Buspirone for Irritability and Aggression in Chronic Traumatic Brain Injury: A 91-Day Flexible-Dose, Parallel Group, Randomized, Placebo-Controlled Study.

OBJECTIVE: To test the hypothesis that buspirone reduces irritability (primary outcome) and aggression in chronic traumatic brain injury (TBI) as assessed by persons with TBI, their observer, and research clinician. SETTING: Community. PARTICIPANTS: Eighty-one participants (41 buspirone and 40 placebo) > 6 months post-TBI with moderate-to-severe irritability. Analysis samples were intention-to-treat (buspirone n = 41 and placebo n = 40) and per protocol sample (buspirone n = 33 and placebo n = 36). DESIGN: Randomized, double-blind, placebo-controlled, parallel-group trial comparing buspirone titrated up to 60 mg in divided doses with placebo over 91 days. MAIN MEASURES: Observer and participant-rated pre- and post-treatment Neuropsychiatric Inventory Irritability (NPI-I) and Aggression (NPI-A) domains, along with their associated NPI-Distress scores, as well as clinician-rated Clinical Global Improvement. RESULTS: All observer/participant analyses were nonsignificant except participant-rated aggression, the buspirone group had a higher adjusted least square mean (2.9 buspirone versus 1.7 placebo, P = .026). The proportion improving at least 3 NPI-I points on observer ratings was substantial but not statistically significant in both groups (78.9% buspirone versus 77.5% placebo, P = .877). Participant-ratings also revealed a large proportion in both groups improved (55.3% buspirone recipients versus 45% placebo recipients improved at least 3 points, P = .365). Clinician ratings were not significantly different between groups. There were no group differences in adverse event occurrence. CONCLUSIONS: The findings do not support buspirone as effective for post-TBI irritability at the doses and duration examined. Large nonspecific effects in both groups demonstrated high placebo response rates obscuring buspirone-specific benefits. This suggests structured clinical environments and regular monitoring confer substantial therapeutic benefits independent of specific treatment mechanisms. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01821690 https://www.clinicaltrials.gov/study/NCT01821690.