Lifestyle and Molecular Biomarkers as Predictors of Depression Outcomes: The Interplay between Physical Activity, Diet and Gut Microbiota

Background. Depression is increasingly understood as a systemic disorder shaped by lifestyle, metabolic, and inflammatory factors, with anhedonia representing one of its most disabling and treatment-resistant dimensions. This thesis investigates the interplay between adherence to the Mediterranean diet, physical activity, insulin resistance, inflammation, and gut microbiota composition in patients with Major Depressive Disorder (MDD). Aims. The primary aim of this research was to evaluate the associations between lifestyle factors, metabolic status, and systemic inflammation with depressive symptom severity and anhedonia, both cross-sectionally and longitudinally. Secondary aims were to explore gut microbiota diversity and composition as potential correlates and mediators of these associations, and to identify behavioral, metabolic, and clinical predictors of early and sustained antidepressant response, thereby contributing to a multidimensional and precision-oriented understanding of depression. Methods. In a longitudinal observational study, participants were assessed at baseline (T0) and followed at 2 (T1), 4 (T2), and 6 months (T3). Clinical measures included MADRS and SHAPS. Lifestyle was captured through validated questionnaires. Metabolic and inflammatory markers comprised HOMA-IR and CRP. Gut microbiota was profiled at multiple taxonomic levels with alpha- diversity indices. Analyses employed non-parametric tests, Spearman correlations, logistic regression, and negative binomial models; microbiome associations focused on alpha-diversity. Results. The baseline cohort (n = 136) was predominantly female, young-to-middle aged, with moderate depression and moderate anhedonia; insulin resistance was frequent, while CRP was generally low. At T0, lower Mediterranean-diet adherence correlated with higher MADRS (p = 0.013) and SHAPS (p = 0.0034). Low adherence independently predicted moderate/severe depression (OR = 4.72, 95% CI 1.37–16.34, p = 0.014). Physical activity inversely correlated with anhedonia (p < 0.001), and in negative-binomial models, low activity and low diet adherence were associated with higher SHAPS (RR = 2.10, 95% CI 1.31–3.38, p = 0.002; RR = 1.85, 95% CI 1.18–2.91, p = 0.007). The “low diet/low activity” group showed the greatest anhedonia and the highest CRP. Cross- sectionally, insulin resistance was linked to higher anhedonia (p < 0.001). Longitudinally, MADRS improved markedly and SHAPS declined; early response at T1 was associated with higher physical activity, whereas diet–symptom correlations attenuated over time. Microbiome analyses showed greater diversity and evenness in physically active participants (e.g., higher Shannon/Pielou indices), reduced diversity in insulin-resistant individuals, and an inverse association between diversity and depressive severity; richness (ACE) correlated positively with HOMA-IR, suggesting dysbiotic “false richness.” Conclusions. Findings support a multidimensional model in which physical activity, metabolic health, and gut microbial balance jointly influence depressive outcomes, particularly anhedonia. Physical activity emerged as the most consistent behavioral correlate of early improvement and healthier microbiome profiles, while insulin resistance marked greater anhedonic burden. Mediterranean-diet adherence associated with symptom severity and CRP at baseline but showed limited short-term longitudinal effects. Integrating lifestyle counseling, metabolic screening, and microbiome-informed monitoring into routine psychiatric care may advance precision strategies for depression and improve long-term outcomes.