For more than 70 years, the drug treatments available to psychiatrists to help their patients with schizophrenia have barely changed – they all work through the same mechanism in the brain, with the same drawbacks and limitations. To get a sense of how this plays out in practice, consider the case of Gareth.
Gareth was in his early 20s when he and his family first came to our psychosis service in South Wales. He was a casually dressed, slightly distractable young man. His family had become very worried when, first, his academic performance dropped off, and then he stopped going to college altogether. Gareth spent increasing amounts of time alone in his room and no longer met up with his friends. Then his parents found that he had covered the walls of his room in foil saying he needed to keep out the spy rays from nearby agents. Gareth said he could hear them talking about him and his family, and plotting to kidnap them.
Gareth was exhibiting the classic symptoms of psychosis, including delusions (false beliefs) and hallucinations (false perceptions, including hearing voices). He was eventually diagnosed with schizophrenia – a condition characterised by psychotic symptoms in association with other features such as social withdrawal and impairments in thinking. These symptoms can be particularly disabling as sufferers become increasingly withdrawn and isolated from society, affecting their work and social lives.
The early psychosis team offered Gareth antipsychotic medication to treat his psychotic symptoms. This treatment – based on that 70-year-old familiar mechanism of action in the brain – was effective in reducing Gareth’s psychotic symptoms. But it did not improve his other difficulties, such as social withdrawal. Worse still, as is often the case with these drugs, Gareth experienced difficult side-effects including substantial weight gain and changes in hormone levels.
Antipsychotic medications of the kind given to Gareth were first discovered in the 1950s. They were originally developed from antihistamine drugs, which clinicians noticed could calm patients prior to surgery, and then, even more remarkably, they realised that they could decrease symptoms of psychosis such as delusions and hallucinations. This discovery had a major beneficial effect, including contributing to the decreasing numbers of patients incarcerated for long periods in psychiatric hospitals.
Dopamine-blocking antipsychotics drugs have no effect on social withdrawal or cognition
Antipsychotics were later shown to act by blocking a specific class of receptors for the chemical dopamine in the brain. All known antipsychotics have, until now, acted through this same fundamental mechanism of altering dopamine pathway signalling, a system involved in both reward and associative learning processes in the brain. These dopamine-blocking drugs are highly effective in decreasing psychotic symptoms, such as delusions and hallucinations.
However, these dopamine-blocking antipsychotic drugs also have significant limitations. As we saw with Gareth, they have no effect on the social withdrawal also seen in schizophrenia (sometimes referred to as ‘negative symptoms’) or on the difficulties in areas such as cognition. And they cause significant side-effects. The earliest treatments developed were found to have a tendency to induce a Parkinson’s disease-like stiffness and other odd and disabling movement symptoms. New dopamine-blocking antipsychotics were developed in the 1990s that had less tendency to cause movement symptoms. Unfortunately, these medications also had challenging side-effects of the kind that Gareth struggled with, including causing significant weight gain, and worsening fat and sugar levels in the blood.
I’ve seen firsthand how these side-effects can impact my patients’ lives. It’s understandable that many patients are often unwilling to take these medications in the longer term, which then increases their risk of having a relapse.
Psychiatry has been crying out for new treatments for psychotic conditions like schizophrenia that promise broader benefits and fewer side-effects. However, progress has been blighted by the complexity of the brain and a lack of clear understanding of the causes of schizophrenia. The task has been so difficult that major pharmaceutical companies have largely abandoned mental health for other more tractable and lucrative areas of medicine. The situation has been extremely frustrating for patients, their families and clinicians.
That’s why I’m so excited that a new type of antipsychotic medication with a totally different mechanism of action has now been developed and is becoming available to patients. This treatment does not target the dopamine system but instead modulates signalling by another chemical system in the brain – the cholinergic system – which has a wide range of neuro-modulatory functions (affecting the responsiveness of other brain systems).
The cholinergic system has long been of interest as a treatment target, not for schizophrenia, but for Alzheimer’s disease. Loss of cholinergic signalling is a feature of Alzheimer’s disease and has been considered to contribute to memory loss and other cognitive difficulties. That’s why researchers developed drugs to enhance cholinergic signalling, including one called xanomeline.
