Background: Affective disorders are associated with an enormous disease burden, necessitating research on the mechanisms of effective treatments. Objectives: This article introduces the intervention projects of the transregional Collaborative Research Center 393 (CRC/TRR 393). By employing targeted interventions, we aim to induce modifiability in the key mechanisms underlying the trajectories of affective disorders studied in CRC/TRR 393: emotion regulation, expectation, social cognition, and (circadian) cognitive–behavioral rhythms. Materials and methods: The longitudinal design of the CRC/TRR 393 study will examine four interventions targeting specific mechanisms in subgroups of the German Mental Health Cohort (GEMCO). GEMCO includes patients with a current or lifetime diagnosis of major depressive disorder (MDD), bipolar disorder (BD), and healthy control (HC) participants. Multilevel measurements of these targeted mechanisms will allow us to investigate their fine-grained modifiability and their effects on disease trajectories. Results: The results will provide insights into how these mechanisms can be modified. Together with the CRC/TRR 393 mechanisms projects, we will examine the effects of key cognitive–emotional mechanisms on disease trajectories. Conclusion: For the first time, the modifiability of four key mechanisms underlying the trajectories of affective disorders will be investigated both cross-sectionally and longitudinally.