#	Pagina
attuale pagina	/open-h2020/projects/205486/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TREATMENT (Training European Network: Metabolic Dysfunctions associated with Pharmacological Treatment of Schizophrenia)

Teaser

Summary

Drugs are prescribed based on their beneficial effects. However, differences in response among patients are common. A major factor conferring variability is drug induced liver injury, particularly in chronic treatments and in patients treated with multiple drugs. Liver injury impacts glucose and lipid homeostasis, frequently leading to diabetes and cardiovascular (CV) complications.

Schizophrenia is a chronic and disabling disorder affecting about 1% of the population. It captures most of the resources available to psychiatric services. It is the fourth leading cause of disease burden accounting for 4.4% of total disability adjusted life years (DALYs) lost, in 2000. It has been estimated that by 2020 it will be the second leading cause of DALYs lost. Treatments relieve symptoms, but are taken for life. Metabolic dysfunctions are highly prevalent in schizophrenic patients. In fact, diabetes and schizophrenia have for long been linked. Metabolic syndrome Incidence in this population is twice that of the general population, suggesting it might be secondary to the effects of medication.

Over 60 antipsychotic drugs are available and are divided into 2 groups: first generation and second-generation agents (SGAs). SGAs are now the main therapeutic option for schizophrenia, bipolar disorders and other psychotic conditions. However, questions remain regarding their exact mechanism of action.

Metabolic derangements from antipsychotic agents have been the focus of interest for years. Children and adolescents receiving SGAs are particularly vulnerable. Antipsychotic polypharmacy, a common practice, can also be associated with increased risk of pre-metabolic syndrome.

Of all SGAs, olanzapine increases weight gain and cholesterol levels most, while aripiprazol shows the least reported weight gain. While drug-induced weight gain has been associated with T2D, T2D also occurs in absence of weight gain, indicating that metabolic disturbances are not only related to the changes in diet and activity that occur in response to the treatment. Metabolic effects derived from SGAs or other long-term treatments could result from a limited capacity of the liver to catabolize the drug and neutralize toxic intermediates. The cross-stalk between metabolic pathways and neurotransmitters also deserves further investigation.

TREATMENT aims to train ESRs in an area of research that currently lacks highly trained professionals at the interphase of basic, translational and applied pharmacology. Its mission is to develop protocols to match the treatment to the patient. It focuses on SGAs, since they are associated with severe metabolic side effects.

Work performed

The first year was mainly devoted to recruitment and enrollment in PhD programmes of ESRs, and developement of management tools: web page, DMP, tagging system, and organization of the kick-off meeting. The scientific focus was on the standarization of protocols and technical issues for pre-clinical and cell-based studies, while for clinical studies the focus was on protocolâ€™s approval for both the healthy volunteerâ€™s intervention study and the Clinical Trial with newly diagnosed schizophrenic patients.

During the second year recruited ESRs worked on their laboratories, attended training courses & scientific meetings and the Secondmentâ€™s programme started. School 1 & 2 and two general consortium meetings were organized in line with the GA.

The main scientific results are the following:

WP3
SGAs induced oxidative and ER stress in the liver. Aripiprazole induced a more potent response than Olanzapine. The effect of SGAs on the activity of xenobiotic receptors and redox sensitive transcription factors was tested by qRT-PCR analysis of target genes both in vitro and in vivo. Aripiprazole induced a more potent response than Olanzapine.
The effect of SGAs was modified in PGC-1Î± KO and SirT1 KO mice vs WT mice.
IP administration for five weeks of 10 mg/Kg of Olanzapine disrupted glucose homeostasis..
Aripiprazole and Olanzipine induce a rapid inhibition of oxidative phosphorylation, followed by a compensatory induction of mitochondrial antioxidant systems, particularly strong following Aripiprazole administration.

WP4
The characterization of the metabolic adaptations and its pathological effects in different tissues is work in progress.
Testing of antipsychotics on human adipocytes did not result in significant changes in insulin stimulated glucose uptake, while evaluation of lipolysis is ongoing.

WP5
Treatment of healthy volunteers with Aripiprazole or Olanzapine results in a fast inhibition of mitochondrial oxygen consumption that is detectable in PBMCs 5 h after the administration of the drug.

Final results

We aim to define the metabolic nodes associated with different susceptibilities to antipsychotic treatment. We modify metabolic processes to determine which ones best explain differential susceptibility. Once identified, we evaluate the early responses in these pathways to test whether they are associated with long-term metabolic complications. We select biomarkers in blood samples that provide optimal correlation between short- and long-term metabolic responses. To ensure that these data can be translated to the human we will measure, these biomarkers, in both healthy volunteers and newly diagnosed shchizophrenic patients. Novel validated biomarkers will be patented to initiate the process of product development and commercialization.

TREATMENT approach is expected to be applicable to the study of other drugs and other personalized medicine studies. As a result, the capabilities of the trained ESRs will allow them to evaluate the adequacy of pharmacological treatments in general to develop prognosis novel tools. Therefore, TREATMENT impacts ESRâ€™s careers by implementing a multidisciplinary program in research and innovation within the framework of a diverse international consortium that provides a unique blend of expertises and a state of the art training environment.

TREATMENTs program also boosts Management and Leadership, Business Innovation, Problem Solving, Science Communication to Specialists and Non-specialists & IT skill. It includes secondments, networking activities, and a relevant involvement of the private sector that provides training in transferable skills. Mobility also exposes ESRs to trans-national & multicultural environments. ESRs will be independent research leaders in the biomedicine field, representing a new breed of scientists trained in contemporary biology.

Complementary training is also provided through an open communication structure the active participation of ESRs in dissemination activities. ESRsâ€™ CD is also supported by an extensive network of mentors. As a result, ESRs will have advantage career prospects in both academy and industry as needed to empower competitiveness & sustainability in Europe.

In summary, TREATMENT will help retain in Europe young scientists who might otherwise be tempted to leave Europe, damaging the innovation and competitiveness of the European Research Area (ERA) and empowering the EU society to answer both social and economic challenges.