​Title

Neurobiological Substrates of Depression and Treatment Response. From Brain Structure to Sex Hormones.

Assessment Com​mittee

• Prof. Jessica M.C. Lohmann, Competence Centre for Transcultural Psychiatry, Mental Health Services CPH, Denmark
• Prof. Philip Cowen, Department of Psychiatry, University of Oxford, United Kingdom
• Ass. Prof. Daniel Lindqvist, Department of Clinical Sciences, Faculty of Medicine, Lund University, Sweden
  

Academic Advisors​

• Prof. Martin Balslev Jørgensen, Psychiatric Center Copenhagen, Denmark
• Prof. Gitte M. Knudsen, Neurobiology Research Unit, Copenhagen, Denmark
• Dr. Vibeke H. Dam, Neurobiology Research Unit, Copenhagen, Denmark
• Prof. Merete Osler, Frederiksberg Hospital Center for Clinical Research and Prevention, Denmark
  
• Ass. Prof. Anders Jørgensen, Psychiatric Center Copenhagen, Denmark

Thesis summary​

Major depressive disorder (MDD) is a complex and heterogeneous mental disorder causing suffering worldwide. While effective treatments exist, including pharmacotherapy and psychotherapy, more than half of patients do not respond adequately to their first medication. The search for reliable biomarkers to guide treatment selection has largely focused on individual domains, e.g. symptoms, social demographics, neuroimaging, genetics, or blood markers. Yet no single marker has proven clinically useful. This reflects both the disorder's heterogeneity and our limited understanding of the underlying biology.
This thesis investigates neurobiological mechanisms and markers of treatment response in MDD through three studies using data from the NeuroPharm-1 study and presents the ongoing BrainDrugs-Depression cohort study.
Study I challenges traditional views about antidepressant mechanisms by showing that successful SSRI treatment was associated with decreased rather than increased hippocampal volume. This suggests therapeutic effects may involve circuit refinement rather than growth. We also found sex-specific relationships between hippocampal volume and serotonin 4 receptor binding, with correlations present only in women.
Study II failed to replicate previous findings that EEG abnormalities predict poor response to escitalopram. However, patients with EEG abnormalities showed greater emotional disturbance and poorer verbal memory, potentially marking a distinct clinical phenotype rather than treatment resistance.
Study III revealed that in men, low pretreatment sex hormone levels predicted sexual side effects from SSRIs but not treatment response. The finding that higher testosterone levels were associated with vegetative symptoms like weight loss likely reflects metabolic consequences of depression rather than causation.
These studies highlight how depression and its treatment involve complex and sex-specific mechanisms that cannot be reduced to simple biomarker-outcome relations. The work provides a foundation for a more nuanced approach to precision psychiatry that accounts for sex differences and multiple interacting biological systems.
With this in mind, I present the BrainDrugs-Depression cohort study, which aims to enable deep phenotyping of first-episode depression patients in a naturalistic clinical setting in the Capital Region of Denmark. I showcase the study's status and how it may enable studies of predictors and mechanisms of treatment response to identify and understand who benefits from what.