Study could help develop personalized treatment for schizophrenia

International study carried out by the Institute of Medical Research of Hospital del Mar in collaboration with researchers from the Neuropsychopharmacology Group of the University of the Basque Country (UPV/EHU) and researchers from CIBER Mental Health (CIBERSAM) and published in journal Nature Communicationscould help create new personalized 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, which primarily target a specific therapeutic target, the serotonin type 2A receptor, fail to selectively target the symptoms experienced by the patient, causing side effects and metabolic or motor problems, among others, that lead to treatment failure.

In this context, research has revealed 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 core symptoms of this disorder. Dr. Jana Celente, one of the study's principal authors and coordinator of the G protein-coupled receptor drug discovery group at the Hospital del Mar Institute for Medical Research, notes that "these proteins are bound to the same receptor, but they act in different ways, causing a variety of reactions 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 comprehensive studies. 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 type 2A receptor. This led to the selection of four compounds that were first studied in cells, where they were shown to trigger responses in different types of G proteins when bound to a receptor.

These results were applied to analyzes 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, with some activating them and others deactivating them," explains Dr. Patricia Robledo, also the study's primary author and a researcher in the Integrated Pharmacology and Systems Neurobiology group. In this regard, "the possibility of inhibiting the binding of the serotonin 2A receptor to certain G proteins has been proposed as an area of interest for the development of a new type of drugs known as inverse agonists, as potential tools against psychotic conditions," noted Rebeca Diez-Alarcia, first co-author of the paper and researcher at UPV/EHU.

Additionally, 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, one of these G proteins was found to be involved in symptoms associated with psychosis, and another type of G protein was implicated 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 Selent emphasizes that “this multidisciplinary work identifies a roadmap for the chemical design of future drugs that target more specific pathways for the treatment of schizophrenia, avoiding pathways associated with side effects.” 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 drugs for the treatment of schizophrenia, which may offer better tolerability and greater accuracy for the symptoms of the disease." All this will promote better treatment compliance, which is key to preventing relapse and achieving a better quality of life."