Personalized care for immuno-metabolic depression

Depression increases the risk of subsequent cardiometabolic conditions, partly through its negative impact on biological mechanisms such as immune and metabolic processes. However, such dysregulated processes are not present in all individuals with depression. The starting point of this thesis was the growing evidence that the link between depression and immune-metabolic dysregulation varies according to symptom heterogeneity. In particular, these dysregulations are more frequently observed in individuals with specific depressive symptoms partly overlapping with atypical depression but primarily related to altered energy homeostasis, including increased appetite and weight during depressive episodes, fatigue, leaden paralysis, and hypersomnia. These findings contributed to the emerging concept of immuno-metabolic depression as a biologically informed dimension of depression, characterized by the clustering of an atypical, energy-related symptom profile with immune and metabolic dysregulations. This concept may provide a useful framework for understanding depression heterogeneity and identifying individuals at increased cardiometabolic risk. It also offers potential clinical relevance within the growing field of precision psychiatry. The main aim of this thesis was to enhance understanding of the conceptualization of immuno-metabolic depression and to investigate its implications for depression treatment. First, we aimed to replicate and refine previous findings on the characterization of immuno-metabolic depression at a larger scale (using data from 13,965 individuals with lifetime depression across eight Dutch cohorts) and across populations at different stages of depression and immuno-metabolic health (using baseline clinical trial data). Second, we examined whether immuno-metabolic depression may serve as a useful profile for identifying patients less likely to benefit from current first-line treatments and who may require alternative or complementary strategies. To that end, we conducted a pooled analysis of four RCTs (N = 2,551) to examine whether immuno-metabolic depression features were associated with poorer outcomes following antidepressant treatment. Third, using data from existing clinical trials on running therapy (N = 141), light therapy (N = 77), and dietary interventions (N = 933), we investigated whether lifestyle-based interventions hold promise for individuals with immuno-metabolic depression. We hypothesized that such interventions may help normalize immune and metabolic dysregulation, thereby alleviating depressive symptoms, particularly in those with such dysregulations at baseline. We also evaluated whether lifestyle-based interventions can reduce features of immuno-metabolic depression, thereby offering insight into the extent to which immuno-metabolic depression can be targeted through lifestyle interventions. We confirmed on a large scale that symptoms of the atypical, energy-related depressive symptom profile tend to co-occur more often than other depressive symptoms and are consistently associated with adverse metabolic health indicators, thereby reinforcing the current conceptualization of immuno-metabolic depression. Moreover, we found that individuals with features of immuno-metabolic depression seem to respond marginally worse to antidepressants and that antidepressant use may even be linked to worsening of immuno-metabolic depression features. This underscores the importance of monitoring somatic health during conventional pharmacological treatments for depression and the need to explore alternative approaches. Although lifestyle-based interventions such as exercise, dietary strategies, and light therapy did not lead to markedly better depression outcomes in immuno-metabolic depression, running therapy and a food-related behavioral activation intervention were associated with reductions in immuno-metabolic depression features themselves. This indicates the potential value of exercise and dietary behavioral interventions as part of a lifestyle-based treatment approach for individuals with immuno-metabolic depression. Further research is needed to refine the immuno-metabolic depression concept and evaluate its clinical utility in guiding depression treatment. Overall, this work represents a first step toward more personalized and integrated care for individuals with depression, moving closer to the goals of precision psychiatry. Such efforts are crucial for reducing the global burden of depression and its frequently overlooked physical health comorbidities.