Increased Morning Cortisol Levels across Different Mood States in Bipolar Disorder: A Systematic Review and Meta-Analysis.

Objective

Bipolar disorder (BD) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. However, findings regarding morning cortisol levels across different mood states remain inconsistent. This systematic review and meta-analysis aimed to synthesize evidence on morning cortisol levels in BD across different mood states, while considering the effects of various clinical moderators.

Methods

A systematic search of seven databases was conducted for articles published up to August 31, 2026. Studies were included if they reported cortisol levels measured under eligible morning sampling protocols in BD patients and healthy controls. A total of 39 studies (n = 3,611) were included. A multilevel mixed-effects meta-analysis was applied to account for the dependence of mood-state subgroups within studies. Moderator analyses were conducted via meta-regression.

Results

Compared with healthy controls, BD patients exhibited significantly elevated morning cortisol levels, both overall and across specific mood states. In exploratory moderator analyses, earlier age at onset was associated with higher morning-cortisol, whereas a greater proportion of participants receiving medication was associated with lower morning cortisol after adjustment for mood state.

Conclusion

BD is associated with a significant elevation in morning cortisol across mood states. This pattern is consistent with a potential trait-related component of HPA-axis dysregulation, although its expression may vary with clinical state and sampling conditions.