New Paths to Personalized Schizophrenia Treatments

An multinational study that was published in Nature Communications may make it easier to develop novel, individualized therapies for individuals with schizophrenia. These people have a variety of symptoms, including depression symptoms, hallucinations, delusions, and cognitive impairments like memory or language problems.

The type 2A serotonin receptor is the main therapeutic target of current medications, but they do not allow for selective action on the patient’s symptoms. This results in side effects, metabolic problems, and motor problems, among other problems, which cause patients to stop their therapy.

In this regard, the research has revealed the function of specific proteins, known as G proteins, which are essential for controlling cell responses in schizophrenia. It was demonstrated, in particular, that two varieties of these proteins enable the modification of the primary symptoms associated with this illness.

The Neuropsychopharmacology Group at the University of the Basque Country (UPV/EHU) and the CIBER of Mental Health (CIBERSAM) collaborated with researchers from the Hospital del Mar Medical Research Institute to lead the study.

Dr. Jana Selent, one of the principal authors of the study and coordinator of the Drug Discovery Group based on G protein-coupled receptors at the Hospital del Mar Medical Research Institute, says, “These proteins are coupled to the same receptor, but they do not act in the same way, causing diverse reactions in the cells, which provides us with very valuable information for future studies that will enable the development of drugs for the treatment of schizophrenia in a personalized manner, tailored to each patient’s symptoms.”

high level of complexity

The researchers had to carry out intricate investigation in order to arrive at these conclusions. The first step was choosing a variety of existing compounds, some of which are not licensed medications for human use, and analyzing their molecular structure and potential interactions with the type 2A serotonin receptor using atomic-level simulations. This made it possible to choose four compounds, which were then investigated in cells. It was found that these compounds caused various types of G proteins to respond when they bound to the receptor.

These findings were utilized in examinations of human brain tissue samples from the University of the Basque Country’s (UPV/EHU) Neuropsychopharmacology Group collection. “The compounds had very different activity concerning the G proteins: some activated them, but others deactivated them,” according to Dr. Patricia Robledo, a researcher at the Integrated Pharmacology and Systems Neuroscience Group and one of the study’s principal authors.

In this regard, “the possibility of inhibiting the coupling of the serotonin 2A receptor to certain G proteins has been proposed as an area of interest for designing a new type of drug, known as inverse agonists, as potential tools against psychotic conditions,” notes Rebeca Diez-Alarcia, first co-author of the article and researcher at UPV/EHU.

Furthermore, according on which G protein these chemicals activated, they produced different behavioral effects in a mouse model intended to mimic the symptoms of schizophrenia. Thus, it was discovered that one of these G proteins is linked to psychosis-related symptoms in mice, whereas another type of G protein is linked to cognitive deficiencies through the use of pharmacological and genetic approaches.

According to Dr. Robledo, “This is the first time that promising therapeutic targets have been identified for developing drugs that act and benefit a specific profile of schizophrenia patients.”

Although the compounds used in the study are not yet approved drugs for human use, Dr. Jana Selent says that “this multi-scale work reveals a plan for the chemical design of future drugs that address more specific pathways to treat schizophrenia, avoiding pathways associated with side effects, which is of great relevance for a more personalized treatment.”

Dr. Daniel Berge, a psychiatrist at the Mental Health Institute of the Hospital, who did not participate in the work, points out that “this study will help design more selective drugs for the treatment of schizophrenia, which can offer better tolerance and higher precision on the symptoms of the disease. All this would promote better treatment adherence, which is key to preventing relapses and achieving a better quality of life.”

For more information: G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits, Nature Communications (2024), https://dx.doi.org/10.1038/s41467-024-48196-2