Markers of therapy refractory depression and gait disturbance: is there a relationship to normal pressure hydrocephalus?

Introduction:

Increased aldosterone levels cause central mineralocorticoid receptor (MR) overactivity and is associated with therapy refractoriness in patients with major depression. Heart-rate-variability, changes in slow-wave sleep and an increased salt appetite have recently been demonstrated to be predictive biomarkers for such a condition. Those patients also show increased volume of the cerebral ventricular system, potentially related to MR activation of cerebrospinal fluid secretion. This resembles mild forms of idiopathic normal pressure hydrocephalus (iNPH). Therefore, the present study was conducted to investigate possible relationships between the MR overactivity and gait disturbances, which are typical symptoms of iNPH.

Methods:

Ten inpatients with major depression were observed for six weeks. They were examined at the baseline and, after two weeks and 6 weeks of entering the observational study. MR-related biomarkers and clinical outcome were determined (saliva aldosterone and cortisol, HAMD-21, GAF). Furthermore, the gait of the patients was analyzed by measuring gait speed, cadence, step length, its coefficient of variation, with the smartphone app GaitAnalysisPro Application, which analyzes gait after mounting the device to the subject. To explore the symptoms of normal pressure hydrocephalus the idiopathic normal pressure hydrocephalus grading scale (iNPHGS) was used. A correlative analysis of the pooled dataset, combining data from all visits, was performed.

Results:

High aldosterone levels correlated to a lower gait speed (p = 0.031; Pearson Corellations Coefficient R =-0.45). Also, a low cortisol-aldosterone-ratio correlated with low gait speed (p = 0.036; R = 0.44) and a shorter step length (p = 0.022; R = 0.485). A low coefficient of variation of gait cycle correlated with higher scores in iNPHGS (p = 0.026; R =-0.453). Higher scores in iNPHGS also correlated by trend with higher scores in HAMD-21 (p = 0.062; R = 0.372) and significantly with lower scores in GAF (p = 0.021) as well as with lower HRV (p = 0.050; R =-0.396). No relationship to sleep parameters were detected.

Conclusion:

Low gait speed, a low coefficient of variation and a low step length seem to be marker for increased aldosterone levels, which previously have been linked to therapy refractoriness of depression as well as increased cerebral ventricular volume. If confirmed, gait disturbances in MDE may reflect iNPH like symptoms and point to therapy refractoriness.