Periodic Reporting for period 2 - TREATMENT (Training European Network: Metabolic Dysfunctions associated with Pharmacological Treatment of Schizophrenia)
Reporting period: 2019-01-01 to 2021-06-30
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 poly-pharmacy, 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 aimed 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.
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 poly-pharmacy, 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 aimed 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.
The management of the action (WP1) has been implemented as informed in the GA of the action. All the deliverables and milestones have been submitted and informed on time.
Regarding WP2, fifteen ESRs were recruited following the OTM-R principles. All were then enrolled in PhD programmes of excellence. They have been exposed to a multidisciplinary training programme during 36 months, that included secondments and work visits. Five training Schools and Two Conferences have been organized by the Action. All the ESRs have also participated in dissemination and outreach activities.
Cell based studies, pre-clinical models and clinical trials were conducted to reach the proposed scientific aims in full compliancy with Ethics Regulations. The main findings are:
In the liver (WP3), the SGAs Olanzapine and Aripiprazole were found to inhibit mitochondrial oxidative activity, alter metabolic fluxes, induce insulin resistance, endoplasmic reticulum stress, inflammation and fibrosis.
The characterization of SGAs extra-hepatic tissues metabolic related alterations (WP4)
Identified novel targeted pathological processes. The main affected tissues were, white and brown adipose tissues, heart, pancreas, vasculature, immune system and the CNS.
The correlation of cell-based, pre-clinical and human studies (WP5), allowed the identification of short-term biomarkers of metabolic alterations that predict long-term effects at least in the pre-clinical setting, the human clinical trial is still ongoing at the closure of the action.
The action adhered to the Open Data Pilot, prepared its own Data Management Plan, and it is actively loading the derived data as Open Data in repositories.
TREATMENT has been active in scientific forums, including participation in join-activities, together with other EU-funded ITNs. It has also organized and participated in activities targeting the general public, patient’s associations, secondary and high school students, policy makers, stake holders, etc.
The action has its own web page, a promotional video, prepared several MOOCs and informative videos, and has been present in all main social media.
Regarding WP2, fifteen ESRs were recruited following the OTM-R principles. All were then enrolled in PhD programmes of excellence. They have been exposed to a multidisciplinary training programme during 36 months, that included secondments and work visits. Five training Schools and Two Conferences have been organized by the Action. All the ESRs have also participated in dissemination and outreach activities.
Cell based studies, pre-clinical models and clinical trials were conducted to reach the proposed scientific aims in full compliancy with Ethics Regulations. The main findings are:
In the liver (WP3), the SGAs Olanzapine and Aripiprazole were found to inhibit mitochondrial oxidative activity, alter metabolic fluxes, induce insulin resistance, endoplasmic reticulum stress, inflammation and fibrosis.
The characterization of SGAs extra-hepatic tissues metabolic related alterations (WP4)
Identified novel targeted pathological processes. The main affected tissues were, white and brown adipose tissues, heart, pancreas, vasculature, immune system and the CNS.
The correlation of cell-based, pre-clinical and human studies (WP5), allowed the identification of short-term biomarkers of metabolic alterations that predict long-term effects at least in the pre-clinical setting, the human clinical trial is still ongoing at the closure of the action.
The action adhered to the Open Data Pilot, prepared its own Data Management Plan, and it is actively loading the derived data as Open Data in repositories.
TREATMENT has been active in scientific forums, including participation in join-activities, together with other EU-funded ITNs. It has also organized and participated in activities targeting the general public, patient’s associations, secondary and high school students, policy makers, stake holders, etc.
The action has its own web page, a promotional video, prepared several MOOCs and informative videos, and has been present in all main social media.
TREATMENT has already impacted ESRs scientific development through their participation in an innovative and competitive program, boosting their future scientific careers, and enabling them to answer future social and economic challenges as a whole. The provided complementary training, implemented through an open communication structure, the participation in dissemination activities, and the support of extensive network of mentors, will serve as an advantage point for their future career prospects in academy and industry alike.
TREATMENT has set up the scientific basis that links acute stress responses following administration of a pharmacological drug to its long-term metabolic side effects, which are the most common adverse effect derived from long term medication. Therefore, its results can be easily applied to the study of other pharmacological treatments, already in the market or before approval for commercialization. Implementation of these procedures would dramatically shorten the drug testing periods (both pre-clinical and clinical), and would reduce the costs derived henceforth impacting both the pharmacological industry and the health care system.
Implementation of the results derived from TREATMENT can directly be used in Personalized medicine approaches, since it identifies, following administration of the first pill, if the chemistry is well tolerated or not by the patient, as it regards metabolic side effects. Since the development of pharmacological drugs, includes chemical variants that target the same pathways, it would be simple to use this information to match the chemistry of the medication to the patient. This would also reduce the economic and social cost derived from the advent of metabolic diseases.
Social challenges include the increased exposure to chemical stressors in the environment, therefore it is necessary to ensure the safety of chemicals used widely, specially, those in the food chain. TREATMENT results open a new perspective also in this regard, since it could likely be facilitating the identification of metabolically harmful chemicals, and as well the metabolic benefits of dietary interventions and nutraceuticals.
TREATMENT has set up the scientific basis that links acute stress responses following administration of a pharmacological drug to its long-term metabolic side effects, which are the most common adverse effect derived from long term medication. Therefore, its results can be easily applied to the study of other pharmacological treatments, already in the market or before approval for commercialization. Implementation of these procedures would dramatically shorten the drug testing periods (both pre-clinical and clinical), and would reduce the costs derived henceforth impacting both the pharmacological industry and the health care system.
Implementation of the results derived from TREATMENT can directly be used in Personalized medicine approaches, since it identifies, following administration of the first pill, if the chemistry is well tolerated or not by the patient, as it regards metabolic side effects. Since the development of pharmacological drugs, includes chemical variants that target the same pathways, it would be simple to use this information to match the chemistry of the medication to the patient. This would also reduce the economic and social cost derived from the advent of metabolic diseases.
Social challenges include the increased exposure to chemical stressors in the environment, therefore it is necessary to ensure the safety of chemicals used widely, specially, those in the food chain. TREATMENT results open a new perspective also in this regard, since it could likely be facilitating the identification of metabolically harmful chemicals, and as well the metabolic benefits of dietary interventions and nutraceuticals.