Research Violette Coppens

Abstract

Psychiatric treatment of patients with bipolar disorder is characterized by very low remission and recovery rates due to a high non-responsiveness to all psychopharmacological medication (30-35%). With this project, we aim to optimize treatment strategies for bipolar disorder with or without psychotic symptoms by finding alternative entry points for the development of new mood stabilizing drugs. In order to establish databases of relevant biomarkers as well as putative targets for future development of psychopharmacological drugs, we will conduct a prospective clinical trial in which patients with bipolar disorder with or without psychotic symptoms, will receive electroconvulsive therapy (ECT), the treatment of last resort when other pharmacotherapeutic strategies have failed. In parallel, post-mortem patient brain tissues will be retrospectively investigated. Samples of both research arms will be analyzed by proteomic and metabolomic methodologies using state of the art liquid chromatography-mass spectrometry (LCMS). Final comparative analyses of differentially expressed proteins, protein networks and metabolic pathways will result in the establishment of drug target candidate (DTC) databases for both types of bipolar disorder. These databases will likely, in follow-up trajectories, lead to the development of novel drugs.

Researcher(s)

• Promoter: Morrens Manuel
• Co-promoter: Coppens Violette
• Fellow: Janssens Jonas
• Fellow: Skorobogatov Katrien

Research team(s)

• Collaborative Antwerp Psychiatric Research Institute (CAPRI)

Project type(s)

• Research Project

Abstract

Major depressive disorder (MDD) is a severe psychiatric condition with a major impact on quality of life. Some MDD-patients experience psychotic symptoms (such as hallucinations or delusions) and are therefore classified under psychotic major depression (PMD). As this condition is associated with a high mortality risk, it should be identified as soon as possible. However, PMD remains underdiagnosed and thus undertreated, even though up to 20% of MDD-patients present with psychotic features. Moreover, little is known about the biological mechanisms underlying these two distinct types of depression. The recommended first line treatment for PMD consists of either combining an antidepressant with an antipsychotic, or electroconvulsive therapy (ECT). However, pharmacotherapy is linked with several disadvantages, such as delayed start of treatment effects and lower responsiveness in PMD-patients, whereas ECT provides faster effects and seems to be more effective in PMD than non-PMD. Although ECT appears to be a valuable therapeutic option, the biological mechanisms underlying its effects remain yet unclear. This project aims to establish biomarkers linked to ECTresponse in psychotic depressed patients. We will explore changes in several peripheral biomarkers related to ECT response in PMD. We will investigate effects on molecules of interest (immune markers, oxidative stress markers, growth factors), but will also explore new potential biomarkers by use of genomics, transcriptomics and proteomics. Moreover, structural and resting-state MRI will provide information on specific brain region and/or network alterations to differentiate psychotic from non-psychotic major depression. In total, 100 subjects will be allocated to age- and gender-matched groups: 1) PMDpatients(n = 40), 2) non-PMD patients (n = 40) and 3) healthy controls (n = 20). PMD- and non-PMD patients will undergo ECT and will therefore be evaluated before and after completion of the ECT treatment schedule.

Researcher(s)

• Promoter: Morrens Manuel
• Co-promoter: Coppens Violette

Research team(s)

• Collaborative Antwerp Psychiatric Research Institute (CAPRI)

Project type(s)

• Research Project

Abstract

A depressive disorder is a psychiatric disorder characterized by a depressive state of mind, negative thoughts, anhedonia and suicidality. Patients often suffer from recurrent psychotic episodes, which has an enormous impact on all aspects of their lives. A subpopulation of these patients also suffers from psychotic symptoms such as delusions and auditory hallucinations (Schatzberg, 2006) on top of the characteristic depressive symptoms. Current imaging studies and molecular studies point to specific characteristics that differentiate between psychotic depression and non-psychotic depression, such as reduced functional activity in the insula in psychotic depression (Farret et al., 2011), and to shared factors between both forms such as disruption of the HPA axis (review Dean and Keshavan, 2017). Although there is already some knowledge about the underlying neurobiology of psychotic depression, the characterization is far from complete, which is illustrated by the low diagnosis and suboptimal treatment of this serious disorder. This is problematic as these patients account for a significant 14-20 percent of patients (Ohayon & Schatzberg, 2002) and this subpopulation shows a different course of disease and a different response to treatment (Buoli et al., 2013, Van Diermen et al. , 2018). New techniques such as proteomics and transcriptomics can offer a solution. These techniques provide the opportunity to map both syndromes on a large scale and from an atheoretical perspective. For example, interesting findings have been made in post-mortem brains of patients with various syndromes such as schizophrenia, bipolar disorder and depressive disorder (review Saia-Cerada, 2017). As far as psychotic depression is concerned, so far only a small-scale study has been undertaken by Martin-De Souza et al (2012) in which quantitative differences were found between protein concentrations related to energy metabolism and synaptic activity. Furthermore, differences were also found in the expression of proteins previously linked to schizophrenia, as one would expect given the aforementioned overlap in genetic risk factors. Although these interesting initial findings show that this form of research can make a valuable contribution to the knowledge of psychotic depression in the field of neurobiology, larger studies are needed that ideally use predictive statistical methods such as sensitivity, specificity and reclassification tables (Pencina, 2008) to distill potential biomarkers for psychotic depression. Furthermore, knowledge of the underlying interaction network can yield interesting drug targets (Hopkins, 2008).  These two goals are therefore central to this PhD. In order to achieve this, brains from the Corsella collection will be examined with different molecular techniques. In the first phase medical records will be read and inventoried in an electronic database together with information about the available tissue. In a second phase, four types of cases will be selected from this database, namely healthy controls, patients with a depressive disorder without psychotic characteristics, patients with a psychotic depressive disorder and patients with a psychotic disorder without affective characteristics. These samples will then be analyzed by means of proteomics and transcriptomics.

Researcher(s)

• Promoter: Morrens Manuel
• Co-promoter: Coppens Violette

Research team(s)

• Collaborative Antwerp Psychiatric Research Institute (CAPRI)

Project type(s)

• Research Project