Acetylcholine’s back: Move over dopamine

Kaul et al (2024) report the results of a trial of xanomeline–trospium (KarXT) in people with schizophrenia experiencing acute psychosis. Even though we’ve been told that dopamine blockade is the way to treat schizophrenia, KarXT does not block D2 dopamine receptors. Instead xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist. It is combined with trospium chloride, a peripherally restricted muscarinic receptor antagonist, to ameliorate peripheral muscarinic effects.

Side effects of KarXT include constipation, dyspepsia, headache, nausea, vomiting, hypertension, dizziness, gastro-oesophageal reflux and diarrhoea. The gastrointestinal side effects of xanomeline had previously stopped its development as a psychotropic drug. The combination with trospium is designed to reduce frequency and severity of such adverse events. 

Schizophrenic symptoms were significantly reduced by KarXT more than placebo after 5 weeks. The study was said to be masked but no measures of unblinding are included in the research report, so it is difficult to assess its bias. If unblinded, it is likely that the fact that this is a new agent, with the hope, therefore, and maybe expectation, that it will be effective could have influenced results. The trial was funded by Karuna Therapeutics, which has other drugs in its pipeline, and has recently been acquired by Bristol Myers Squibb. Already a global pharmaceutical giant, I’m sure KarXT, if successful, will enhance Bristol Myers Squibb’s finances at least over the next decade.

Acetylcholine is a neurotransmitter. It was the first to be discovered as it is secreted by the vagus nerve. There are two main types of receptors: muscarinic and nicotinic. Muscarinic receptors are the main end-receptor in the postganglionic fibres of the parasympathetic nervous system. They are also present in the brain where all five subtypes are expressed.

The dopamine theory of schizophrenia hasn’t stood up for some time (see eg. previous post). Despite some protests that they do not, psychiatrists generally believe that psychotropic medication corrects chemical imbalances in the brain. They’ll adjust without any qualms to thinking that muscarinic receptor agonists modulate dopaminergic, GABAergic, and glutamatergic signaling in schizophrenia. They’ve been waiting for a antipsychotic drug which doesn’t block dopamine D2 receptors for over 70 years, and Karuna Therapeutics has managed to exploit that situation. 

I guess tolerability may be more of a problem than Kaul et al make out, but we shall see. As Cipriani et al (2024) point out, there is no data on comparative benefits and harms of KarXT against existing antipsychotics. Data from longer term trials is also awaited. There are also questions about the actual benefit to patients. Still, I suspect enough has already been invested for the weight of Bristol Myers Squibb to see KarXT to market.