The U.S. FDA has approved a new drug—called Cobenfy—to treat the symptoms of schizophrenia. Unlike traditional treatments, which are based on blocking the effects of dopamine, its mechanism of action simulates the effects of another neurotransmitter, acetylcholine. It is the first drug to be approved with a different mechanism of action in over 70 years.
Eduard Vieta - KarXT EN
Eduard Vieta
Researcher of the Centre for Biomedical Research in Mental Health Network (CIBERSAM). Head of the Psychiatry and Psychology Department at the Hospital Clínic de Barcelona and lecturer at the University of Barcelona
This drug represents a significant advance in the treatment of schizophrenia, as it is the first medication that does not act directly on dopamine receptors, but rather on muscarinic receptors. In this regard, although acetylcholine and dopamine are interconnected, it constitutes a very relevant innovation because it represents a mechanism of action different from existing drugs and with a different adverse effect profile. It could be a good alternative for patients who do not tolerate the drugs currently used.
Furthermore, the size of the effect in the acute phase and the results of the extension study are also positive regarding long-term safety and effectiveness. After its approval, clinical experience will determine to what extent it represents a true advance in clinical practice for this disease, which is in great need of new approaches.
“I have no conflicts of interest related to this product and the company that will market it. However, I do have other conflicts of interest related to other products, which may be worth mentioning, as I have received grants and acted as a consultant, advisor, or speaker for the following entities: AB-Biotics, AbbVie, Adamed, Alcediag, Angelini, Biogen, Beckley-Psytech, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Luye Pharma, Medincell, Merck, Newron, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, Teva, and Viatris.”
Celso Arango - KarXT EN
Celso Arango
Head of the Department of Child and Adolescent Psychiatry and Director of the Institute of Psychiatry and Mental Health of the Hospital General Universitario Gregorio Marañón
The most novel aspect is that, for the first time, an indication for schizophrenia will be given (since the use of chlorpromazine began in 1952!) to a drug that does not act directly on dopamine receptors. Despite this, the agonist mechanism of muscarinic receptors can, through two distinct pathways involving GABAergic and glutamatergic neurons, produce a decrease in dopaminergic activity in areas where dopaminergic hyperactivity has been implicated with psychotic symptoms.
Regarding efficacy, the two phase III clinical trials have been robust and, more rarely, very consistent (effect size 0.6). As for side effects, it should be noted:
- Xanomeline was tested decades ago and was effective, but it was abandoned due to peripheral muscarinic side effects. Now, they have added a second substance (trospium), which blocks peripheral receptors to prevent those side effects.
- Since it does not have a direct dopaminergic effect, the typical side effects of the drugs (antidopaminergic or partial agonists) that we have used until now to treat schizophrenia/psychosis, such as extrapyramidal symptoms or hyperprolactinemia, do not appear or are greatly reduced.
“I have given lectures funded by Karuna and BMS.”
