Longitudinal hair cortisol in bipolar disorder and a mechanism based on HPA dynamics

Bipolar disorder (BD) is a dynamic disease in which mania, depression and mixed states vary on a timescale of months to years. BD patients characteristically exhibit elevated levels of the hormone cortisol. Persistently elevated cortisol can also cause mood episodes in a substantial fraction of the general population. Although BD is a dynamic disease that is related to cortisol, longitudinal cortisol dynamics in BD have rarely been studied. Here we use hair to measure past cortisol where each cm of hair corresponds to a month of growth. Cortisol was measured in 12 cm hair samples from people with BD (n=26) and controls (n=59), corresponding to one year of cortisol data. We found that hair cortisol exhibited a frequency spectrum with enhanced year-scale fluctuations whose amplitude was about 4-fold higher on average in BD compared to controls. Cortisol in the proximal 2 cm hair segment correlated with mood scales that report on mood in the past two months. In line with the notion that cortisol correlates with mood, we find that the mean frequency spectrum of depression (n=266) and mania (n=273) scores from a large longitudinal study of BD is similar to the hair cortisol spectrum from the present cohort. Taken together, these results suggest a mechanism for BD as the intersection of two neuropsychological traits: cortisol-induced mood episodes (CIM) and high emotional reactivity (ER). High ER causes fluctuations in which cortisol is elevated for months, as shown by a mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis that regulates cortisol. In individuals with CIM, the magnitude of these persistent cortisol fluctuations can be high enough to trigger mood episodes. Thus, this study combines longitudinal cortisol measurements and mathematical modeling to provide a potential mechanistic link between the timescales of cortisol and moods in BD.