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Projekte: Exzellenzzentrum für Psychiatrie- und Psychotherapieforschung

Meyer-Lindenberg A, Leweke FM. EU - Europäische Union 241909: EU-GEI: European Network of National Schizophrenia Networks Studying Gene-Environment Interactions. 05/2010-04/2015.

The aim of EU-GEI is to identify, over a 5-year period, the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia. In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-the-art assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in (i) the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and (ii) the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in helpseeking individuals with an at-risk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of aim of EU-GEI is to identify, over a 5-year period, the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia. In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-theart assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in (i) the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and (ii) the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in help-seeking individuals with an atrisk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of skills required to deliver a program of research that meets all the call’s requirements and who have access to / will collect a number of unique European samples. The The aim of EU-GEI is to identify, over a 5-year period, the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia. In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-the-art assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in (i) the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and (ii) the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in help-seeking individuals with an at-risk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of skills required to deliver a program of research that meets all the call’s requirements and who have access to / will collect a number of unique European samples. The partners in EU-GEI represent the nationally funded schizophrenia / mental health networks of the UK, Netherlands, France, Spain, Turkey and Germany as well as other partners.

Leweke FM. EU - Europäische Union 223427: SchizDX: Developing minimally invasive tools and technologies for high throughput, low cost molecular assays for the early diagnosis of schizophrenia and other psychiatric disorders. 10/2008-03/2012.

Problem: Schizophrenia is a complex psychiatric disorder affecting approximately 1% of the population with equal risk across genders. The current diagnosis of schizophrenia (and other psychiatric disorders, such as bipolar depression) is rightly subjective, not only because of the complex spectrum of symptoms and their overlap with other mental disorders, but also due to the lack of empirical markers or objective tests specific for the disease. In addition, contemporary drug treatments do not effectively treat all aspects of the disease and can often have severe side effects that make it difficult for many patients to continue with medication. Despite intensive efforts by the pharmaceutical industry, therapeutic regimes available to treat these disorders are largely aimed at relieving symptoms and work best at slowing or halting the underlying disease progression in early stage or less severe cases, making early and accurate diagnosis essential. However, psychiatrists currently come to their diagnosis based on observation of both the presence and duration (up to 6 months) of certain signs and symptoms. Many times patients visit their doctor during the prodrome phase due to anxiety, social isolation, difficulty making choices, and problems with concentration and attention, symptoms presenting many psychiatric and medical conditions, making absolute diagnosis difficult and protracted. This often results in long periods (up to 1-3 years) of untreated psychosis during which the disease severity increases before appropriate therapeutics are prescribed to first episode schizophrenics. It is worth noting that, where early treatment has been possible, it is associated with greatly improved patient outcomes. Solution: The SchizDX application proposes to identify and validate up to 50 biomarkers relevant to the first onset of schizophrenia. In this project label free nano-LC-MS based proteomic profiling, in combination with glycoprotein profiling and existing analyte assay screening, will be utilised to establish a schizophrenia-specific disease biomarker pattern/signature detectable in blood. The identification of specific biomarkers for mental disorders would revolutionise the clinical management of affected individuals. Biomarkers have the potential to help in the identification of disease sub types, aid in predicting and monitoring treatment responses and compliance, and facilitate novel approaches to drug discovery. This approach would also allow us to develop an understanding of the basic mechanisms that underlie the disease processes of schizophrenia and bipolar disorder. If such biomarkers can be found in readily accessible body fluids, they open up the possibility of developing new early or pre-symptomatic clinical tools to aid diagnosis, speed up treatments and improve patient outcomes or even prevent disease. Furthermore, biomarker assays that can detect early changes specifically correlated to reversal or progression of clinical symptoms of schizophrenia would have tremendous potential benefit for intervention studies. Used as predictors, these biomarkers can help to identify high risk individuals and disease sub groups who could serve as target populations for chemo-intervention trials, whilst as surrogate end points, biomarkers have the potential for assessing the efficacy and cost effectiveness of novel preventative interventions with an efficiency not possible currently, when the severity of manifest mental disorder is used as the end point.

Leweke FM. BMBF - Bundesministerium für Bildung und Forschung 01KG0910: SWITCH: Antipsychotische Behnadlung bei Schizophrenie . 10/2009-02/2012.

Gegenstand der Studie ist es, zu untersuchen, ob schizophrene Patienten, die auf eine zweiwöchige Therapie mit einem Antipsychotikum nicht ausreichend angesprochen haben, von einer frühzeitigen Umstellung der medikamentösen Behandlung profitieren.

Leweke FM. EU - Europäische Union 242114: OPTiMiSE: Optimization of Treatment and Management of Schizophrenia in Europe. 02/2010-02/2010.

