Background
Treatment resistant depression (TRD) and difficult to treat depression (DTD) refer to deficient responses to antidepressant therapy (i.e., pharmaceuticals, psychotherapy, electroconvulsive therapy (ECT) or other approaches) after several weeks of treatment. The response rates decrease with the duration of the disease and about 20% of the patients develop a chronic course. Various influencing factors in the multicausal pathogenesis of depression have already been identified, but the complete understanding of its pathophysiology still remains elusive. Probable causes include ineffective drug metabolism or undetected somatic or psychiatric comorbidities. In addition, the different subtypes of depression assumingly have distinct pathomechanisms, of those some cannot be treated by classical antidepressants. Our working group focuses on identifying clinical and molecular biological markers of DTD to improve and personalize its therapy regiments. Highly promising alternatives to pharmacological treatments are techniques that stimulate the brain electrically (e.g., ECT) or magnetically (e.g., transcranial magnetic stimulation (TMS)).
We specialize in ECT given it is still one of the most effective therapeutic methods for the treatment of severe psychiatric conditions, such as DTD or pharmacotherapy-resistant psychoses. ECT has been proposed to improve neuronal processes such as synaptogenesis (the creation of new nerve cells) by releasing neurotransmitters and nerve growth factors. Another theory lies in the possible interruption of pathological neurotransmitter patterns that are associated with psychiatric illnesses and that are possibly rearranged by ECT, similar as rebooting a PC. Nevertheless, its mechanism of action has not yet been fully clarified. In the past years we have assuringly performed ECT on a high number of patients suffering from major depressive disorder (MDD) or DTD. The clinical and physiological data is maintained in NEKTOR (=Lower Saxony ECT Outcome Registry) and is available for collaborations and further research questions.
Other non-invasive brain stimulation methods we are interested in are transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). The transcranial application of small currents can be used to specifically influence neuronal excitability (tDCS) or the oscillatory dynamics of nerve cell assemblies (tACS). These brain stimulation methods allow the non-invasive testing of hypotheses regarding the relevance of cortical brain regions and specific oscillatory patterns for cognitive processing. In addition, research is currently being conducted into the extent to which dysfunctional neural networks in psychiatric diseases such as schizophrenia can be positively influenced by transcranial current stimulation.
Overall objectives
The overall goal of our research group is to develop biomarkers for the subtyping of patients with severe affective disorders in order to enable personalized therapy. A main focus of the working group is the investigation of non-invasive brain stimulation methods such as electroconvulsive therapy.
- Deep phenotyping of DTD
- Identification of epigenetic markers to predict the course of therapy in depressed patients
- Epigenetic Imaging for prediction of response
- Analysis of predictive biomarkers in ECT
In our prospective and longitudinal registry study, we assess patients receiving electroconvulsive therapy (ECT) systematically at several time points. The aim of the study is to investigate the influence of clinical and molecular biological factors on the course of disease and therapy course of the patient. Neurological soft signs and a differentiated psychometry are assessed in the registry. Furthermore, a focus is placed on the identification of epigenetic response markers that aim to subtype patients who are most likely to benefit from ECT. The registry contributes to the Genetics of ECT International Consortium (GenECT-ic).
Resulting publications:
- Moschny N, Zindler T, Jahn K, Dorda M, Davenport CF, Wiehlmann L, Maier HB, Eberle F, Bleich S, Neyazi A, Frieling H. Novel candidate genes for ECT response prediction-a pilot study analyzing the DNA methylome of depressed patients receiving electroconvulsive therapy. Clin Epigenetics. 2020 Jul 29;12(1):114. DOI
- Neyazi A, Theilmann W, Brandt C, Rantamäki T, Matsui N, Rhein M, Kornhuber J, Bajbouj M, Sperling W, Bleich S, Frieling H, Löscher W. P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy. Transl Psychiatry. 2018 Jan 22;8(1):25. DOI
- Maier H, Helm S, Toto S, Moschny N, Sperling W, Hillemacher T, Kahl KG, Jakubovski E, Bleich S, Frieling H, Neyazi A. S100B, Homocysteine, Vitamin B12, Folic Acid, and Procalcitonin Serum Levels in Remitters to Electroconvulsive Therapy: A Pilot Study. Dis Markers. 2018 Jan 10;2018:2358451. DOI
A proportion of patients who suffer from severe depressive episodes develop a DTD during their lifetime. Patients with DTD often do not achieve full remission despite multiple attempts at therapy. The possible causes are varied: psychiatric or somatic comorbidities, genetic polymorphisms in cytochrome P450 enzymes (CYP) (and thus the failure to reach efficient, i.e., therapeutic drug levels) or the presence of pseudo-resistance (caused by inadequate drug intake or administration). The aim of our registry study is the deep phenotyping and subtyping of patients with DTD, as well as the identification of epigenetic predictive parameters.
Resulting project of the NEKTOR & DTD Registry:
A subgroup of depressive patients is characterized by dysregulated neuronal synapse formation and/or a malfunctioning of the immune system. ECT influences both processes but how this correlates to remission (i.e., the improvement of depressive symptoms) remains unexplained. Therefore, we are investigating ECT responders and non-responders with respect to the composition of their immune system and DNA methylation. Our initial results show particular subsets of natural killer cells to play a role in ECT’s acute effect and its clinical outcome. Further investigations are ongoing to delineate the role of the immune system in the mechanism of ECT and its relevance for ECT response.
