KarXT and the End of Dopamine-Only Schizophrenia Treatment
This episode explores a new mechanistic approach to treating schizophrenia with xanomeline-trospium, which targets central muscarinic receptors to reduce psychosis without directly blocking dopamine. It also breaks down the EMERGENT trial results, including efficacy, gastrointestinal side effects, and the practical limits of this emerging therapy.
Show Notes
- Efficacy and safety of the muscarinic receptor agonist KarXT ... - PubMed: https://pubmed.ncbi.nlm.nih.gov/38104575/
- Efficacy and Safety of Xanomeline-Trospium Chloride in ...: https://pubmed.ncbi.nlm.nih.gov/38691387/
Chapter 1
Bypassing Dopamine: The Muscarinic Breakthrough in Psychosis
Dr. James Whitfield
Since 1952, when chlorpromazine, or Thorazine, first came onto the scene, every single medication we have approved for schizophrenia has done the exact same fundamental thing. They all block dopamine D2 receptors in the brain. Every single one.
Dr. Elena Rodriguez
And, and that trade off has been brutally consistent for seventy years, right? I mean, you get control over hallucinations and delusions, but in exchange, patients suffer from weight gain, severe sedation, or, or motor issues like tardive dyskinesia.
Dr. James Whitfield
Right, exactly. I see this in clinic constantly. You, you have patients who are, um, essentially forced to choose between experiencing terrifying psychotic episodes or living with severe metabolic syndrome and involuntary muscle movements. It is a terrible dilemma.
Dr. Elena Rodriguez
Which is why this new approach is so fascinating biologically. Instead of touching dopamine D2 receptors directly, xanomeline selectively targets central M1 and M4 muscarinic acetylcholine receptors. And by turning those on, it indirectly dampens down dopamine release in the midbrain mesolimbic pathway, right where the psychosis is generated.
Dr. James Whitfield
But wait, xanomeline isn't actually a brand new molecule, is it? Didn't we try this back in the nineties?
Dr. Elena Rodriguez
We did! Back in the 1990s, early trials for xanomeline stalled out completely. The drug worked in the brain, but it hit muscarinic receptors all over the body too. Patients were experiencing, uh, severe nausea, vomiting, profuse sweating, diarrhea. It was completely intolerable.
Dr. James Whitfield
So how did they fix that peripheral nightmare?
Dr. Elena Rodriguez
It is such a clever pharmacological trick. They paired xanomeline with trospium chloride. Now, trospium is a muscarinic antagonist, meaning it blocks those exact same receptors. But trospium cannot cross the blood brain barrier at all. It stays entirely in the body, sitting on gut and peripheral receptors to block the side effects, while xanomeline crosses right into the central nervous system to act freely on the brain.
Chapter 2
Parsing the EMERGENT Trials and Real World Trade Offs
Dr. James Whitfield
That, that ring fencing strategy is brilliant. And we finally have the phase 3 data testing this combination in acute schizophrenia. The EMERGENT trials.
Dr. Elena Rodriguez
Right, EMERGENT 2 published in The Lancet with 252 patients, and EMERGENT 3 in JAMA Psychiatry with 256 patients. Both were five week, double blind studies in hospitalized adults experiencing acute psychotic exacerbations, with baseline Positive and Negative Syndrome Scale, or PANSS, scores hovering around 98.
Dr. James Whitfield
And looking at those primary endpoints, in EMERGENT 2, there was a mean change from baseline to week 5 in PANSS total score that favoured KarXT, dropping score by minus 21.2 points compared to minus 11.6 for placebo. That was an effect size d of 0.61.
Dr. Elena Rodriguez
And EMERGENT 3 showed almost the exact same thing. In that study, xanomeline trospium significantly reduced PANSS total score compared with placebo, dropping minus 20.6 points versus minus 12.2 on placebo, an effect size d of 0.60. What really stands out to me is that it improved both positive symptoms like delusions, and negative symptoms like emotional withdrawal.
Dr. James Whitfield
Okay, but what about the side effect trade off? Did the trospium actually shield the peripheral body like it was supposed to?
Dr. Elena Rodriguez
Mostly, yes, but with a whole different profile than traditional antipsychotics. There was zero excess extrapyramidal motor symptoms compared to placebo. Zero weight gain. No somnolence. But you do see distinct gastrointestinal effects. Nausea was around 19 percent, dyspepsia 16 to 19 percent, vomiting 14 to 16 percent, and constipation 13 to 21 percent. Plus some mild, transient increases in heart rate and blood pressure.
Dr. James Whitfield
So, no metabolic weight gain or movement disorders, but a significant hit of GI discomfort when starting out. That is a completely different clinical conversation with a patient.
Dr. Elena Rodriguez
It really is. Though, as a researcher, I have to point out the clear boundaries of these trials. These were five week inpatient studies. We do not have long term outpatient adherence data yet. And there were no head to head active comparator trials against established atypical antipsychotics like olanzapine or risperidone.
Dr. James Whitfield
Plus, it requires twice daily dosing, which can be tough for adherence in acute illness. And because of trospium's anticholinergic activity in the body, it is contraindicated in patients with urinary retention or narrow angle glaucoma.
Dr. Elena Rodriguez
Absolute game changer in mechanism, but like every tool in medicine, we have to learn exactly where its clinical boundaries lie.
Dr. James Whitfield
Well said. Good chatting, Elena.
Dr. Elena Rodriguez
Talk soon, James.