

“Although the current range of antipsychotics may provide some relief from positive symptoms in schizophrenia patients, there are still several large unmet needs that remain,” said Summer Colling, an analyst at Citeline. “Some of the greatest unmet needs include drugs targeting the negative and cognitive symptoms of schizophrenia, drugs with improved tolerability, therapies encouraging enhanced compliance rates and more effective treatment options for refractory schizophrenia.”

However, the treatment landscape may change this year if Karuna’s drug KarXT gets the green light from the FDA, a decision expected in September. The drug, a muscarinic agonist, would be a first-in-class approval for Schizophrenia.

Muscarinic receptors have become a tantalizing target for central nervous system disorders. But harnessing their potential power has been challenging. Muscarinic receptors aren’t only found in the brain, but exist in other places in the body, raising the potential for side effects. Karuna’s approach confines the drug’s effects to the brain. 

The drug’s potential caught the eye of pharma giant Bristol Myers Squibb, which announced a $14 billion deal to acquire Karuna in December. The deal will give KarXT a leg up in the commercial arena considering BMS’s prior experience in multiple neuropsychiatric indications, Colling said.

KarXT has the potential to reduce positive, negative and cognitive symptoms of schizophrenia and also brings fewer problematic side effects, such as weight gain, metabolic side effects and uncontrolled movements, which often cause patients to stop taking them. 

“What we see in our clinical trials is an absence of those side effects because we don’t have that dopamine and serotonin-based pharmacology at the core of what KarXT is now,” Miller said. “That’s not to say that KarXT is a side-effect-free treatment. We do generally have mild to moderate transient GI side effects.”  

Many drugs in development

While KarXT may be generating the most buzz, it’s not the only drug finding its way to the schizophrenia market, which could reach $7.11 billion by 2028. Much of the ongoing work is focused on shifting toward precision psychiatry, understanding the neurobiology of the condition instead of using symptoms to give patients better, more targeted treatments, Colling said. 

“A lack of validated biomarkers is hindering the transition towards precision psychiatry currently,” Colling said. “There is also generally less investment in chronic conditions with large populations as firms need a broad commercial strategy and must be prepared to engage with many healthcare providers.”