Longitudinal neuropsychological safety assessment of biperiden treatment following traumatic brain injury.

Traumatic brain injury (TBI) is associated with cognitive impairment and neurobiological alterations potentially influenced by cholinergic signaling. Although biperiden has been investigated as a potential antiepileptogenic therapy after TBI, its neuropsychological safety remains poorly understood. To evaluate the longitudinal neuropsychological safety of biperiden following TBI using standardized cognitive assessments and longitudinal analyses. Patients with moderate-to-severe TBI previously enrolled in a randomized controlled trial received biperiden or placebo treatment in the acute post-injury phase. Neuropsychological outcomes were assessed using tests from the Wechsler Adult Intelligence Scale, Five Digit Test, Rey Auditory Verbal Learning Test and Rey-Osterrieth Complex Figure Test. Fifty-four participants (placebo n = 30; biperiden n = 24) were included, with follow-up at 3-9, 10-16, and 20-36 months. Linear mixed-effects models showed no differences in cognitive outcomes between treatment groups. Greater TBI severity was associated with poorer processing speed, working memory, and verbal performance, including vocabulary and delayed recall. Temporal and parietal lesions were associated with reduced language and executive performance and recovery. Higher educational level was associated with better performance across specific domains. Biperiden showed no evidence of detrimental long-term neuropsychological effects following TBI. Cognitive outcomes were primarily determined by injury severity, lesion distribution, and cognitive reserve rather than pharmacological exposure, supporting its tolerability in acute post-TBI interventions targeting neuroplasticity modulation.