New targets for treatment of schizophrenia

In an article published by npj Schizophrenia, researchers at the University of Campinas in Brazil identify proteins that appear to explain why some patients respond better to antipsychotics.

By Karina Toledo  |  Agência FAPESP – When researchers at the University of Campinas (UNICAMP) in São Paulo State, Brazil, evaluated blood samples from schizophrenic patients before and after treatment with antipsychotic drugs, they identified a group of proteins that were differently modulated in patients who responded well to the treatment compared with those who did not respond.

According to the researchers, the differentially expressed proteins are potential targets for exploration in the search for new drugs to treat schizophrenia. The complete list of proteins is included in an article in npj Schizophrenia, an online journal published based on a partnership between Nature Publishing Group and the Schizophrenia International Research Society.

“After validating these findings in a larger number of patients, we can think about creating a test to predict, even before the start of treatment, whether a patient will respond to a given drug,” said Daniel Martins-de-Souza, principal investigator for the project, which was supported by FAPESP.

Both the diagnosis of schizophrenia and its treatment, which consists mainly of administering antipsychotics, are currently based only on the patient’s clinical data and the psychiatrist’s experience. Approximately 40% of schizophrenics do not respond to initial treatment with drugs, and 60% eventually give up taking drugs because of their side effects.

“You have to wait six weeks to find out whether the drug is having an effect,” Martins-de-Souza said. “If there’s no improvement, physicians must decide based solely on their experience whether to increase the dose or try a different drug. There are no biomarkers to help in this decision-making process. This is what we’re working on.”

The study began when Martins-de-Souza was a principal investigator in the Psychiatry & Psychotherapy Department of Ludwig Maximilian University Munich (LMU) in Germany, but the analysis was done after his return to Brazil, where he is a professor at UNICAMP.

Blood samples were taken from 58 German patients who were undergoing treatment with three different antipsychotics: olanzapine (18 volunteers), quetiapine (14) and risperidone (26). The third was included in the list of prescription drugs authorized by Brazil’s Unified Health System (SUS) in 2014.

“These three drugs are atypical or second-generation antipsychotics, which appear to impact a broader spectrum of symptoms than typical or first-generation drugs,” Martins-de-Souza said.

First-generation drugs mainly block dopamine receptors and attenuate so-called productive symptoms (delirium and hallucinations), whereas second-generation drugs also affect glutamatergic neurotransmission and reduce negative symptoms (apathy, lack of drive, slowness, social withdrawal and cognitive problems).

About half the patients studied were “drug-naive”, i.e., they had never taken antipsychotics before, whereas the rest were classified as “drug-free” because they had not taken any antipsychotic medication for at least six weeks.

Methodology

Blood samples were taken at the psychiatric clinic of the University of Magdeburg in Germany before treatment began (T0) and again six weeks later (T6), when it was possible to verify which patients were responding (36 patients) and which were not responding (22 patients).

The researchers then performed a proteomic analysis of the blood samples, measuring the amounts of all proteins produced by the organism. The patients were divided into four different groups: T0 responders, T0 non-responders, T6 responders, and T6 non-responders.

Differentially expressed proteins across these four groups were classified by biochemical pathway, i.e., according to the biological processes in which they are involved: cell communication and signaling; protein metabolism; regulation of nucleic acid metabolism; transport; cell growth and maintenance; the immune response; energy metabolism; and “unknown,” the largest set of all.

“We found that although drugs modified protein expression via the same biochemical pathways in responders and non-responders, the way modulation occurred was different,” Martins-de-Souza said. “Modulation [increasing or decreasing protein expression] was diametrically opposed in two pathways – protein metabolism and nucleic acid regulation – but further research is needed to answer the question of whether this is what leads to the deficient response to medication.”

According to Martins-de-Souza, this is the first study ever to have investigated the circulating proteins involved in the response to antipsychotic drugs, and it has pointed to a number of hitherto unknown biomarkers of potential interest to researchers in the area.

“The drugs available today treat very generic aspects of the disease, such as neurotransmitter regulation,” he said. “Our research shows that other biochemical pathways are involved and specifies proteins that are sensitive to treatment. These are extremely interesting targets.”

As early as T0, he added, it was possible to observe differences between responders and non-responders that suggest the possibility of developing a predictive test.

“We haven’t published this finding yet because we want to validate it in new sets of samples, including one from Brazilian patients, whose genetic diversity is far greater than that of Germans,” Martins-de-Souza said.

This research is being conducted as part of Sheila Garcia’s PhD, in partnership with researchers Wagner F. Gattaz and Martinus T. van de Bilt at the University of São Paulo’s Psychiatry Institute (IP-USP).

The article “Biological pathways modulated by antipsychotics in the blood plasma of schizophrenia patients and their association to a clinical response” (doi: 10.1038/npjschz.2015.50) can be read at www.nature.com/articles/npjschz201550.