Xanomeline

Genuinely important, and easy to overstate. The mechanism is new in a field that has recycled one mechanism since the 1950s, and the effect sizes in the phase 3 trials sit in the same range as existing antipsychotics rather than above them. The real gain is the side effect profile it does not have: no weight gain, no extrapyramidal symptoms, no prolactin rise. It swaps those for a gut that complains. Not a cure, and not hype either.

The limiting problem with xanomeline has always been cholinergic activation outside the brain: nausea, vomiting, dyspepsia, constipation, sweating and syncope. In the 1990s Alzheimer's programme these effects were bad enough on the oral formulation to end development, and the paper says so directly ^[1]. Pairing it with trospium blunts much of this but does not remove it; in EMERGENT-2 the combination produced constipation in 21 percent, nausea in 19 percent, dyspepsia in 19 percent, vomiting in 14 percent and hypertension in 10 percent, against 10 percent or less on placebo for each, while discontinuation for adverse events matched placebo at 7 percent versus 6 percent ^[2].

The approved product is contraindicated in urinary retention, gastric retention, untreated narrow-angle glaucoma and moderate to severe hepatic impairment, and carries warnings for biliary disease, decreased gastrointestinal motility, angioedema and increases in heart rate. Long term safety is not yet characterised; the pivotal controlled trials ran five weeks.

Xanomeline came out of Eli Lilly's cholinergic programme in the early 1990s as LY246708 and was tested in Alzheimer's disease. A 343 patient trial found a cognitive benefit at the top dose and a strongly dose dependent reduction in vocal outbursts, suspiciousness, delusions, agitation and hallucinations; the antipsychotic signal was the surprise, and the gastrointestinal tolerability was the reason the oral programme stopped. Karuna Therapeutics, a company founded by PureTech, picked the compound back up and paired it with trospium so the peripheral effects could be blocked without touching the brain. Bristol Myers Squibb acquired Karuna for 14 billion dollars in March 2024, and the FDA approved the combination as Cobenfy on 26 September 2024 for the treatment of schizophrenia in adults.

Regarded in psychiatry as the most significant mechanistic change in antipsychotic treatment in fifty years, and covered as such when it was approved. Enthusiasm has cooled somewhat since: the phase 3 ARISE trial of Cobenfy added on top of an atypical antipsychotic missed its primary endpoint in April 2025 with a 2.0 point PANSS separation at p equal to 0.11, and the Alzheimer's psychosis readouts have slipped. The monotherapy data in acute schizophrenia remain solid.