The aim of the Optimise trial is to improve treatment for patients with schizophrenia. This goal will be reached in two ways: 1. by optimising currently existing treatment 2. by identifying new treatment strategies. Path 1: To optimise existing treatment The first drug with specific anti-psychotic action was produced in 1950. Since then, numerous new anti-psychotic drugs have been introduced. Most of these drugs are largely equal in efficacy and differ mainly in profile of side effects. Up till now, it has remained unclear which anti-psychotic drug should be the first choice for schizophrenia patients with a first psychotic episode. Furthermore, if the first drug fails to induce remission of psychosis after several weeks of treatment, it is unclear if another anti-psychotic drug should be tried or if treatment should be continued with the first drug. For patients who fail to reach remission after two anti-psychotic agents, general consensus is that clozapine, the most potent anti-psychotic drug, should be started. However, despite this general agreement, clozapine treatment is frequently delayed for years or not commenced at all. This large scale European study aims to improve current treatment of schizophrenia by finding treatment guidelines for drug therapy of first episode psychosis. To achieve this, a consortium of 18 European Psychiatric Institutes has been formed from which 350 medication naïve patients with first episode psychosis and a diagnosis of schizophrenia or schizophreniform disorder will be enrolled. All patients that participate in the study will start a four-week period of treatment with amisulpride. This drug showed high efficacy in the Eufest study, another European study that included 500 first episode schizophrenia patients. In addition to high efficacy, amisulpride had a favourable side effect profile, with few motor problems and no general weight gain. After four weeks on amisulpride, those patients who have not obtained remission of psychosis will be randomized over two treatment conditions: continue on amisulpride or switch to olanzapine. Olanzapine is another anti-psychotic drug, that has a mechanism of action slightly different from amisulpride that showed favourable efficacy in the Eufest study. However, Olanzapine induced weight gain and drowsiness in many patients. This part of the study will be blind, which means that both patients and their doctors will not know who is taking olanzapine and who continues to use amisulpride. A small part of the initial 350 patients, approximately 25-30% will still have many psychotic symptoms even after this blind treatment phase. These patients will be treated with clozapine in an open label fashion. Although psychotic symptoms are frequently a first sign of schizophrenia, they can also be the result of neurological abnormalities, such as a brain tumour. It is essential to identify these patients, as they may need urgent neurosurgical interventions. It is currently unknown which percentage of patients with a first psychosis has such a brain abnormality. Because the exact percentage is unclear, it also remains uncertain if general screening of all psychotic patients for neurological abnormalities is useful. In the Optimise trial, 200 patients with a first episode psychosis will have an MRI scan of the brain. If a relatively large percentage of these patients will show neurological abnormalities that necessitate an intervention, it will be recommended in future to screen all psychotic patients with an MRI scan of the brain. Most patients will obtain remission of psychosis with a first, second, or third anti-psychotic agent. Once in remission, many patients wish to discontinue their anti-psychotic treatment because of side effects, because they experience loss of autonomy or fear stigmatization by taking psychiatric drugs. However, anti-psychotic drug therapy is not only necessary to obtain remission, it is also of pivotal importance to stay on these drugs in order to remain in remission. The main reason why patients relapse into psychosis is because they discontinue drug therapy. In the Optimise trial, psycho-social interventions such as family psycho-education, motivational interviewing and mobile phone text message reminders for drug intake will be used in an attempt to increase treatment adherence. If treatment adherence could indeed be increased, this would reduce the number of relapses and improve long-term outcome for patients with schizophrenia. Path 2: Finding new treatment strategies Current pharmacological treatment for schizophrenia is largely based on blockade of the dopamine D2 receptors in the midbrain. For most patients, this is an effective strategy to combat psychotic symptoms, although not without side effects. However, a significant minority of patients do not respond to current anti-psychotic treatment. In addition, the negative symptoms of schizophrenia show almost no improvement with this type of medication. It is therefore necessary to expand current therapeutic options. One candidate drug that may have anti-psychotic potentials and could also ameliorate negative symptoms is cannabidiol, a non-psychoactive constituent of the cannabis plant. Cannabidiol does not block the dopamine D2 receptor, but rather affects the internal cannabinoid system. The first studies in schizophrenia with this new compound are promising, but they need to be replicated in a large group. As part of the Optimise trial, 150 patients with a first psychosis will be treated with either cannabidiol, the anti-psychotic drug olanzapine or placebo. The type of treatment will not be known to patients or their doctors. If cannabidiol is indeed an effective agent for schizophrenia, the group treated with cannabidiol will do better than the group on placebo and similar to, or perhaps even better than the group on olanzapine. Apart from cannabidiol, other strategies to improve drug therapy will be studied. This will be done by means of blood analysis. All 350 patients that participate in the medication trial will be asked to provide a small quantity of blood at several stages of the treatment. The expression of several compounds, such as proteins, fatty acids and inflammation parameters as well as the genetic code of the DNA will be measured in the blood, that could provide new directions for treatment. We aim to use these genetic and neurochemical markers to predict response to treatment. In addition, a special type of MRI scan will be performed in a subgroup of patients. This MRI scan is called Magnetic Resonance Spectroscopy (MRS) and is sensible for a specific chemical compound in the brain. In the Optimise trial we will apply MRS to investigate glutamate in the brain of patients with psychosis. The Optimise trial will last six years. At the end of this study, we will be able to provide treatment guidelines for drug therapy of patients with a first episode psychosis. We will also be able to recommend if MRI screening for neurological abnormalities is necessary. Further, we will know the efficacy of psycho-social interventions to improve drug adherence. And finally, we hope to have new treatment strategies for those patients who respond poorly to current anti-psychotic treatment.


Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de