674. Cognitive and neurobiological indicators of risk and prognosis in mood disorders
Abstract Background Mood disorders are major contributors to the global burden of disease. There is a critical need for reliable markers that can identify individuals at elevated risk for developing mood disorders and predict poor prognosis among those already affected, in order to guide personalized interventions. Aims & Objectives This presentation summarizes findings from a series of studies examining: (1) risk markers for the future development of a first episode of major depressive disorder (MDD) in initially healthy individuals; and (2) markers of adverse outcomes, including treatment non-response and psychiatric hospitalization, in individuals with MDD and bipolar disorder (BD). Method Longitudinal data on depression diagnoses, treatment resistance, and psychiatric hospitalizations were obtained from Danish national health registers across multiple cohorts: (1) 372 individuals without prior psychiatric diagnoses who completed cognitive and personality assessments, and positron emission tomography (PET); (2) 518 individuals diagnosed with BD or MDD who completed cognitive assessments, with a subset also undergoing structural (sMRI) and functional MRI (fMRI); (3) 98 unmedicated individuals with MDD enrolled in an antidepressant treatment trial who underwent PET, sMRI, fMRI, and cognitive assessments. All analyses were conducted using Cox proportional hazards regression models, adjusting for relevant demographic and clinical covariates. Results Cognitive impairments, as well as serotonin system dysfunction in combination with high personality trait neuroticism, were associated with increased risk of subsequent MDD onset in initially healthy individuals (HR=1.14 CI [1.02-1.25], p=0.018). In individuals with mood disorders, cognitive impairments were associated with a higher risk of psychiatric hospitalization (HR = 1.84, [CI:1.05–3.25], p = 0.034), alongside alterations in neurocircuitry supporting cognitive control and emotional processing. Within the antidepressant treatment trial, approximately 20% of participants met criteria for treatment-resistant depression within 3 years, although 50% of these individuals had initially responded or remitted within 12 weeks of SSRI treatment initiation. Multimodal biomarker analyses suggested the presence of early clinical and cognitive profiles associated with long-term treatment non-response. Discussion & Conclusions These findings indicate that serotonin neurotransmission, emotional neural processing, cognition, and personality traits contribute to both risk for the onset of mood episodes and risk for adverse clinical events. The results reinforce that early markers can track future risk and therefore potentially guide identifying high-risk individuals and possibly treatment selection.