Background Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington’s disease (HD) mutation carriers. In non-HD populations, alterations in HPA axis activity have been associated with the presence of depression and suicidality.

Aims To compare HPA axis activity between HD mutation carriers and controls and to investigate its association with depressive symptoms and suicidality.

Methods Salivary cortisol levels at seven timepoints, and both depressive symptoms and suicidality according to the Problem Behaviours Assessment were determined in 48 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in basal and post-dexamethasone parameters of HPA axis activity between these groups and its associations with depressive symptoms and suicidality were analysed by multilevel regression analysis.

Results Pre-motor symptomatic mutation carriers had a significantly higher area under the ground to the increase (AUCi) compared with motor symptomatic mutation carriers, while none of the parameters of HPA axis activity were significantly different between mutation carriers and controls. In the entire HD group, there was no association between parameters of HPA axis activity and depressive symptoms or suicidality. When stratifying mutation carriers in pre-, early (Total Functional Capacity (TFC) stage 1 and 2) and late (TFC stage 3–5) motor symptomatic stages, there was a significant association between a higher AUCi and depressive symptoms in both pre- and early motor symptomatic mutation carriers and between a lower cortisol suppression ratio and suicidality in pre-motor symptomatic mutation carriers.

Conclusions Exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity might explain the lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-, early and late symptomatic mutation carriers.