He came up with the idea of combining the drug with a second agent to mitigate xanomeline’s side-effects
A large trial of xanomeline in people with Alzheimer’s disease in the 1990s showed a small beneficial effect on memory and cognition. However, echoing the role of serendipity in the discovery of antipsychotic treatments in the 1950s, the researchers testing xanomeline noticed a much more striking and unexpected beneficial effect of the drug on the psychotic and behavioural symptoms often seen in people with Alzheimer’s disease. They conducted a subsequent trial of xanomeline in 20 people with schizophrenia and, excitingly, this suggested that the drug could be beneficial in the treatment of psychosis in this group too. However, progress with the drug stalled at that point for Alzheimer’s disease and schizophrenia because of its marked side-effects, such as nausea, vomiting and fainting. Most patients were simply unable to tolerate taking the medication.
Several years later, Andrew Miller, a scientist working at the psychiatry-focused biotech startup Karuna, took another look at xanomeline. Miller came from an engineering background and had no formal training in psychiatry or neuroscience, but he brought a highly analytical mindset to the task. Tasked with identifying promising new mechanisms for the treatment of conditions like psychosis, he revisited the promise of xanomeline. He came up with the idea of combining the drug with a second agent that could mitigate xanomeline’s side-effects.
After looking at many possible drug combinations, Miller and his colleagues hit upon trospium; a drug that has the opposite effects to xanomeline, but acts only outside the brain. Miller’s proposal was that a xanomeline-trospium combination would have the beneficial effects of xanomeline on psychosis (through action in the brain) but with lower side-effects (as trospium would block these effects outside the brain). Miller and Karuna had an uphill struggle to persuade the world to take this proposed drug combination seriously. But with support from the Wellcome Trust in the UK, in 2021 they were able to show that the combination drug (known initially as KarXT) was safe and, importantly, that patients found it much easier to tolerate compared with taking xanomeline on its own. Miller’s hunch appeared to be paying off, but KarXT still needed to be tested in patients with schizophrenia.
Karuna then obtained funding to conduct a number of large-scale clinical trials of KarXT in people with schizophrenia, and these showed consistent beneficial effects in reducing psychotic symptoms. Remarkably, unlike the older antipsychotic treatments, the trials also showed that KarXT can improve the negative symptoms of schizophrenia such as social withdrawal and may even have some benefit for cognition. Perhaps most notable of all, however, was that KarXT was not associated with any of the side-effects that have blighted the older antipsychotics, such as movement changes and weight gain. KarXT did have some side-effects of its own, most notably nausea, but most patients in the trials found this was tolerable and decreased over time, and rates of stopping the drug did not differ from placebo.
Since then, things have moved quickly. On the basis of these findings, Karuna submitted a new drug application to the Food and Drug Administration (FDA) in the United States. In 2024, Karuna was purchased by the major pharmaceutical company Bristol Meyers Squibb and later that year the FDA approved KarXT as a therapy for schizophrenia. KarXT is now on the market with the brand name Cobenfy. It is hoped that Cobenfy will soon be licensed in other countries as well. Consequently, for the first time in many decades, psychiatrists like me who treat people with schizophrenia might be able to offer patients a therapy that works through a new biological pathway.
It will take time for doctors and patients to judge when to use Cobenfy in the treatment of schizophrenia. Many questions remain unanswered: for example, how effective Cobenfy is in the long term; whether there are any other as-yet undetermined side-effects; and whether Cobenfy will be of use in other mental health conditions such as bipolar disorder. However, I believe this is a landmark moment in psychiatry – to have, for the first time in so many years, a drug with a fundamentally new mechanism of action for the treatment of psychosis.
I’m hopeful that this development will have other knock-on benefits, such as encouraging more investment in the development of treatments for conditions such as schizophrenia. Most importantly, as a clinician, I am excited to be able to offer people like Gareth a new medication with potentially fewer side-effects and that offers a better chance of living a full and fulfilling life.
Conflicts and disclaimers
Jeremy Hall has sat on a paid advisory board for Bristol Myers Squibb, who own Cobenfy. He is not a shareholder in Bristol Myers Squibb and has no ongoing financial interest in the company. The individual with psychosis discussed in this article is fictionalised.
