Schizophrenia: A New Hope

For about one in a hundred people worldwide, there comes a time when their lives completely fall apart. 

This often begins during adolescence with trouble focusing, memorizing, and making plans. Thinking becomes harder. 

Along with these thinking problems, they find their emotions fading, their motivation dropping, and it becomes harder to socialize and connect with others. Doctors call these 'negative symptoms'.

People become more worried when other symptoms appear: hearing threatening voices and seeing or smelling unusual things (hallucinations), feeling persecuted, or believing unusual ideas (delusions). These symptoms, known as 'positive symptoms' by doctors, are all signs of psychosis. 

If family or friends can get the person to see a doctor, the common diagnosis is schizophrenia.

A bit of history...

Over 100 years ago, Swiss psychiatrist Eugen Bleuler, who was working at the Burghölzli in Zürich at the time, gave this mental disorder its name to distinguish it from other conditions. 

Back then, being diagnosed with schizophrenia often meant spending the rest of your life in specialized hospitals (asylums) since there were no effective treatments available, a situation that persisted for decades after his groundbreaking work. 

Doctors tried electroshocks or insulin to cause seizures, hoping the brain would "reset." Another method, brain surgery, ended up causing more harm than good. 

A breakthrough for patients came in the early 1950s, thanks to French psychiatrists Pierre Deniker and Jean Delay at Paris’s Saint Anne Hospital. They found that a new drug originally tested for a different purpose also turned out to reduce psychotic symptoms. This drug, called Chlorpromazine, and later developed substances with similar effects, quickly became available worldwide and greatly improved patients’ lives to this day. 

However, there are serious downsides. Long-term use causes major side effects, including movement problems, restlessness, weight gain, extreme tiredness, hormonal changes, and a risk of developing permanent movement disorders.

These drugs have another important limitation: they only treat psychotic symptoms. Problems with focus, memory, emotions, and motivation remain, and these untreated symptoms make it difficult for patients to go back to their previous lives. In some cases, mild psychotic symptoms remain or do not respond to treatment at all.

Another result of this accidental discovery was that research into the brain mechanisms of schizophrenia gained momentum. This led to the discovery that these new antipsychotic drugs help reduce the overactivity of a brain chemical called dopamine in certain areas deep in the brain which are involved in hallucinations and delusions. 

However, in the forebrain—the area responsible for memory, focus, and planning—the dopamine levels are unusually low. These drugs only have a limited effect on restoring dopamine levels to healthy levels in this part of the brain.

Despite decades of research and drug development since the 1950s, these shortcomings of standard antipsychotics are unresolved.

A new hope...

Yet, there is new hope now with a drug approved by the FDA in the US in September 2024. 

Interestingly, the groundwork for this drug was laid around the same time the first antipsychotic drug was discovered. It is linked to an ancient tradition of betel nut chewing in Southeast Asia and the Western Pacific. This practice has stimulating and mood-enhancing effects and can also improve learning.

These effects are caused by arecoline, which affects another brain chemical called acetylcholine. In the 1950s, researchers Pfeiffer and Jenny found that arecoline may have antipsychotic effects. While the antipsychotic potential of chlorpromazine was quickly used, it took nearly 70 years for the potential of arecoline to be developed into a new drug for schizophrenia patients.

First, the focus shifted to treating Alzheimer’s disease by using substances similar to arecoline to boost progressive memory loss. Since acetylcholine levels continuously drop in Alzheimer’s disease, the goal was to enhance the effect of the remaining acetylcholine in the brain. Among the candidates tested, a drug called Xanomeline, developed by Eli Lilly & Company, showed the most promise in improving memory in patients with Alzheimer’s disease.

Similar to the discovery of chlorpromazine’s antipsychotic effects decades earlier, Xanomeline was found in the 1990s to dramatically reduce psychotic symptoms, which are also common in Alzheimer’s disease. A follow-up clinical study in 2008 tested Xanomeline on schizophrenia patients and confirmed its effectiveness. 

Even more surprisingly, it not only reduced psychotic symptoms but also helped to improve emotional, motivational as well as memory, and focus difficulties—areas where standard treatments had failed. 

Additionally, its effects were fast, even in patients, where previous treatments had failed, and it did not cause the usual side effects associated with classic antipsychotics.

However, despite the initial excitement, there were also disappointing results. The drug caused severe side effects, including nausea, vomiting, sweating, excessive salivation, and acid reflux. The acetylcholine-stimulating effects impacted not only the brain but also the intestines and glands. The side effects were so discouraging that the drug was eventually put back on the shelf.

Eventually, a new idea led to a breakthrough and FDA approval: combining Xanomeline with a second drug, Trospium, which blocks the influence of Xanomeline outside the brain but cannot enter the brain itself. This combination allowed Xanomeline to work fully in the brain while keeping side effects at tolerable levels. 

A series of clinical studies (EMERGENT 1-3) showed that this drug cocktail remained effective for treating psychotic symptoms. They also helped with negative symptoms, and problems with concentration and memory, although more research is still needed to confirm this. The combination therapy, developed by Karuna Therapeutics (now Bristol Myers Squibb), convinced the FDA to approve it. The drug is called KarXT and is sold under the name Cobenfy.

What we do not know...

While doctors in the US can start prescribing the new drug and patients are beginning to benefit, scientists are still left with some important questions. Overall, they do not fully understand why Xanomeline works so well. 

One idea is similar to the old dopamine theory. It has been found that increased levels of acetylcholine can reduce dopamine release deep in the brain, which helps control psychotic symptoms, much like traditional antipsychotics. However, unlike older treatments, Xanomeline does not affect the parts of the brain that cause the motor side effects.

Surprisingly, in experiments where the drug mainly targeted the forebrain, it also reduced psychosis. The reason for this is still unclear. Stimulation of acetylcholine effects in the forebrain is known to improve learning and memory, which may help explain the improvement in memory and attention in schizophrenic patients.

One idea to explain these antipsychotic effects is that Xanomeline activates specific inhibitory neurons, which helps reduce overactivity in the cortex. This overactivity is believed to overstimulate the deep brain areas and contribute to psychotic symptoms. However, this is challenging to confirm because many different types of neurons are involved. It is also possible that simply enhancing forebrain functioning, without directly affecting dopamine, could reduce psychosis.

While Xanomeline acts on both the forebrain and deep brain areas, drugs are actively being investigated that bind to their targets differently from Xanomeline. One such drug, Emraclidine, developed by Cerevel Therapeutics (now AbbVie), targets mainly deep brain areas and has advanced the furthest in clinical development so far.

There is much excitement around KarXT since it is a new drug with a different mechanism of action after 70 years. It comes at a time when the drug industry has had many failures in creating effective psychiatric medicines, and many projects have been stopped. However, it is important to remember that it has only been tested on a limited number of patients thus far, and more time is needed to see how well the drug works in the long run.