Brain Medicine
Autonomic dysfunction may underlie some treatment-resistant depression
Clinical takeaway: In patients with persistent depression and prominent fatigue, dizziness, or brain fog, check orthostatics and consider autonomic dysfunction as a reversible contributor.
In an observational study of 8,128 patients with autonomic dysfunction (including 2,197 with depression), nearly all demonstrated measurable imbalance in parasympathetic and sympathetic activity, with alpha-sympathetic withdrawal (79.5%) and parasympathetic excess (54.6%) most common. These abnormalities were associated with symptoms such as fatigue, cognitive impairment, sleep disturbance, and orthostatic intolerance—features often attributed to depression.
Targeted, physiology-based treatment—including low-dose midodrine, low-dose nortriptyline, supplements, and structured exercise—was associated with substantial symptom improvement over 6 to 12 months, including reductions in fatigue (77%), sleep disturbance (77%), and brain fog (69%). Overall symptom burden fell from 23.2 to 5.2. Nearly half of patients had long COVID, reinforcing autonomic dysfunction as a potential shared mechanism.
If a significant proportion of patients with treatment-resistant depression “have measurable autonomic dysfunction fueling their symptoms, then we have a responsibility to screen for it, to measure it, and to address it before concluding that a patient has failed treatment,” said Dr. Michele Pato, first author and professor in the Department of Psychiatry at Rutgers.
Source: Pato MT, et al. (2026, March 30). Brain Medicine. Is it really treatment-resistant depression? Parasympathetic and sympathetic dysfunction as a treatable contributor to depressive symptoms