KarXT (Cobenfy) is the first antipsychotic that doesn’t block dopamine. We trace the origins of this new drug to a South Asian herb used for over 5,000 years, up to the three EMERGENT trials that led to its FDA approval.

Publication Date: 10/07/2024

Duration: 12 minutes, 27 seconds

KELLIE NEWSOME: Last week, the FDA approved Cobenfy, the first antipsychotic to make a clean break with the usual dopamine-blocking mechanism of action. But its origins go way back to the betel leaf, an herbal stimulant used in Asia for over 5,000 years.

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor-in-chief of the Carlat Report. 

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

CHRIS AIKEN: Every September, I give a talk on the top research updates of the past year at the North Carolina Psychiatric Association’s annual meeting. This year, I didn’t give the talk. As the conference opened in Asheville, NC, we heard a loud crash above our heads. Part of the Renaissance hotel had fallen on the flat roof above our heads. The lights went out. The windows moved in the wind and rain. But the group pulled together, setting up flashlights in the pitch-dark auditorium, as Mehul Mankand continued his seminar.

We didn’t know where this was headed, but we all figured if things got worse we could drive home. We were wrong. Within a few hours, every road out of Asheville was closed. There was no phone or internet – news came in by word of mouth. Food, water, and gasoline were in short supply, as only a few restaurants stayed open and the ones that did quickly ran out of supplies. 60 miles away, the Nolichucky River flooded into a Tennessee hospital that sat on its banks, forcing patients and staff onto its roof, where 3 Blackhawk helicopters lifted them to safety.

My main fear in all this was riots – but I was wrong. People didn’t act worse in duress. They were more friendly and helpful as they waited in 2-hour long lines to buy a box of crackers. Neighbors went house to house to check on each other and offer support.    

The cause of all this chaos was Hurricane Helene brought similar damage to communities from Florida to Indiana, taking over 200 lives as of this writing. Needless to say, I didn’t give the talk, but I did make it back home after 2 days of looking for a way out, so I’ll present the top 10 findings here, starting with an update that wasn’t in the talk. This one hit the news Thursday night just as Helene was touching ground: The FDA approved Cobenfy, the first antipsychotic that is not a dopamine blocker.

Cobenfy is the brand name for KarXT, and KarXT is a combination of Xanomeline, the X, and Trospium, the T. Xanomeline is the main ingredient, it’s a muscarinic agonist that is selective for the M1 and M4 receptors. When you hear “muscarinic” think acetylcholine – that’s the neurotransmitter that activates muscarinic receptors, so giving xanomeline is a bit like giving acetylcholine, just more selective. And when you hear “acetylcholine” you ought to conjure up a drug that help dementia and – on the other side – might flood patients with cholinergic side effects. And that is how xanomeline began, and how it almost ended. The drug was synthesized in the early 1990s and developed as a therapy for Alzheimer’s dementia. It worked, improving cognitive and behavioral symptoms of dementia, but there was a big catch: over half the patients stopped xanomeline because of cholinergic effects, mainly gastrointestinal.

KELLIE NEWSOME: We’re used to worrying about anticholinergic effects in psychiatry, where people are dried up with dry mouth, constipation, urinary retention, and overheating from the inability to sweat. With xanomeline, we’ve entered the realm of cholinergic crisis, which is when the muscarinic receptors are overexcited, and everything is too wet. Salivation, diarrhea, vomiting, tearfulness, muscle cramps, and twitching.

CHRIS AIKEN: With 50% discontinuation rates, xanomeline was shelved, but psychiatrists took note of something in the dementia trials – delusions and hallucinations improved on the drug. This took them back to a study from 1957 when an extract of the betel leaf – arecoline – improved symptoms in schizophrenia. In Southern Asia, people have chewed the betel leaf for over 5,000 years to improve energy and alertness, and psychiatrists have long noted a pattern where people with schizophrenia have better outcomes if they are heavy users of the betel leaf. Arecoline is the main ingredient in the betel leaf, and it’s a muscarinic agonist much like xanomeline. Muscarinic neurons reaches into the dopaminergic and glutamatergic systems, indirectly regulating these neurotransmitters that are central to psychosis.

