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Study will help develop personalized treatment for schizophrenia

 
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Last reviewed: 02.07.2025
 
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31 May 2024, 10:29

An international study conducted by the Institute of Medical Research of the Hospital del Mar in collaboration with researchers from the Neuropsychopharmacology Group of the University of the Basque Country (UPV/EHU) and researchers from CIBER for Mental Health (CIBERSAM) and published in the journal Nature Communications, could lead to the development of new personalised treatments for people diagnosed with schizophrenia.

These patients suffer from various types of symptoms such as delusions, hallucinations, cognitive deficits, memory or language impairment, and depressive symptoms. Current treatments, mostly targeting a specific therapeutic target, the serotonin type 2A receptor, fail to selectively address the symptoms experienced by the patient, causing side effects and metabolic or motor problems, among others, that lead to treatment abandonment.

In this context, the study has highlighted the role of certain proteins, G proteins, which play a vital role in modulating cellular responses in schizophrenia. In particular, two types of these proteins have been shown to modulate the main symptoms of this disorder. Dr. Jana Celente, one of the study's lead authors and coordinator of the G protein-coupled receptor drug discovery group at the Hospital del Mar Institute of Medical Research, points out that "these proteins are linked to the same receptor, but they act differently, causing different responses in cells," which "provides us with very valuable information for future research that will allow us to develop drugs to treat schizophrenia in a personalized way, taking into account the symptoms of each patient."

High complexity research

To reach these conclusions, the researchers conducted a comprehensive study. The starting point was to select various available molecules, although they are not approved drugs for humans, to analyze at the molecular level and through atomic simulations their ability to interact with the serotonin receptor type 2A. This allowed them to select four compounds that were first studied in cells, where they were shown to elicit responses in different types of G proteins when they bound to the receptor.

These results were applied to analyses of human brain tissue samples from the collection of the Neuropsychopharmacology Group of the University of the Basque Country (UPV/EHU). In these studies, it was observed that "the compounds had very different activities on G proteins: some activated them, while others deactivated them," explains Dr. Patricia Robledo, also the study's lead author and a researcher in the Integrated Pharmacology and Systems Neuroscience Group. In this regard, "the possibility of inhibiting the binding of the serotonin 2A receptor to certain G proteins has been suggested as an area of interest for the development of a new type of drug, known as inverse agonists, as potential tools against psychotic conditions," noted Rebeca Díez-Alarcia, first co-author of the article and a researcher at the UPV/EHU.

Furthermore, in a mouse model designed to mimic the symptoms of schizophrenia, these compounds had specific behavioral effects depending on which G protein they activated. Thus, using pharmacological and genetic methods in mice, it was determined that one of these G proteins is involved in symptoms associated with psychosis, and another type of G protein is involved in cognitive deficits.

Dr. Robledo notes that "this is the first time that promising therapeutic targets have been identified for the development of drugs that act and benefit a specific profile of patients with schizophrenia." Although the compounds used in the study are not yet approved as drugs for use in humans, Dr. Jana Celente emphasizes that "this multidisciplinary work identifies a blueprint for the chemical design of future drugs that target more specific pathways in the treatment of schizophrenia while avoiding pathways associated with side effects, which is of great importance for more personalized treatment."

Dr Daniel Berge, a psychiatrist at the hospital's Institute of Mental Health, who was not involved in the work, notes that "this study will help develop more selective medications for the treatment of schizophrenia that may offer better tolerability and greater precision in terms of the symptoms of the disease. All this will contribute to better compliance with treatment, which is a key factor in preventing relapses and achieving a better quality of life."

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