BrainDrugs

Neuropharmacological treatment: Precision medicine in epilepsy and
depression

Project start: July 1st, 2019
Project end:
June 30th, 2024
Grant:
40 mio DKK from Lundbeck Foundation
PI:
Prof. Gitte Moos Knudsen, NRU

A 2-min video pitch of the project can be found here.
An interview about the project with Gitte on DR P1 Morgen is available here.

The aim
of this thematic alliance is to establish which key features predict drug response in patients with epilepsy or depression.

Background:
There is currently an enormous unmet need for the development of effective precision medicine approaches for brain disorders. More precise treatment strategies are needed to replace the present “one-size-fits-all” and subsequent “trial-and-error” approach currently  applied in our patients. An important step to achieve this goal is to uncover endophenotypes and biomarkers that can critically help to stratify patient cohorts (see figure below).

To enable stratification of patients based on their underlying pathogenetic and pathophysiological brain disturbances will provide “enriched” patient populations that are more likely to benefit from specific interventions. Stratification will also be enormously beneficial for interpretation of clinical trials that aim to test new compounds and is essential to allow for an optimised treatment of patients with brain disorders. Another important challenge is to determine the target engagement of pharmacological interventions, and to predict occupancy based on, e.g., plasma drug concentrations.

With BrainDrugs, we will focus on two frequent and devastating brain disorders: epilepsy and major depression (MDD). We have chosen to study epilepsy and MDD because they are frequent and devastating brain disorders with significant comorbidity and because both conditions are treated with pharmacological interventions that often fail to succeed, including failure due to intolerable adverse effects. Epilepsy often co-occurs with mood disorders and there is reason to believe that the comorbidity is underrecognized in both patient groups. Comorbidity is also associated with less favorable outcome of drug treatment. That is, there is a huge unmet medical need to better diagnose and treat these two serious brain disorders.

Initially, we aim at understanding the mechanisms which explain the variation in drug response using a diverse set of methodologies, including standard epidemiological biostatistical approaches with national registry data and machine learning based on big data from routine care, e.g., clinical (symptom) characterization, neuroimaging, or genetics. The discovery phase will likely identify features of drug resistance, which will be used to characterize groups of patients and identify clusters of factors associated with comparable types of drug responses. From this, we will formulate a series of drug response indices that when validated, can be used to personalise drug interventions and to establish a recommendation for treatment of the individual patient.

Methods and Materials:
We will make use of Danish registries to identify associations between intake of brain targeting drugs and clinical outcomes in order to uncover which patient features define a successful antidepressive or antiepileptic drug treatment. To investigate if we can identify patient subgroups, we will conduct advanced text-mining analyses which extract specific clinical features from electronic patient records. Through existing deep phenotyping or genetic databases with biobanks, those features will be related to, e.g., genetic and neuroimaging data to define biologically valid patient subgroups suffering from depression and epilepsy. To increase power to detect biomarkers and treatment response, we will establish new cohorts of patients with epilepsy and depression that we follow longitudinally.

BrainDrugs will consist of seven coherent work packages, as depicted in the figure below.


Expected outcome and perspectives:
It is our ambition to set the stage for a precision medicine approach in pharmacological treatment of epilepsy and depression, for the benefit of future patients. To succeed in our mission, we have devised a strategy for implementation of research outcomes in the clinic. It is our hope that in the long run, BrainDrugs can serve as a model to be implemented internationally, and for other brain disorders.

Project management:
The organization of BrainDrugs is depicted in the organogram below.


The Executive Board (EB) consists of six senior scientists that will oversee and review the progress of the work and make all relevant strategic decisions. The EB will gather physically at least once yearly, at the annual meeting, and will have audiovisual conferences in-between. The board is composed to broadly ensure coverage of most of the disciplines exerted in BrainDrugs:

- Gitte Moos Knudsen, MD, DMSc. PI of BrainDrugs. Chairperson at NRU, Rigshospitalet. Neurologist with research focus on translational neurobiology and neuropharmacology. Director of The Innovation Fund Denmark funded Center for Experimental Medicine Neuropharmacology (www.neuropharm.eu) and president-elect for the European College of Neuropharmacology (ECNP). Professor Knudsen will be overall responsible for BrainDrugs, including the financial and reporting responsibility, and she will be assisted by administrative staff to cover daily administration as well as financial and legal aspects of BrainDrugs.