KELLIE NEWSOME: The first clinical trial of xanomeline came in 2008, where it improved both cognitive and psychotic symptoms in 10 patients with schizophrenia compared to another 10 who took placebo. This was promising, but there was still concern about cholinergic side effects, so Eli Lilly shelved the drug. Ten years later they sold it to Karuna Therapeutics, who paired it with an anticholinergic med for overactive bladder, trospium, brand name Sanctura. Trospium had recently gone generic, and Karuna thought they could use it to damp down xanomeline’s side effects because trospium only acts on the periphery. It doesn’t enter the brain. They patented the combo as karXT and tested it in healthy volunteers, where it cut the rate of cholinergic side effects in half.

CHRIS AIKEN: The next major leap came in 2021 when KarXT improved positive and negative symptoms of schizophrenia in a study of 182 patients published in the New England Journal of Medicine. The main side effects – as we might expect – were a mix of cholinergic and anticholinergic effects: constipation, dry mouth, nausea, and vomiting. What was missing from the list were side effects we normally associate with antipsychotics: fatigue, weight gain, akathisia, and extrapyramidal symptoms. That trial is called EMERGENT-1, and it was followed by EMERGENT-2 and -3, with the third installment published this August.

KELLIE NEWSOME: Here’s what emerges from those 3 trials. All were double-blind, placebo-controlled, and all enrolled hospitalized patients with acute exacerbation of schizophrenia, 690 patients in all. All were positive, with effect sizes ranging from 0.6-0.75, similar to what we see with other antipsychotics. Where KarXT stands out is in its side effects. Patients were no more likely to stop the drug than they were placebo in these 5-week trials, and none of the usual metabolic and extrapyramidal problems we associate with antipsychotics showed up.

CHRIS AIKEN: We don’t know how xanomeline will fair when it comes to long-term risks like tardive dyskinesia (TD). I suppose it’s possible that it could cause that through downstream dopaminergic effects, but similar cholinergic medications like donepezil and galantamine once thought to treat TD. That hope didn’t pan out, but at least they didn’t cause it. Anticholinergics, on the other hand, can worsen tardive dyskinesia, something to watch for when adding benztropine (Cogentin) to an antipsychotic.

KELLIE NEWSOME: One thing that is missing from this story is cognitive symptoms. Part of the hope with this drug is that it would improve those, as it did in dementia. But its cognitive benefits in schizophrenia are less clear. Negative symptoms improved in some, but not all, of the trials, but that doesn’t say much. Negative symptoms usually get better when psychotic symptoms are treated in an acute-phase trial with antipsychotics. The real question is whether a medication will help the chronic negative symptoms that cause so much disability in the illness. Most antipsychotics have failed there, with the possible exception of cariprazine (Vraylar). The first KarXT trial did look at cognitive testing, but the drug didn’t make a difference there except in a secondary analysis that included only the patients with severe cognitive problems. We’ll keep an open mind, but so far none of this is enough to convince us that KarXT improves cognition in schizophrenia. 

CHRIS AIKEN: The FDA added a few warnings about KarXT that you need to know about before prescribing it. The drug can cause urinary retention, particularly in the elderly, and it can also slow down the GI tract. KarXT has a rare association with liver toxicity and angioedema – an allergic reaction involving swelling in the face and eyes. It is primarily metabolized through CYP2D6, and it has a short half-life – 5 hours – so is dosed twice a day. We expect it on the pharmacy shelves as early as this November.

KELLIE NEWSOME: In the early 1950’s, first dopamine-blocking antipsychotic revolutionized psychiatry: chlorpromazine. 70 years later, KarXT brings a new mechanism to the table. Whether it will change the game or just reduce the side effects we don’t know, but it certainly earns a place in the top 10 research updates of the past year, which we’ll continue with next week with updates on treatment-resistant depression and a surprising study of benzodiazepine withdrawal.  Can’t wait till then? Get more updates in the September edition of Carlat Psychiatry News – search for it on YouTube. We cover new guidelines on benzo tapering and new studies of brexpiprazole in PTSD, antidepressants in bipolar, oral ketamine, CBD oil, e-Cigs, and fraudulent stimulant scripts.

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