KarXT is the first antipsychotic in over 70 years that introduces a new working mechanism. The drug combines xanomeline, an agonist of the muscarine M1 and M4 receptors, with trospium, a peripheral antagonist.

KarXT: Critical observations

Unlike current antipsychotics, that mainly focus on dopamine D2 receptors, KarXT focuses on the muscarinic acetylcholine receptors, which are thought to, however without any scientific proof as of yet, play a part in the pathophysiology of psychological problems that are diagnosed as schizophrenia. By combining it with trospium they try to limit the peripheral side effects of xanomeline. Because of this, KarXT offers an alternative approach to the treatment of “schizophrenia”, that is mainly known for the absence of direct dopamine blockage.

But despite this seemingly new mechanism there are critical comments to be made about the clinical research that underlie the approval of KarXT.

That’s because history shows us that when a new drug is introduced, everybody gets very excited about it, until 25 years later it becomes clear the drug hardly works, or doesn’t work at all. So let’s stay critical. I hope that this new drug will contribute to peoples’ treatment, but my default position is critical because of the following factors:

1.Conflict of interest and risk of bias

Three clinical studies, that led to the approval of KarXT, were organised and financed by Karuna Therapeutics, the company that has vast financial interests in positive results of their medication. The potential profit of the drug amounts to tens of billions of dollars. Research shows that studies sponsored by the industry carry a higher risk of bias, which can influence the results in favour of the drug. It is important to recognise that these interests can have a scientifically proven influence on the way in which the results are reported and interpreted.

2.Limited blinding in clinical studies

Another criticism is the lack of ‘blinding’ (a research method that prevents participants, researchers, or other parties from knowing certain information that could influence the results of a study) in the studies. When a drug has obvious side effects and psychotropic effects, it can put pressure on the blinding in randomised, double-blind (Neither patients nor the researchers know which group they’re in and which drug they received), placebo-controlled trials.

In the research on KarXT an inert placebo has been used instead of an active placebo with side effects. Because of this, neither the patients nor the medics know who received the active drug, and who received the placebo. Scientific research has shown that this can have a positive impact on the results of the active drug, because the expectations of patients and medics can affect the outcomes of the studies.

3.Patients’ expectations and side effects

Using a new medication with significant side effects can lead to patients having positive expectations about the efficacy of it, especially if they know they are taking part in a trial of a drug that has high expectations. In the case of KarXT this would mean that the side effects like gastrointestinal problems, add to the conviction that they received the active drug, which can have an effect on their improvement.

This is part of the well known placebo effect, that we know plays an important part in the treatment of psychological issues, including vulnerability to psychosis. This potentially paints the wrong picture of the efficiency of KarXT.

4.The use of PANSS to measure efficiency

The efficiency of KarXt was assessed using the PANSS (Positive and Negative Syndrome Scale), a scale that measures positive, (so called) negative, and general psychopathological symptoms of schizophrenia. Although a reduction of the PANSS-score is often interpreted as an improvement of schizophrenia-symptoms, the scale contains many items concerning general psychopathology, like fear, tension, and depression. Psychotropic drugs usually have a general pathological effect, which can result in a decrease of the PANSS-score. Because of this, it is unsure whether a lower score is specifically connected to an improvement of ‘schizophrenia’ symptoms.

It’s also possible that the pro cholinergic effects of KarXT, that can cause psychoactive effects, contribute to a general improvement of the well-being, which is picked up by the PANSS as a therapeutic effect on symptoms of “schizophrenia”.

In other words: there’s a reasonable chance that the effects of KarXT would have occurred just as well if an antidepressant had been used instead of KarXT. It’s worrying that governments will possibly be spending billions of euros on a general pathological effect whilst a much cheaper antidepressant would have sufficed.

5. Strict selection of participants

Participants of clinical trials regarding KarXT were carefully selected, and many patients with more complex illnesses were excluded. This means that people who would possibly benefit mostly from a new medicine, like patients who are resistant to other treatments, or who suffer from other conditions as well as “schizophrenia”, like suicidality or substance abuse, or who are on antidepressants or mood stabilisers (usually an indicator of an illness that’s more complex and more difficult to treat) were not included in the studies.

This limits the ability to generalise the findings of the research, and raises questions about the target population in which KarXT should really be tested, before we spend billions on it.

6. Cost and diminished clinical relevance

Despite the reservations concerning the examination procedure, it’s likely that governments and healthcare insurers will spend a lot of money on the use of KarXT. And though the studies show a significant difference in PANSS-score between KarXT and placebo, this says very little about the clinical relevance to patients’ everyday lives. The question whether this drug actually offers an improvement compared to existing treatments for psychological problems collectively known as ‘schizophrenia’, remains.

KarXT;  Conclusion

 Although KarXT offers a new approach to the treatment of mental health issues collectively known as ‘schizophrenia’, and has generated enthusiasm amongst investors and within the psychiatric field, there are significant methodological and ethical caveats within the clinical research. The financing by the manufacturer, the lack of blinding, the measuring of the effect of the drug using the PANSS, and the selective inclusion of the participants raises all kinds of noteworthy biases and limitations.

It is of vital importance that we remain critical when looking at the new drug and the impact it can have on the lives of people who have been diagnosed with ‘schizophrenia’, before we class it as a break through in the treatment of people who are vulnerable to psychosis.

Translated from Dutch by S.G.M. Taplin