Uruguayan study improves medication dosage for treatment-resistant schizophrenia

November 29, 2023

A Uruguayan study analyzed the interaction in the body of a drug used to treat a type of schizophrenia that affects around 10,000 people in the country, and the knowledge that was generated benefited patients by adjusting doses and reducing side effects associated with this medication.

Based on genetic and metabolic analyses, the team of researchers – made up of experts from Hospital Vilardebó, Facultad de Química and the Institut Pasteur de Montevideo – observed that, in patients who smoke, the drug is metabolized more quickly, so doses must be higher. Meanwhile, overweight patients are associated with slower metabolization rates and increased adverse effects compared to non-overweight ones.

The work -funded by the Agencia Nacional de Investigación e Innovación (ANII)- won the first prize at the XI Uruguayan Congress of Psychiatry held last week.

Treatment-resistant schizophrenia: getting to know clozapine

In Uruguay, more than 30,000 people suffer from schizophrenia, and 30% do not respond to conventional antipsychotics. This type of schizophrenia is called teatment-resistant schizophrenia.

For this group of patients there is clozapine, which controls the disease, but generates some adverse effects. Therefore, it requires continuous monitoring and strict dosage adjustment.

In order to understand the effect of this drug, the project motinored 108 adult men and women treated with clozapine at the Hospital Vilardebó for two years.

On the one hand, specialists from the Hospital Vilardebó and the Departamento de Ciencias Farmacéuticas de la Facultad de Química analyzed the concentration of clozapine and its metabolite – norclozapine – in the blood to determine parameters to understand its metabolization pattern. In addition, they registered their lifestyle habits.

On the other hand, genetic research led by the Laboratorio de Genética Molecular Humana del Institut Pasteur de Montevideo studied the genes responsible for the drug’s metabolization and observed the presence of mutations that affect their function.


The analyses found a high frequency of a smoking-induced mutation in the patients that causes clozapine to be metabolized faster. Thus, the study was able to understand why patients that smoke need higher doses of clozapine.

In addition, they detected that obesity is associated with slower metabolization rates and increased adverse effects compared to non-overweight patients receiving the same dose.

These findings led to personalized clozapine dosing, which not only improved treatment efficacy but also reduced adverse effects.

The interdisciplinary approach underlines the importance of collaborative studies to treat mental health problems in the country and opens doors to personalized treatments with better outcomes for patients.