Chronic Stress in Bipolar Disorders Across the Different Clinical States: Roles of HPA Axis and Personality.

Introduction: Chronic stress has been linked to the pathophysiology of bipolar disorder (BD); however, the underlying mechanism remains unclear. In BD patients, hypothalamic-pituitary-adrenal (HPA) axis activity is associated with stress. This study aimed to examine the relationship between HPA axis activity and BD symptoms in various clinical states, as well as how personality influences the process. Methods: This study investigated the differences in HPA axis activity among four BD states. We enrolled 813 BD patients in an 8-week longitudinal study to examine the relationship between HPA axis activity and symptom trajectories using dynamic temporal warping (DTW) analysis and an unsupervised machine learning technique. Furthermore, using mediation analyses, the relationship between the HPA axis, personality, and BD symptoms was investigated. Results: Analysis of variance (ANOVA) analysis showed that glucocorticoid cortisol (CORT) and adrenocorticotropin (ACTH) did not differ significantly among the four clinical states of BD. The DTW integrating clustering analysis revealed that the two clusters were optimal, with cluster 1 characterized by severe manic symptoms, which then improved, and cluster 2, characterized by milder manic severity, which also improved. The two clusters showed different ACTH levels (t = 2.289, p = 0.022), and logistic regression analysis revealed a slight positive association between ACTH levels and cluster 1. Furthermore, the mediation analysis indicated that ACTH influences curative efficacy via conscientiousness (βc =0.103, p=0.001). Discussion: In conclusion, we found that a higher level of ACTH is associated with severe manic symptoms, indicating a chronic stress response in BD patients. Additionally, the ACTH levels affect short-term BD curative efficacy via the mediation of conscientiousness, providing a psychotherapeutic strategy direction for BD.