Last fall, we hosted a virtual presentation featuring the esteemed Dr. David Pickar who spoke about the new antipsychotic medication, Cobenfy. The presentation received rave reviews and it was clear that our audience was interested in learning more about this new drug. More recently, we connected Dr. Pickar with the podcast Head Inside Mental Health hosted by Todd Weatherly where Dr. Pickar shared his breadth of knowledge about this new medication with a wider audience. Among his many accolades, Dr. Pickar served in the Intramural Research Program of the National Institute of Mental Health (NIMH) for over 20 years where he was the Chief of the Experimental Therapeutics Branch dedicated to studying schizophrenia and psychosis. In this month’s blog, Dr. Pickar joins us as a guest blogger to summarize his expert and unique insights on a medication that is getting a lot of good buzz and providing a new hope for those suffering from psychosis and those who support them.
What’s the Big Deal?
Cobenfy (Xanomeline) was approved by the Food and Drug Administration in September 2024 for the treatment of schizophrenia. While there have been numerous drugs approved for the treatment of schizophrenia over the past 25 years, Cobenfy stands alone because it is the first drug approved by the FDA for the treatment of schizophrenia that doesn’t block the dopamine D2 dopamine receptor – for that matter, it doesn’t block any dopamine receptors. It was the discovery decades ago that antipsychotic drugs “block” the D2 receptor that essentially established the dopamine hypothesis of schizophrenia, to this day an enduring and informative hypothesis about the pathophysiology of schizophrenia. To have a drug that is not fundamentally related to dopamine AND treats the psychosis of schizophrenia is a very big deal indeed. It’s a big deal for scientists, clinicians and, yes, patients, as it does not have the range of side effects that dopamine blocking antipsychotic drugs have. These side effects unequivocally contribute to patients’ discomfort that often contributes to discontinuation of treatment. Yes, this is a big deal!
Why The Big Buzz?
Schizophrenia is the most serious of all mental illnesses. It causes suffering in patients and families and challenges and stretches society’s resources. The idea that there is a new drug, and one that doesn’t have the breadth of side effects that characterize dopamine-based antipsychotics, has created a buzz among all of us who treat, care for and suffer from schizophrenia. It has been a long time since there has been this degree of enthusiasm and expectation for a drug to treat schizophrenia.
On a personal note, I recall being asked by colleagues at Eli Lilly over 25 years ago to visit and cast my opinion about a drug that was quite far along in development. The drug was Xanomeline, yes, the active therapeutic compound in Cobenfy. Xanomeline is an agonist (it enhances) the acetylcholine neurotransmitter system, aka cholinergic neurotransmission, and was actually related to cholinergic drugs that could be used to treat Alzheimer’s disease. One thing that was quite clear and was surprising for that matter was that it could also treat psychoses. Unfortunately, it also produced cholinergic side effects, including a host of gastrointestinal disruptions, as well as disruptions in heart rate. With these in mind, it seemed best to Eli Lilly to put full development on an extended hold.
Steve Paul, who had been the scientific director of the intramural NIMH, and a longtime colleague of mine, “moved” Cobenfy from Lilly to his company, Karuna Therapeutics, and after it’s FDA approval to the large pharmaceutical company Bristol Myers Squibb where it is to this day. Cleverly, the drug Trospium, a strong anticholinergic antagonist, was added to Xenomeline to create the drug Cobenfy which now does not have the limiting side effects the Xenomeline itself has. It was a long but worthwhile process that has provided for a new drug to treat schizophrenia with a different mechanism and a good therapeutic package.
Now, a word about dopamine. There are several dopamine neurotransmitter systems in the brain. The mesolimbic dopamine system in the midbrain is thought to be the site where dopamine is linked to psychosis and where antipsychotics bind to the D2 receptor, reduce mesolimbic dopamine activity and ultimately produce antipsychotic effects. The mesocortical dopamine system is in the prefrontal cortex and modulates the limbic dopamine and is essential for important frontal neuropsychological properties. Although Cobenfy does not bind to dopamine receptors, it turns out that Cobenfy, an agonist for the M1 and M4 cholinergic receptors in the frontal cortex, produces inhibitory/modulating effects on the mesolimbic dopamine systems. Reduction of limbic dopamine activity is likely the key to how Cobenfy produces antipsychotic effects. More will be learned, but it is reassuring to us “old” folks who grew up focusing on dopamine to see a neurotransmitter poke its head up once again in relation to schizophrenia.
How Good Is Cobenfy?
What we know is that Cobenfy is an effective antipsychotic drug that appears to affect dopamine systems indirectly. Its fundamental therapeutic properties fall well within the range of second-generation antipsychotic drugs. There are some key elements, however, that might suggest in some way that it is better. The best of these is the fact that Cobenfy does not produce any of the dopamine-related movement side effects (extrapyramidal movement problems), nor the flatness in affect and an overall dysphoric feeling. Cobenfy appears to be overall more “comfortably” tolerated by patients than first- or second-generation antipsychotics, possibly leading to fewer drug discontinuations.
There certainly are several questions about Cobenfy therapeutics that hopefully will be answered as we become more experienced in its use. For example, is it therapeutic in otherwise treatment resistant patients? Would its best therapeutics be seen when it is added to traditional dopamine receptor antipsychotics? Might it be suited to enhance therapeutics in depressive illness when added to antidepressants? Given its lack of Parkinson life side effects (EPS) might it be particularly useful in those patients who experience EPS. A final thought based on some circumstantial but not fully developed data; might Cobenfy help cognitive deficits in patients with schizophrenia? This would be something very important.
It’s hard to know when we will learn the full range of Cobenfy’s therapeutics, although my guess is these answers will emerge over the next couple of years, supported one way or the other by emerging clinical experience. One thing we know is that it is an antipsychotic with a different mechanism than traditional antipsychotics and potentially a different range of therapeutics. On a final note, it has already made a substantial contribution by just being approved by the FDA and being available. The positive impact on the spirit and “mood” of schizophrenia clinicians alone has been an important and meaningful accomplishment.
How Does Cobenfy Fit in Today’s World?
The US leadership today has brought into question many medical issues that had been well settled through experimentation and excellent supervision by the well run and very focused FDA. Questions regarding vaccinations and, more recently, the effectiveness of SSRI antidepressants have left those of us who have focused on these sorts of issues for our professional life with our heads shaking. Is this a good time to introduce a new and different antipsychotic? It should be good timing for the reasons discussed above, but we will all need to keep an eye on how this “new world” handles a new drug. Most of all, it is critical to keep in mind what carefully controlled investigation has demonstrated about the Cobenfy. More information will be coming. On a personal level, Cobenfy’s emerging helpfulness in treating schizophrenia simply stands out. A new or unusually modified mechanism of antipsychotic action is all very welcome. It is important for those of us in medicine and medical research to keep our eye on controlled clinical science. The distortion of medical research by a new generation of political leaders was an unexpected development. The key is to keep our purpose and goals clear and stand by the “rules” and world of science through this difficult time.
We are so fortunate to have Dr. Pickar as one of Advisory Council members. We hope you found his expertise and message of hope as informative and inspiring as we do.
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Thank you for this information. I’d like to suggest that in a future blog, HitH focus on Dr. Steven Israel, MD. Dr. Israel has taken the route of prescribing me Caplyta as an antipsychotic.