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

Abstract

Bipolar disorder (BD) is marked by fluctuating mood states over months to years, often with elevated cortisol levels. Elevated cortisol can also trigger mood episodes. Here, we combine longitudinal hair cortisol and mood measurements with mathematical modeling to provide a potential mechanistic link between cortisol and mood timescales in BD. Using 12 cm hair samples, representing a year of growth, we found enhanced year-scale cortisol fluctuations whose amplitude averaged 4-fold higher in BD (n = 26) participants than controls (n = 59). The proximal 2 cm of hair correlated with recent mood scores. Depression (n = 266) and mania (n = 273) scores from a longitudinal study of BD showed similar frequency spectra. These results suggest a mechanism for BD in which high emotional reactivity excites the slow timescales in the hypothalamic-pituitary-adrenal (HPA) axis to generate elevated months-scale cortisol fluctuations, triggering cortisol-induced mood episodes.

Keywords: Clinical neuroscience; Endocrine system physiology; Neuroscience; Systems psychiatry.

Graphical abstract

Figure 1

BD participants had higher hair cortisol than control participants Cortisol levels of control (orange) and BD patients (blue) along six successive 2-cm hair segments of a 12 cm hair sample, where segment 1 is closest to the scalp. Effect sizes, calculated as the ratio between BD and control median cortisol, and Mann-Whitney U test p values for segment 1 to 6 are: 1.7, p = 0.008; 1.8, p = 0.003; 1.85, p = 0.01; 1.7, p = 0.04; 2.2, p = 0.005; 2, p = 0.01. Boxes show 25%, 50% (median) and 75% percentiles.

Figure 2

Participants with BD showed enhanced year-scale fluctuations of hair cortisol (A) Individual cortisol time series of 6 hair segments after correcting for the cortisol decay along the hair. (B) Median Fourier amplitudes of longitudinal hair cortisol. Error bars are 68% confidence intervals from bootstrapping. The ratios between BD and control median Fourier amplitudes were: 3.9 (p = 0.001) for the 1 $yea{r}^{-1}$ frequency; 2.55 (p = 0.0003) for the 2 $yea{r}^{-1}$ frequency, and 2 (p = 0.02) for the 3 $yea{r}^{-1}$ frequency. All p values from Mann-Whitney U test. (C) Fourier amplitudes of all participants (dots). Boxes show 25%, 50% (median) and 75% percentiles.

Figure 3

Frequency spectra of mood scales from a cohort of individuals with BD show year scale fluctuations (A) Median Fourier amplitudes of PHQ-9 depression scale scores from 266 BD and 179 control participants measured every 2 months for at least two years. (B) Median Fourier amplitudes of ASRM mania scale scores from 273 BD and 178 control participants measured every 2 months for at least two years. Error bars are 68% confidence intervals from bootstrapping.

Figure 4

HPA model with gland mass changes predicts enhanced year-scale fluctuations in BD in agreement with the experimental measurements (A) HPA axis circuit with gland mass dynamics. Red arrows represent growth-factor activities of hormones on the pituitary ACTH-secreting cells and the adrenal cortex. (B) One realization of simulated noisy daily stressor inputs in time for BD (blue) and control (orange). (C) A flat Fourier spectrum of the simulated white noise inputs. (D) The simulated response of cortisol to the stressor inputs shown in (B) over a year, where a baseline cortisol level was set to be the mean of the first segment hair data (E) Fourier spectra of simulated cortisol shown in (D). The three gray dashed lines mark the frequencies measured in the present hair cortisol experiment. Data shown in (C) and (E) are simulation means +/− SEM.

Figure 5

Hypothesis for a pathophysiological mechanism for the timescales of BD (A) Overview of the proposed mechanism. BD can occur in individuals with both cortisol-induced mania (and depression) susceptibility and emotional hyper-reactivity. Emotional hyper-reactivity causes higher HPA inputs that fluctuate over hours and days. The HPA axis transforms these into months-scale fluctuations because of gland mass changes. High cortisol over months increases the probability of mania and depression in individuals with susceptibility to cortisol induced mood episodes. Percentages are estimates of the fraction of the population with each trait (STAR methods and Tables S3 and S4). (B) Risk of mania in a population (n = 372,696) taking glucocorticoid steroids representing 89,298 years of glucocorticoid exposure compared to a control population. Normal cortisol baseline is equivalent to about 5 mg prednisone. Adapted from the data of error bars are 95% CI.