New avenues to developing personalized treatments for schizophrenia

According to an international survey, Published in Nature CommunicationsThis could potentially facilitate the development of new personalized treatments for people diagnosed with schizophrenia, who suffer from a range of symptoms including delusions, hallucinations, cognitive impairment, memory and language problems, and depression.

Current therapies, which primarily target a specific therapeutic target, the type 2A serotonin receptor, are unable to act selectively on the symptoms experienced by patients and can cause side effects as well as metabolic and motility problems that lead to treatment discontinuation.

In this context, the study identified the role of certain proteins, G proteins, that play a key role in regulating cellular responses in schizophrenia. Specifically, it was shown that two types of these proteins allow the regulation of the main symptoms of this disorder.

The study was led by the Medical Research Institute of Del Mar Hospital, in collaboration with researchers from the Neuropsychopharmacology Group of the University of the Basque Country (UPV/EHU) and the Mental Health Institute (CIBERSAM).

“Although these proteins are coupled to the same receptor, they do not act in the same way and trigger diverse responses in the cell. This provides invaluable information for future research that will allow the development of medicines to treat schizophrenia in an individualized way, tailored to each patient’s symptoms,” said Dr. Jana Celent, one of the study’s lead authors and coordinator of the G Protein-Coupled Receptor Based Drug Discovery Group at the Del Mar Hospital Medical Institute.

Highly complex research

To reach these conclusions, the researchers had to carry out complex studies. Their starting point was to select different molecules that are available, but are not approved drugs for humans, and analyze their ability to interact with the serotonin type 2A receptor through molecular and atomic simulations. This allowed them to select four compounds, which were first studied in cells and demonstrated that, upon binding to the receptor, they trigger responses in different types of G proteins.

These results were applied in the analysis of human brain tissue samples taken from the collection of the Neuropsychopharmacology Group at the University of the Basque Country (UPV/EHU). In these studies, “the compounds showed very different activities with regard to G proteins: some activated them, others inactivated them”, explains Dr. Patricia Robledo, lead author of the study and researcher in the Integrative Pharmacology and Systems Neuroscience Group.

In this regard, “the possibility of inhibiting the binding of the serotonin 2A receptor to specific G proteins has been proposed as an area of ​​interest for designing a new type of drug, known as inverse agonists, as a potential tool against psychiatric diseases”, points out Rebecca Diez Alarcia, first co-author of the paper and researcher at UPV/EHU.

Moreover, in mouse models designed to simulate the symptoms of schizophrenia, these compounds showed specific behavioral effects depending on which G protein they activated.Thus, using pharmacological and genetic techniques in mice, we found that one of these G proteins is involved in symptoms associated with psychosis, while another type of G protein is involved in cognitive impairment.

“This is the first time that a promising therapeutic target has been identified for the development of a drug that will be effective in targeting a specific profile of schizophrenia patients,” said Dr Robredo.

While the compounds used in this study are not yet approved as drugs for human use, Dr. Jana Celent said, “This multi-scale study reveals a blueprint for the chemical design of future drugs that address more specific pathways to treat schizophrenia while avoiding pathways associated with side effects, which is crucial for more personalized treatment.”

Dr. Daniel Berge, a psychiatrist at the hospital’s Mental Health Institute, who was not involved in the study, said: “This research will help us to develop more selective drugs to treat schizophrenia, which will be better tolerated and allow for a more precise treatment of the symptoms of the disease. All this will promote better adherence to treatment, which is key to preventing relapse and achieving a better quality of life.”

Provided by IMIM (Hospital del Mar Medical Research Institute)