Schizophrenia is classified as a mental health condition impacting the behaviors and thoughts of an affected individual. The primary symptoms of this disorder are divided into three main categories, including psychotic symptoms, cognitive symptoms, and negative symptoms. Psychotic symptoms are altered perceptions, such as hallucinations, that a patient experiences. Cognitive symptoms are typically characterized by impairments in memory, judgment, and decision making. Negative symptoms describe the lack of normal functioning, such as having no motivation or reduced social interaction skills. Current treatments for schizophrenia include forms of psychotherapy and antipsychotic medications, such as clozapine, which work primarily on dopaminergic and serotonergic receptors.
In Dr. Monsheel Sodhi’s research article and in her presentation that she gave during class, she discussed schizophrenia and its potential causes by describing differences that she and other researchers have found when comparing the brain activities of those with and without schizophrenia. For instance, in her presentation, she explained that reduced glutaminergic gene expression was seen in prior studies looking at brains of those with schizophrenia. In her presentation, she also touched on the involvement of RNA editing in schizophrenia, citing a study where it was discovered that there was reduced GluA2 RNA editing in the post-mortem brains of schizophrenia patients. In addition, she mentioned that prenatal stress or being exposed to major stress events in one’s life could lead to an increased risk for their offspring to develop neurological disorders, such as schizophrenia, autism, or PTSD. In her research paper, Sodhi and her colleagues looked at both prenatal stress and RNA editing and its relation to the development of neurological deficits (lack of social interaction ability). In this study, pregnant mice were exposed to prenatal restraint stress (PRS) by being put into tubes 3 times a day for 45 minutes. Some mice were given medications, such as clozapine, while others were treated with saline. The social interaction (SI) of the offspring were tested in a “three-chambered apparatus” and it was found that those exposed to PRS had reduced SI activity. However, administering clozapine was able to reverse this effect and lead to higher SI behavior. When looking at SI behavior and RNA editing, it was found that editing of GluA2, specifically the flop R/G site, had a linear correlation with SI behavior, indicating a potential mechanism of action of clozapine.
Although Dr. Sodhi examined one major symptom of and treatment option for schizophrenia, I was curious about other treatment options for schizophrenia and whether they have similar mechanisms of action to that of clozapine. I found an article titled Cobenfy (Xanomeline-Trospium Chloride): A New Frontier in Schizophrenia Management by researchers Hasan and Abid. This article reported on an antipsychotic drug just recently approved by the FDA that could assist in the treatment of schizophrenia. This drug is called Cobenfy and combines xanomeline, a muscarinic receptor modulator that reduces psychotic symptoms and impairments in cognitive abilities, with trospium chloride, a muscarinic antagonist that serves to reduce the side effects of xanomeline. In comparison to previous treatments for schizophrenia, Cobenfy does not act on the dopaminergic system, but rather cholinergic receptors. In clinical studies, Cobenfy has also been shown to reduce both positive and negative symptoms of schizophrenia and have fewer side effects than other schizophrenia medications.
The findings and study design that Dr. Monsheel Sodhi presented in class and reported in her research article could be beneficial to learning more about Cobenfy, its mechanism of action, and its influence on symptoms of schizophrenia. Cobenfy was approved by the FDA very recently, in September of 2024. Although clinical trials conducted have shown promising results, few studies have been published about the medication and how it interacts with receptors and neurotransmitters in the brain, as it is still a new medication. Therefore, just as Sodhi and colleagues examined clozapine and its relation to prenatal stress and a common symptom of schizophrenia (reduced social skills), similar studies can be conducted with Cobenfy. Since Cobenfy interacts with cholinergic receptors, rather than the serotonergic and dopaminergic receptors that clozapine interacts with, it would be interesting to see whether it would lead to similar increased social interaction behavior that the clozapine-treated mice exposed to the prenatal stress showed. It would also be beneficial to compare Cobenfy and clozapine’s effects on other major schizophrenic symptoms, such as impairments in cognitive functioning. If Cobenfy has similar efficacy to clozapine in treating symptoms commonly associated with schizophrenia, it would be beneficial to see what other neurological disorders it could be used to treat, such as autism, which was also explored in Dr. Sodhi’s paper. Using the results and understanding of prenatal stress, schizophrenia, and social interaction that Dr. Sodhi’s paper provided, future research can be conducted on new and developing drugs, like Cobenfy, to analyze its efficacy in treating major symptoms of schizophrenia and potentially other neurological disorders.
References
Bristow, G.C., Dong, E., Nwabuisi-Heath, E., Gentile, S., Guidotti, A., & Sodhi, M. (2021). Deficits of hippocampal RNA editing and social interaction resulting from prenatal stress are mitigated by clozapine. bioRxiv. doi: https://doi.org/10.1101/2021.02.02.429408
Hasan, A.H. & Abid, M.A. (2024). Cobenfy (Xanomeline-Trospium Chloride): A new frontier in schizophrenia management. Cureus, 16(10), e71131. doi:10.7759/cureus.71131
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