Two studies by scientists at Hospital for Special Surgery (HSS) offer possible insights into treating mild traumatic brain injury (mTBI), including a potential blood biomarker for injury assessment that could shed light on the role of inflammation, and evidence supporting the use of amitriptyline, historically used as an anti-depressant, but now commonly used for migraine relief, to speed recovery. The research team shared their results today at the American Academy of Neurology 2025 annual meeting.

There are currently no objective biomarkers for concussion, an invisible injury and form of mTBI, which often remains difficult to diagnose and treat. Although there are broad consensus guidelines, individual treatment decisions for this heterogeneous injury are largely left to the discretion of the physician. Previous studies have suggested a link between C-reactive protein (CRP), an inflammatory biomarker in the blood, and TBI, but the relationship is still under-explored. Because the underlying pathophysiology remains poorly understood, it remains challenging to create a treatment plan, noted Ayse Erdemir, clinical research coordinator at HSS, and first author of both studies.

“Currently there are no established pharmacological treatments for mTBI,” Erdemir noted. Standard treatment involves physical therapy, guided exercise, and lifestyle modifications, with some options for treating headache, head pressure, and insomnia, common symptoms that can impact recovery. While previous studies of amitriptyline in this population have been inconclusive, the team's research provides new data which may support its use in specific circumstances.

These studies, if further validated, have the potential to influence the treatment of mTBI, she added.

For the first retrospective study of 383 concussion patients, researchers focused on measurements of high sensitivity CRP (hsCRP), an inflammatory biomarker in the blood. Erdemir pointed out, “We found that higher levels of hsCRP were associated with more frequent reporting of symptoms like sadness and trouble falling asleep. Notably, patients with abnormal hsCRP took longer to recover compared to those with normal levels. These patients also tended to be older and have higher BMI.”

Additionally, she said "The findings suggest that hsCRP could potentially be a candidate for inclusion in biomarker panels for acute mTBI assessment, but more research is needed to understand its long-term role in tracking symptom resolution and recovery."

The results also offer a possible new insight into the pathophysiology of the disease, suggesting that, at least in some patients, the concussion may be characterized by low levels of inflammation in the brain that resolves with tailored treatment paradigms.

For the second study, the researchers analyzed data from the same group of patients, focusing on those who were prescribed amitriptyline. They found that patients who had received the drug more often had histories of depression, anxiety, and migraines, and also had more severe concussion symptoms than those who did not receive the medication. Even though their concussions appeared to be more complex and severe, patients in the amitriptyline group recovered at the same rate as more straightforward cases.

“Amitriptyline seems to play a supportive role in helping patients with more frequent and severe baseline symptoms to recover,” said Erdemir. “A tool to treat headache and insomnia in concussion patients doesn’t just improve quality of life throughout recovery; it may also facilitate and potentially expedite recovery. Restoring normal sleep and improving sleep quality is especially important to helping the brain heal from mTBI.”

While researchers believe patients with more severe concussions are more likely to benefit, the drug may still be prescribed in other patients to relieve symptoms.

More research is clearly needed to develop clinical applications. Researchers hope to follow up by analyzing longitudinal trends of hsCRP across recovery, to further support its use as a biomarker. Additional study of amitriptyline should include a randomized, controlled trial comparing the medication to placebo as well as other medications used to treat headache.

References:

High-sensitivity C-Reactive Protein (hsCRP): Retrospective Study of Potential Blood Biomarker of Inflammation in Acute Mild Traumatic Brain Injury (mTBI)

Authors: Guzide Ayse Erdemir, Niluckshi Pitigala, Joseph T. Nguyen, Teena Shetty, MD, MPhil, FAAN (HSS).

Amitriptyline for Acute Mild Traumatic Brain Injury (mTBI)

Authors: Guzide Ayse Erdemir, Niluckshi Pitigala, Joseph T. Nguyen, Teena Shetty, MD, MPhil, FAAN (HSS).

About HSS

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 15th consecutive year), No. 3 in rheumatology by U.S. News & World Report (2024-2025), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2024-2025). In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a fifth consecutive year (2025). Founded in 1863, the Hospital has the lowest readmission rates in the nation for orthopedics, and among the lowest infection and complication rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. In addition, more than 200 HSS clinical investigators are working to improve patient outcomes through better ways to prevent, diagnose, and treat orthopedic, rheumatic and musculoskeletal diseases. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 165 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.

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