Huntington’s Disease: Can Beta Blockers Help?

In a recent study, beta blockers appeared to significantly lower both the annualized risk for conversion from presymptomatic to symptomatic Huntington’s disease (HD) and the rate of worsening among symptomatic patients. Accordingly, authors suggested, beta blockers one day may play a role in treating HD, perhaps by blocking norepinephrine signaling or reducing patients’ anxiety. However, an expert not involved with the study, which appeared online on December 22, 2024, questioned its generalizability.

Altering Clinical Course? 

To investigate whether beta blockers can affect the clinical course of HD, investigators led by Jordan L. Schultz, PharmD, of the Department of Psychiatry at the Carver College of Medicine, University of Iowa in Iowa City, Iowa,included 174 adults with genetically confirmed premanifest HD (preHD) from the Enroll-HD global research platform. When researchers compared these patients’ trajectories with those of 174 matched beta-blocker nonusers, beta blockers were associated with a statistically significant reduction — hazard ratio, 0.66 (P = .02) — in the annualized risk of receiving a motor diagnosis.

Among Enroll-HD patients with early motor-manifest HD (mmHD), comparing 149 beta-blocker users against 149 matched nonusers revealed an association between beta blockers and slower mean annualized worsening in total motor score (mean difference (MD), −0.45; Q = .025), total functional capacity score (MD, 0.10; Q = .025), and symbol digit modalities test (MD, 0.33; Q = .017).

Why Beta Blockers? 

A study published in Brain Communications in 2022 by the same research group showed that autonomic nervous system dysregulation in HD likely occurs early in life and is associated with reduced functional connectivity within the central autonomic network. “Consequently,” wrote Schultz and colleagues in the present paper, “the autonomic nervous system may be a novel target to help slow the progression of Huntington’s disease.” And beta-adrenergic receptor blockers may uniquely block an overactive sympathetic nervous system, the authors surmised.

Although beta blockers appeared to help patients with both preHD and mmHD, post hoc analyses showed that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers did neither. Authors therefore hypothesized that noradrenergic transmission through beta-1 receptors may play a role in HD pathogenesis, although further research is required.

Interpret With Caution

“Interesting findings,” said Kara Wyant, MD, clinical assistant professor of neurology at the University of Michigan Medical School in Ann Arbor, Michigan. “But it’s important to interpret the findings with caution, based on the type of study that it is.” She was not involved with the research but was asked to comment.

Observational studies can reveal relationships but cannot establish causality, Wyant explained, a limitation that study authors acknowledged. She added that within the Enroll-HD database, which skews toward large academic institutions, “there may be bias because people who participate in longitudinal clinical research tend to have a little higher education and better socioeconomic status and access to healthcare.” Therefore, she said, results might not reflect patients in rural populations or underserved areas.

Moreover, said Wyant, mean cytosine-adenine-guanine repeat numbers of 40.9-42 in both the preHD and mmHD subgroups are relatively low, so these participants manifest HD later than what neurologists typically see. PreHD study participants were in their mid-to-upper 40s, and patients with mmHD were in their late 50s. “Also, 97% of them are White,” she added. “Again, that limits how we can interpret the findings.”

Regarding the hypothesis that inhibiting noradrenergic transmission by blocking beta-1 receptors may provide a therapeutic target, said Wyant, “the only evidence for targeting that beta receptor right now is this study. We need good follow-up studies to show from a basic science perspective that it makes sense to block that beta receptor, and that it might change some process within the disease.”

Schultz and colleagues acknowledged that beta blockers’ anxiety-reducing effects could have improved motor symptoms and functionality, indirectly affecting the timing of clinical diagnosis and patients’ progression metrics. Physicians treat performance anxiety with nonselective beta blockers such as propranolol, added Wyant. And 59 preHD patients were on propranolol — 40% of them for anxiety and depression.

“It’s not a big step to say this drug may have decreased that performance anxiety at the study visit, making these patients appear more calm and relaxed, with fewer involuntary movements,” she said.

Moreover, Wyant said that beta-blocker users and nonusers had a higher rate for vascular risk factors — most notably smoking history, 50-52.9% — than physicians typically see among patients with HD. According to a study published in the Journal of Neurology, Neurosurgery, and Psychiatry in 2018, 25.8% of Enroll-HD patients with mmHD reported cigarette smoking. The apparently slower decline in the mmHD subgroup notwithstanding, she said, these patients’ older age, higher rates of smoking and hypertension, and use of cardioselective beta blockers obscure whether these drugs modified HD or vascular risk factors.

“It’s important for the general neurologist to be aware that there is potentially autonomic dysfunction in patients who have Huntington’s disease,” said Wyant. “But we need a lot more research before we can make any suggestions about treating that autonomic dysfunction with a specific class of drugs.”

Enroll-HD is a longitudinal observational study sponsored by the CHDI Foundation. Wyant reported no relevant financial relationships.

John Jesitus is a Denver-based freelance medical writer and editor.