Mechanism of Action
What type of receptors does xanomeline primarily activate?
M1 and M4 muscarinic receptors.
What was the primary endpoint of the EMERGENT-2 trial?
Change in PANSS total score at week 5.
Name one "positive" symptom of schizophrenia.
Hallucinations, delusions, disorganized speech.
Why is trospium combined with xanomeline in KarXT?
To block peripheral muscarinic side effects (e.g., nausea, vomiting).
Why did the trial use a "flexible dose" of KarXT for some patients?
To adjust for tolerability (e.g., reduce GI side effects)
Which symptom domain (positive/negative/cognitive) does KarXT uniquely address compared to D2-blocking antipsychotics?
Negative symptoms (e.g., social withdrawal).
How does M4 receptor activation improve positive symptoms like hallucinations?
It inhibits excessive dopamine release in the mesolimbic pathway.
True or False: KarXT caused weight gain like many other antipsychotics.
False! (No significant weight gain vs. placebo.)
What is the biggest safety advantage of KarXT over traditional antipsychotics?
No weight gain/metabolic issues or extrapyramidal side effects.
Name one brain region where M1 receptors are abundant and explain their role in schizophrenia.
Prefrontal cortex (enhances cognition/glutamate signaling) OR hippocampus (memory).
What was the most common type of side effect with KarXT? (Hint: Think general body system.)
Gastrointestinal (e.g., nausea, constipation)
Why might KarXT improve cognition in schizophrenia?
M1 activation enhances glutamate signaling in the prefrontal cortex.
Why don’t current antipsychotics (like risperidone) improve negative/cognitive symptoms as effectively as KarXT?
They block D2 receptors but don’t modulate muscarinic pathways.
What made the EMERGENT-2 trial different from typical antipsychotic studies?
It tested a muscarinic agonist (not a D2 blocker) for schizophrenia.
What future study would you design to address EMERGENT-2’s limitations?
Long-term trial, active comparator (vs. risperidone), or outpatient study.