Resulting publications:
- Moschny N, Jahn K, Maier HB, Khan AQ, Ballmaier M, Liepach K, Sack M, Skripuletz T, Bleich S, Frieling H, Neyazi A. Electroconvulsive therapy, changes in immune cell ratios, and their association with seizure quality and clinical outcome in depressed patients. Eur Neuropsychopharmacol. 2020 Jul;36:18-28. DOI
- Moschny N, Jahn K, Bajbouj M, Maier HB, Ballmaier M, Khan AQ, Pollak C, Bleich S, Frieling H, Neyazi A. DNA Methylation of the t-PA Gene Differs Between Various Immune Cell Subtypes Isolated From Depressed Patients Receiving Electroconvulsive Therapy. Front Psychiatry. 2020 Jun 19;11:571. DOI
Resulting project of the NEKTOR & DTD Registry:
Advances in neuroimaging (e.g., magnetic resonance imaging, MRI) have been instrumental in uncovering the possible neural mechanisms underlying severe depressive episodes. MRI studies (resting-state functional cerebral MRI; rs-fcMRI) have demonstrated changes in connectivity between different brain areas in patients during a severe depressive episode compared to healthy controls. Regarding structural MRI, higher hippocampal and amygdala volumes were often detected in severely depressed patients. MRI analyses and especially epigenetic imaging serve for further understanding of DTD. Currently, the research group is recruiting patients with DTD partially receiving electroconvulsive therapy. The aim of the prospective and longitudinal study is to identify possible predictors of therapy response.
In this clinical trial (Phase IIIB study), the efficacy, safety and tolerability of S-Ketamine nasal spray in comparison to Quetiapine retard in adult patients with refractory major depression (previous treatment with at least two antidepressant drugs from two different drug classes at sufficient doses and for a sufficient period of time) under continuous therapy with a selective serotonin reuptake inhibitor/serotonin noradrenaline reuptake inhibitor is being evaluated in collaboration with the manufacturer Janssen.
Scientific Collaborations
- Prof. Dr. Mike Wattjes, Department of Diagnostic and Interventional Neuroradiology
- Prof. Dr. Tillmann Krüger, Department of Psychiatry, Social Psychiatry and Psychotherapy, Division of Clinical Psychology and Sexual Medicine
- PD Dr. Franz-Josef Müller, Department of Psychiatry and Psychotherapy, Center for Integrative Psychiatry, Kiel
- Prof. Dr. Malek Bajbouj, Department of Psychiatry and Psychotherapy, Charité, Berlin
- Prof. Dr. Jürgen Deckert, Prof. Dr. Sarah Kittel-Schneider, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg
- The Global ECT-MRI Research Collaboration (GEMRIC)
- Genetics of ECT International Consortium (GenECT-ic)
Awards and Promotions
- Award of the German Society for Biological Psychiatry (DGBP; 2019). For the scientific contribution to the DGBP-AGNP Congress 2019 (Poster & Presentation), Nicole Moschny
- Prize of the Annika-Liese Foundation for Depression Research (2018/19). For the work "P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy", Alexandra Neyazi, endowed with: 10.000 €.
- Internal Funding Initiative (HiLF 1, 'Hochschulinterne Leistungsförderung 1'). For the project "Epigenetic regulation and expression of glia cell-derived neurotrophic factor (GDNF) in depressive patients under pharmacological and electroconvulsive treatment", Alexandra Neyazi, grant: 22.397 €
- Poster Prize of the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology (DGPPN; 2016). "Markers for response of electroconvulsive therapy? Homocysteine, vitamin B12, vitamin B11 and S100 plasma levels in the course of treatment", Hannah Maier
Research group members
Research group leaders
Prof. Dr. med. Helge Frieling
Deputy director
Publications: Pubmed
PD Dr. med. Alexandra Neyazi
Managing senior physician
Phone: +49 511 532 2397
Excellence at a glance:
- Specialist in psychiatry and psychotherapy
- Medical representative for medical devices and stimulation procedures
Publications: Pubmed
Dr. med. Hannah Maier
Assistent physician and PostDoc
Phone: +49 511 532 3167
Research focus:
- Difficult to treat depression (DTD) and pharmacotherapy-resistant Depression
- Non-invasive brain stimulation, e.g., electroconvulsive therapy (ECT), vagal nerve stimulation (VNS)
- Neuroimaging, especially epigenetic imaging
Publications: Pubmed
Sekretariat
Phone: +49 511 532 2397
Fax: +49 511 532 8573
folsche.thorsten@mh-hannover.de
Research focus:
- Bipolar disorder
- Pharmacotherapy-resistant Depression
- Epigenetic analyses for response prediction
Research focus:
- Characterization of immune cells using FACS
- Epigenetic analyses using Sanger/NGS/Nanopore sequencing
- Neuroimmunology
Publications: Pubmed
Research focus:
- Understanding the molecular basis of predictive biomarkers
- Modulation of methylation to understand its functional importance
Publications: Pubmed
schuelke.rasmus@mh-hannover.de
Research focus:
- Neuronal correlates of coverbal gestures in schizophrenia
- Non-invasive brain stimulation: transcranial Direct Current Stimulation (tDCS), transcranial Alternating Current Stimulation (tACS)
Publications: Pubmed