KarXT is the first antipsychotic in more than 70 years with a new mechanism of action. It combines xanomeline, an agonist of the muscarinic M1 and M4 receptors, with trospium, a peripheral antagonist. In the United States it is sold under the name Cobenfy.

Critical notes on KarXT

The current antipsychotics mainly target dopamine D2 receptors. KarXT targets the muscarinic acetylcholine receptors, which are thought, so far without scientific proof, to play a part in the pathophysiology of the problems under the diagnosis ‘schizophrenia’. The combination with trospium is meant to limit the peripheral side effects of xanomeline. KarXT thus offers an alternative approach, notable for the absence of direct dopamine blockade.

Despite this apparently new mechanism, there are critical notes to make about the clinical studies on which the approval of KarXT rests.

History teaches that when a new medicine is introduced everyone is wildly enthusiastic, until after 25 years it turns out that the new medicine adds little or nothing. So let us stay critical. I too hope that the new medicine will add something, but my basic attitude is critical, for the following reasons.

1. Conflicts of interest and risk of bias

The three clinical studies that led to the approval of KarXT were funded and organised by Karuna Therapeutics, the company with enormous financial interests in positive results. The potential profit runs into tens of billions of dollars. Research shows that industry-sponsored studies carry a higher risk of bias in favour of the active medicine. These interests have a scientifically demonstrated influence on how results are reported and interpreted.

2. Limited blinding in the clinical studies

A second point is the lack of blinding. When a medicine has clear side effects and psychotropic effects, blinding in randomised, double-blind, placebo-controlled studies comes under pressure. The KarXT studies used an inert placebo, not an active placebo with side effects. Participants and clinicians could therefore guess who received the active medicine and who the placebo. We know from research that this can push results in favour of the active medicine, because the expectations of participants and clinicians steer the outcomes.

3. Expectations and side effects

A new medicine with noticeable side effects can raise positive expectations in participants, certainly when they know they are taking part in a trial of a medicine of which much is expected. In the case of KarXT, side effects such as gastrointestinal complaints can strengthen the belief that one is receiving the active medicine, and that belief alone can affect the improvement people report. This is part of the placebo effect, which plays an important part in the treatment of mental health problems, including psychosis susceptibility. It can distort the picture of how effective KarXT is.

4. The PANSS as the measure of effect

The effect of KarXT was assessed with the PANSS (Positive and Negative Syndrome Scale), a scale that measures positive, so-called negative and general psychopathological symptoms of ‘schizophrenia’. A lower PANSS score is often read as an improvement in ‘schizophrenia’ symptoms, but the scale contains many items on general psychopathology, such as anxiety, tension and depression. Psychotropic medicines usually dampen symptoms across the board, and that lowers the PANSS score. It is therefore not certain that a lower score reflects an improvement in ‘schizophrenia’ symptoms specifically.

It is also possible that the procholinergic effects of KarXT, which can be psychoactive, contribute to a general improvement in wellbeing that the PANSS picks up as a therapeutic effect on ‘schizophrenia’ symptoms.

In other words: there is a fair chance that the effects of KarXT would have occurred just as well if an antidepressant had been used. It is worrying that governments may soon spend billions on a general dampening effect for which a very cheap antidepressant would have worked just as well.

5. Strict selection of participants

Participants in the KarXT studies were carefully selected, and many people with more complex problems were excluded. People who might benefit most from a new medicine were not included: those for whom other treatments have not worked, those who also have to deal with suicidality or substance misuse, and those who use antidepressants or mood stabilisers, which usually points to a more complex picture that is harder to treat. This limits how far the findings can be generalised. It raises questions about the real target population in which KarXT should be studied before billions are spent on it.

6. Costs and limited clinical relevance

Despite the weaknesses in the study design, governments and health insurers are likely to face considerable costs for KarXT. The studies show a significant difference in PANSS score between KarXT and placebo, but that in itself says little about clinical relevance in the daily life of participants. The question remains whether this new medicine offers a meaningful improvement over existing treatments.

Conclusion

KarXT offers a new approach and has aroused enthusiasm among investors and within psychiatry. There are important methodological and ethical notes to place on the clinical studies: the funding by the manufacturer, the lack of blinding, the use of the PANSS, and the selective inclusion of participants all bring potential bias and limitations.

It is essential that we keep looking critically at this new medicine and at the impact it really has on the lives of people with the diagnosis ‘schizophrenia’, before we see it as a breakthrough in the treatment of psychosis susceptibility.

Jim van Os

Read more: Schizophrenia spectrum versus psychosis spectrum and Different types of antipsychotics.

Prof. dr. Jim van Os, Chair Division Neuroscience, Utrecht University Medical Centre. Jim works at the interface of ‘hard’ brain science, health services research, art and subjective experiences of people with ‘lived experience’ in mental healthcare. 

Jim has been appearing on the Thomson-Reuter Web of Science list of ‘most influential scientific minds of our time’ since 2014. In 2014 he published his book ‘Beyond DSM-5‘, and in 2016 the book ‘Good Mental Health Care’. In 2026 he published 'Wat psychisch lijden is'.

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