Predicting Treatment Outcome in Major Depressive Disorder Using Serotonin 4 Receptor PET Brain Imaging, Functional MRI, Cognitive-, EEG-Based, and Peripheral Biomarkers: A NeuroPharm Open Label Clinical Trial Protocol

Kristin Köhler-Forsberg, Anders Jorgensen, Vibeke H Dam, Dea Siggaard Stenbæk, Patrick M Fisher, Cheng-Teng Ip, Melanie Ganz, Henrik Enghusen Poulsen, Annamaria Giraldi, Brice Ozenne, Martin Balslev Jørgensen, Gitte Moos Knudsen, Vibe Gedsoe Frokjaer, Kristin Köhler-Forsberg, Anders Jorgensen, Vibeke H Dam, Dea Siggaard Stenbæk, Patrick M Fisher, Cheng-Teng Ip, Melanie Ganz, Henrik Enghusen Poulsen, Annamaria Giraldi, Brice Ozenne, Martin Balslev Jørgensen, Gitte Moos Knudsen, Vibe Gedsoe Frokjaer

Abstract

Background: Between 30 and 50% of patients with major depressive disorder (MDD) do not respond sufficiently to antidepressant regimens. The conventional pharmacological treatments predominantly target serotonergic brain signaling but better tools to predict treatment response and identify relevant subgroups of MDD are needed to support individualized and mechanistically targeted treatment strategies. The aim of this study is to investigate antidepressant-free patients with MDD using neuroimaging, electrophysiological, molecular, cognitive, and clinical examinations and evaluate their ability to predict clinical response to SSRI treatment as individual or combined predictors.

Methods: We will include 100 untreated patients with moderate to severe depression (>17 on the Hamilton Depression Rating Scale 17) in a non-randomized open clinical trial. We will collect data from serotonin 4 receptor positron emission tomography (PET) brain scans, functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), cognitive tests, psychometry, and peripheral biomarkers, before (at baseline), during, and after 12 weeks of standard antidepressant treatment. Patients will be treated with escitalopram, and in case of non-response at week 4 or intolerable side effects, offered to switch to a second line treatment with duloxetine. Our primary outcome (treatment response) is assessed using the Hamilton depression rating subscale 6-item scores at week 8, compared to baseline. In a subset of the patients (n = ~40), we will re-assess the neurobiological response (using PET, fMRI, and EEG) 8 weeks after initiated pharmacological antidepressant treatment, to map neurobiological signatures of treatment responses. Data from matched controls will either be collected or is already available from other cohorts.

Discussion: The extensive investigational program with follow-up in this large cohort of participants provides a unique possibility to (a) uncover potential biomarkers for antidepressant treatment response, (b) apply the findings for future stratification of MDD, (c) advance the understanding of pathophysiological underpinnings of MDD, and (d) uncover how putative biomarkers change in response to 8 weeks of pharmacological antidepressant treatment. Our data can pave the way for a precision medicine approach for optimized treatment of MDD and also provides a resource for future research and data sharing.

Clinical trial registration: The study was registered at clinicaltrials.gov prior to initiation (NCT02869035; 08.16.2016, URL: https://ichgcp.net/clinical-trials-registry/NCT02869035&cntry=&state=&city=&dist=).

Keywords: biomarker; cognition; electroencephalogram; functional magnetic resonance imaging; major depressive disorder; positron emission tomography; serotonin 4 receptor; treatment response.

Copyright © 2020 Köhler-Forsberg, Jorgensen, Dam, Stenbæk, Fisher, Ip, Ganz, Poulsen, Giraldi, Ozenne, Jørgensen, Knudsen and Frokjaer.

Figures

Figure 1
Figure 1
Flowchart of study trial assessments for patients with MDD.
Figure 2
Figure 2
Flow diagram (CONSORT) of the NeuroPharm trial.
Figure 3
Figure 3
Response categorization for patients with MDD after 4 and 8 weeks of antidepressant treatment based on changes in HAMD6 score.

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