Piazza, Giulia; (2025) Deconstructing depression: a symptom-level investigation of genetic risk, brain morphology, and treatment effects. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BACKGROUND: Depression can consist of many combinations of heterogeneous symptoms, which are often shared with other disorders. Despite this complexity, symptoms are typically aggregated into summary scores, potentially obscuring key insights into the origins and treatment of depression. To remedy this, my thesis deconstructs depression by adopting a symptom-level approach, allowing me to provide novel insights into the genetic origins, underlying neurobiological mechanisms, and sensitivity to treatment of depression and its comorbidities. METHODS: In the first study, I examine the link between genetic risk and individual indicators of childhood psychopathology, combining network analysis and polygenic scores for depression and related traits. This study uses data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and replicates findings in the Twins Early Development Study (TEDS). The second study builds on these findings by exploring the associations between genetic risk, regional brain volumes, and symptoms of depression and anxiety in a sample of adults from the UK Biobank. Using a mediation approach, I assess whether regional brain volumes mediate the relationship between polygenic scores for mental health disorders and individual symptoms. The third study evaluates the effects of the selective serotonin reuptake inhibitor sertraline on individual symptoms of depression and anxiety and their longitudinal associations, using data from the PANDA (“What are the indications for Prescribing ANtiDepressAnts that will lead to a clinical benefit?”) randomised controlled trial. RESULTS: This thesis yields three key findings. First, polygenic scores for traits relevant to depression are associated with a restricted set of cross-trait and trait-relevant symptoms, suggesting that specific components of depression and comorbid disorders may drive associations between genetic risk and psychiatric phenotypes. Second, regional brain volumes are associated with a subset of symptoms of depression and anxiety, indicating that symptoms may differ in the extent to which they are linked to brain morphology. Third, sertraline affects core emotional and volitional symptoms, with beneficial effects emerging after two weeks of treatment, earlier than previously reported. Beneficial effects may be hidden by concurrent detrimental effects on somatic indicators when aggregating symptoms into summary scores. CONCLUSIONS: These findings highlight the potential of symptom-level approaches to uncover patterns of associations that advance our understanding of depression and its comorbidities. Aggregating heterogeneous symptoms of depression can hide granular information on the genetic aetiology, brain mechanisms and treatment response in psychopathology.

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