Background. Studies with the Temperament and Character Inventory (TCI) in depressive disorders have shown changes (Δ) of the character of Self-Directedness (SD) and the temperament of Harm Avoidance (HA). The central question of this study is which of these two changes is most proximally related to the production of depressive symptoms. Methods. The start and endpoint data from a two-year followup of 58 depressed patients were reanalyzed. We used the ΔHA and ΔSD scores as well as the Δ scores on three dimensions of psychopathology, called Emotional Dysregulation (ED), Retardation (RET), and Anxiety (ANX). The presence of the main relation between personality and psychopathology was tested in all patients and in four subcategories. The data were analyzed by MANCOVA and Structural Equation Modelling (SEM). Results. ΔHA and ΔSD correlated negatively, and only ΔSD was related (negatively) to ΔED. This pattern was found in all subcategories. SEM showed ΔHA and ΔSD had an ambiguous causal interrelationship, while ΔSD, ΔRET, and ΔANX had unidirectional effects on ΔED. Conclusion. The results correspond with a central pathogenetic role for a state-related deficit at the character level in depression. This may have important consequences for investigations of endophenotypes and clinical treatment.