- Søren Brunak, PhD. Professor of Disease Systems Biology at the University of Copenhagen and professor of Bioinformatics at the Technical University of Denmark. He has expertise within bioinformatics, systems biology and medical informatics.

- Vibe G. Frøkjær, MD, PhD. Psychiatrist, Psychiatric Center Copenhagen and Neurobiology Research Unit, Rigshsopitalet. Her scientific interest is the influence hormonal changes on mental health, major depression and in translational research and clinical research into affective disorders.

- Lars H. Pinborg, MD, DMSc. Lundbeck Foundation associate professor in precision medicine, University of Copenhagen. He is in charge of the Epilepsy Clinic at RH and his scientific focus area includes clinical epileptology, molecular and structural neuroimaging, drug resistance in epilepsy, and epilepsy surgery.

- Thomas Werge, PhD. Professor at Department of Clinical Medicine, University of Copenhagen and Director of Institute of Biological Psychiatry, Mental Health Services, Capital Region of Denmark. He has expertise within precision psychiatry, neurogenetics, translational psychiatry, and translational genomics.

- Leif Østergaard, MD, DMSc. Professor at Department of Neuroradiology at Aarhus University and Director of Center of Functionally Integrated Neuroscience (CFIN) and MINDLab, Aarhus University. His main research area is neuroimaging in humans and it involves modeling and development of methods.

Project members:
The BrainDrugs alliance builds on strong cross-disciplinary research environments within universities and hospitals in Denmark and is supported by two European partners from Lausanne University Hospital (CHUV), Switzerland and VU University Medical Center (VUMC) in Amsterdam, Netherlands. The involved Danish institutions span several different departments at Copenhagen University Hospital, Rigshospitalet (RH), University of Copenhagen (UCPH), Aarhus University Hospital (AUH), and Aarhus University (AU), as well as the Filadelfia Epilepsy Hospital (Filadelfia) and three different mental health centers from the Capital Region of Denmark, namely Psychiatric Center Copenhagen, Psychiatric Center Glostrup, and Mental Health Center Sct. Hans.  The research team is composed of the following list of highly experienced clinical and academic partners:

Prof. Gitte Moos Knudsen - Neurobiology Research Unit, RH & SUND-UCPH

Bioinformatics and Statistics:
Prof. Søren Brunak - NNF Center for Protein Research, SUND-UCPH
Associate Prof. Esben Budtz-Jørgensen - Section of Biostatistics, SUND-UCPH

Clinical Psychiatry:

Head of Department Ida Hageman - Psychiatric Center Copenhagen, RH & SUND-UCPH
Prof. Martin Balslev Jørgensen - Psychiatric Center Copenhagen, RH & SUND-UCPH
Prof. Lars Kessing - Psychiatric Center Copenhagen, RH & SUND-UCPH
Prof. Kamilla Miskowiak - Psychiatric Center Copenhagen, RH & Dept of Psychology, UCPH
Prof. Poul Videbech - Mental Health Centre Glostrup & SUND-UCPH

Clinical Neurology:

Associate Prof. Jakob Christensen - Dept Neurology, AUH & Dept Clinical Medicine, AU
Head of Department Jesper Erdal - Dept Neurology, RH
Prof. Olaf Paulson - Neurobiology Research Unit, RH & SUND-UCPH
Associate Prof. Lars Pinborg - Neurobiology Research Unit & Dept of Neurology, RH & SUND-UCPH
Prof. Guido Rubboli - Filadelfia Epilepsy Hospital & SUND-UCPH
Prof. Philippe Ryvlin - CHUV, Lausanne, Switzerland & SUND-UCPH
Prof. Anne Sabers - Dept of Neurology, RH & SUND-UCPH

Epidemiology:

Prof. Brenda Penninx - Dept Psychiatry, VU University Medical Center in Amsterdam, Netherlands

Text mining:

Prof. Anders Søgaard - Dept Computer Science, UCPH

Neuroimaging Analysis:

Assistant Prof. Melanie Ganz - Neurobiology Research Unit, RH & Dept Computer Science, UCPH
Senior researcher Vibe Frøkjær, Neurobiology Research Unit & Psychiatric Center Copenhagen, RH
Prof. Leif Østergaard, Dept Neuroradiology, AUH & Dept Neuroradiology, AU

Genomics:

Prof. Thomas Werge, Dept Clinical Biochemistry, Mental Health Centre Sct. Hans & SUND-UCPH.