Association Between Plasma SITH-1 Antibody Titers and Treatment Trajectory of Treatment-Resistant Depression

Major depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood and a loss of interest or pleasure. Treatment-resistant depression (TRD) is clinically defined as the failure to achieve an adequate therapeutic response following trials of two or more antidepressant medications of sufficient dose and duration. The neuroinflammation hypothesis proposes that hypothalamic-pituitary-adrenal axis dysfunction and glucocorticoid resistance contribute to TRD pathophysiology, distinct from monoaminergic mechanisms. Human herpesvirus 6B (HHV-6B) reactivation, triggered by stress, increases the risk of depression. Small protein encoded by the Intermediate stage Transcript of HHV-6-1 (SITH-1), a latent HHV-6B protein, may serve as a neuroinflammation biomarker. Previous studies showed elevated SITH-1 antibody titers in depression patients compared to healthy controls. This study investigated the relationship between SITH-1 antibody titers and clinical characteristics, particularly current symptoms and longitudinal depression trajectory, in patients with TRD.

Twenty-five patients with TRD and 18 healthy individuals were registered for the present study. Blood samples were collected from each participant, and clinical characteristics of TRD were assessed. The quantity of SITH-1 was assessed by measuring antibody titers as SITH-1 and calcium-modulating ligand complex.

SITH-1 antibody titers were significantly elevated in the TRD group compared to healthy controls. Binary logistic regression analysis demonstrated that SITH-1 antibody titers were significantly associated with TRD diagnosis, with the odds ratio for TRD of 15.7. Receiver Operating Characteristic analysis revealed that the optimal cutoff value for TRD classification was 2.07, yielding a sensitivity of 82.6% and a specificity of 94.4%. Multiple linear regression analysis demonstrated that the number of depressive episodes was significantly associated with SITH-1 antibody titers, whereas 17-item Hamilton Depression Rating Scale total scores showed no significant association.

These findings suggest that SITH-1 may reflect chronic neuroinflammatory processes and represent a promising novel biomarker for TRD.