Don’t let the picture fool you, this post has nothing to do with psychedelics or magic mushrooms but another compound found in toadstools - muscarine. Like many natural substances, it has binding sites within the human body - muscarinic receptors. These can be found in the brain, where they are thought to be important for learning and memory. They are also found in other parts of the body, such as the gastrointestinal system (this will be important later).
A medication acting on muscarinic receptors, KarXT, has emerged as a new hope for treating schizophrenia - featured last week in the Observer. It is a combination of two older medications, xanomeline and trospium. Words like ‘breakthrough’ and ‘game-changer’ have been used but they seem to be said a lot in psychiatric research. Will expectations be met this time?
Disclaimer
My department at Oxford, led by Professor Belinda Lennox who was interviewed in that Observer article, has been awarded funding from the Wellcome Trust to study KarXT in schizophrenia. I don’t have any direct involvement in that study or any insider information above what’s been released in the press.
Xanomeline
Like many stories in drug development, this one has been decades in the making, and begins with the muscarinic receptor agonist xanomeline. This was discovered in the early 90s and acts primarily on M1 and M4 receptors. As these are important in cognitive processes, it was initially trialled for Alzheimer’s disease and subsequently for schizophrenia.
Both these trials were promising in terms of reducing symptoms but were limited by troublesome side-effects, commonly nausea, vomiting, indigestion and excessive sweating. In the Alzheimer’s trial, over half of the participants who were on a high dose quit the study.
Schizophrenia, unfortunately, tends to be a relapsing life-long illness - so any treatment needs to be well tolerated over the longer-term. Indeed, current antipsychotic medications work pretty well for so-called ‘positive’ symptoms like hallucinations and delusions but many patients experience side-effects that lead to their discontinuation.
For a new antipsychotic medication to really impress us, we want to see three things:
Works in a different way to current medications (a new ‘class’)
Effective for symptoms (ideally the negative and cognitive symptoms which are most difficult to treat)
Minimal side-effects
Xanomeline potentially ticked the first two boxes but fell down with the third. That was until another medication was added in combination, the T in KarXT - trospium.
Trospium
The second half of the combo is even older, having been synthesised in the 60s and is used for overactive bladder. It is a muscarinic receptor antagonist (remember that xanomeline is an agonist). So we are using two drugs that have opposing actions on muscarinic receptors. What gives?
The key property of trospium that makes it the perfect bedfellow for xanomeline is that it does not cross the blood-brain barrier. This means it can block the troublesome peripheral side-effects while not interfering with the stimulation of muscarinic receptors in the brain. Clever, huh?
Karuna therapeutics acquired xanomeline in 2012 and added trospium to make KarXT. In healthy volunteers, this combination resulted in about half the side-effects compared with xanomeline alone.
‘Emerging’ evidence
A phase 2 trial, Emergent-1, was published in the New England Journal of Medicine in 2021. This showed impressive reductions in symptoms, measured by the PANSS score, beating placebo on the primary endpoint. A separately published post-hoc analysis - be appropriately skeptical - suggested it was also beneficial for cognition in a subgroup of patients. The medication was generally well-tolerated and importantly didn’t cause sedation or weight gain, which are issues with many antipsychotics.
Results from two phase 3 trials, Emergent-2 and Emergent-3 have been released to the press but are not yet published in journals. They met their primary end-points, with similar effect sizes to current antipsychotics. The effect seemed to be greater in positive symptoms, with the second trial showing no statistically significant effect on negative symptoms.
What about side-effects? Well 70% of patients taking KarXT experienced at least one ‘treatment emergent adverse event’. This sounds bad, until you see that 50% of patients who received placebo also had such events. This is why we do randomised controlled trials. Reassuringly only a small proportion stopped the medication due to the event - 6% of those in the treatment group and 5% in the placebo group.
If KarXT is approved for schizophrenia, this is a big deal. Antipsychotic drugs were discovered in the 1950s and although there have been some tweaks, there haven’t been any subsequent drugs with a truly novel mechanism of action (perhaps the closest we have is clozapine, which seems to be uniquely effective for patients who don’t respond to other medications).
Frustratingly, the antipsychotics that work best for reducing symptoms also tend to have the worst side-effects. Antipsychotics do reduce mortality in schizophrenia, but many patients don’t like taking them long-term. This is a major unmet need, which KarXT might go some way to addressing.
All roads lead to dopamine
Antipsychotics, more or less, work in the same way - by blocking dopamine. (As a brief aside, this was always thought to be at the D2 receptor but an elegant study in mice suggests D1 might actually be the crucial receptor.) Having a different class of medications that exert their antipsychotic effect through another neurotransmitter system would be huge. At first glance, KarXT’s muscarinic agonism is just that, but the truth might not be so simple.
We probably don’t fully understand the antipsychotic mechanism of action for xanomeline but some animal models suggest it could be through the modulation of dopamine-firing cells. In one study in monkeys, xanomeline was able to block the effects of dopamine agonists.
If KarXT works by inhibiting dopamine at a level upstream to conventional antipsychotics, that would still be something though perhaps not quite a revolution in how we understand and treat schizophrenia.
Remember the atypicals
Now a note of caution. I said there have been no new classes of antipsychotic medication since the initial discovery in the 1950s. Well that is not quite true. In the 1990s, a group of antipsychotics coming off the back of clozapine were termed ‘atypical antipsychotics’ mainly in their lack of extra-pyramidal side-effects (i.e. abnormal movements associated with D2 receptor blockage). These included medications like olanzapine and quetiapine.
As time went on the distinction between typical and atypical became less clear. Some new antipsychotics like risperidone were as ‘typical’ at causing movement problems as many of the older drugs. To get round this, the newer ones were named ‘second generation antipsychotics’ but again this classification, based simply on the era in which the medication was brought to market, had no real basis in pharmacology.
Furthermore, it came to light that those antipsychotics not causing movement problems had other bad side-effects, like weight gain. While those with the most benign profile (I’m thinking of aripiprazole and lurasidone) are among the least effective.
Verdict
KarXT is being lined up as a true first-in-class medication for schizophrenia and time will tell whether it is a genuine improvement on current treatment.
But think of a relatively pessimistic outcome, in which the phase 3 results hold up, but the effects of KarXT are mainly on positive symptoms, without much benefit for negative or cognitive symptoms. Perhaps KarXT is not quite as well tolerated in the real-world as in clinical trials, or there are side-effects that emerge in post market surveillance. Maybe the mechanism of KarXT is just through inhibiting dopamine, in a slightly different way from conventional antipsychotics. Would we as psychiatrists, researchers, patients, be happy with this scenario?
Even in that somewhat gloomy timeline, I think we should be incredibly encouraged. Because it means we are making progress. For such a severe mental illness - that impairs a person’s ability to function in society, to hold down employment, to complete education, to marry or have a family - every small step counts.
And in this case progress will have been made, not in understanding every intricacy of the human brain, but simply by taking an old drug which was effective yet intolerable and then blocking its peripheral side-effects.
What other compounds are already out there, waiting to be re-discovered?
I’ll add that M1 and M4 agonism may even be tapping into an important MOA of Clozapine that makes it uniquely effective. I am very excited!
What is your perspective on the recent results from the two ulotaront trials? Is TAAR1 still a potential target? Thanks for an excellent breakdown of KarXT, fingers crossed it becomes a helpful clinical tool!