Work package leader: Vibe G. Frøkjør, NRU

Major depressive disorder (MDD) most likely comprises a heterogeneous collection of different biological entities, which calls for studies that can inform a targeted treatment and potentially a new etiological classification. Most antidepressants act on the serotonin (5-HT) system but less than 50% of MDD patients respond successfully to 5-HT acting drugs. Identification of biological features that enables a relevant stratification of MDD patients would, importantly, allow for individualized treatment and can help facilitate more efficient clinical drug trials.

The goal of this work package is to identify neurobiological and other predictors of response to pharmacological treatment of depression. The research will illuminate basic mechanisms of action of pharmacological treatment of MDD and will, in the long term, provide a rationale for tailored treatment choice for MDD patients based on quantitative measures of brain function, rather than - as is the case today - rely exclusively on clinical assessment. The NP1 project is carried out in a close collaboration between NRU and the Psychiatric Center Copenhagen and it includes a newly established PET-based marker of the brain serotonin system (5-HT4 receptor binding determined by 11C-SB207145 PET), various MRI techniques, EEG, neuropsychological testing, blood and saliva sampling enabling genotyping and determination of cortisol awakening response, inflammatory markers as well as epigenetic variations across the study period.

We will enroll 100 MDD patients and examine how these markers relate to the outcome of a standard antidepressant treatment. Patients will be treated with standard antidepressant treatment, i.e., a selective serotonin reuptake inhibitor (SSRI), escitalopram, adjusted contingent on effects and side effects. They will have follow-up sessions at week 1, 2, 4, 8, and 12 where a trained psychiatrist will rate their depressive symptoms. Brain imaging with 11C-SB207145 PET, structural and functional MRI with resting state fMRI (rs-fMRI), and EEG will be conducted in all patients before pharmacological intervention is initiated and repeated at week 8 in 40 patients with variable antidepressant response.

The first part of the project is a GCP-monitored clinical trial. A description of this part can be found here at ClinicalTrials.gov.