Buspirone for the Treatment of Traumatic Brain Injury (TBI) Irritability and Aggression

Brain Research in Aggression and Irritability Network (BRAIN): Building Evidence-Based Approaches to Managing Traumatic Brain Injury

The purpose of this study is to improve behavior control displayed by persons with traumatic brain injury by assessing effectiveness of treatments for post-TBI irritability and aggression.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Buspirone; Drug: Placebo

Detailed Description

PURPOSE OF PROJECT: To study the effect expressed by persons with TBI through assessment of buspirone effectiveness for post-traumatic irritability and aggression and development of an irritability/aggression impact measure.

SUMMARY OF PROJECT: It is anticipated that 74 subjects with 74 corresponding subject observers will be recruited for the treatment study. Subjects will be recruited from community and self-referrals.

Interested potential participants will be scheduled for an in-person screening visit. Subjects who consent and qualify will be randomized in a 1:1 ratio, buspirone or placebo. Stratification to randomization group will occur based on the presence of major or minor depression (defined by PHQ-9 total score >5). Randomized subjects will receive active treatment or placebo. There will be 4 clinic visits. Visits will occur at baseline, for consenting and screening, day 35, day 63 and day 91. At all 4 clinic visits, both the subject and the observer will be given questionnaires regarding the subject's behavior and mood. Day 91 ends the period of the randomized clinical trial phase of the study and the subjects will begin the 1 month continuation phase of the study in which all participants receive active buspirone.

The following questionnaires will be used as measures of irritability and aggression for the subject and the observer: Neuropsychiatric Inventory (NPI & NPI-Distress), Aggression & Irritability Impact Measure (AIIM) and Global Impression of Change.

The following questionnaires will be dispensed to the subject only: TBI-Quality of Life-Anger, Personal Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7), PTSD Checklist Civilian (PCL-C), and Glasgow Outcome Scale Extended (GOS-E) The Investigator will complete the Clinical Global Impression of change at Visits 1, 2, 3, and 4. History and Physical Exam, creatinine level (kidney function) and liver function tests will be obtained for eligibility. Serum pregnancy tests will be drawn at screening for females of childbearing potential.

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46254
      • Indiana University and Rehabilitation Hospital of Indiana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Closed head injury (impaired brain function resulting from externally inflicted trauma without penetrating injury as defined below) at least 6 months prior to enrollment
• Irritability that is either new or worse than level of irritability before the traumatic brain injury, by report of observer or person with TBI
• Age at time of enrollment: 18 to 70 years
• Voluntary informed consent of patient and observer
• Subject and observer willing to comply with the protocol
• Observer-rated NPI Irritability Domain score 6 or greater to include only moderate-severe irritability
• Medically and neurologically stable during the month prior to enrollment.
• If taking antidepressant, anxiolytic, hypnotic, or stimulant medications, no change anticipated in these medications during the month prior to enrollment
• No change in therapies or medications planned during the 91-day participation
• No surgeries planned during the 91-day participation
• Vision, hearing, speech, motor function, and comprehension sufficient for compliance with all testing procedures and assessments
• Observer (e.g.: family member, close friend, employer) with whom subject interacts sufficiently to observe occurrences of irritability. The observer interacts with the participant for a period long enough and of a nature to be able to judge the participant's irritability. The interactions would need to be adequate to judge observer distress over the irritability, severity of irritability and frequency of irritability on the following scale: < once weekly; once per week; several times per week, but not every day; essentially continuous.

Exclusion Criteria:

• Potential subject without a reliable observer
• Penetrating head injury as defined by head injury due to gunshot, projectile or foreign object
• Injury < 6 months prior to enrollment
• Ingestion of buspirone during the month prior to enrollment
• Inability to interact sufficiently for communication with caregiver
• History of schizophrenia or psychosis
• Diagnosis of progressive or additional neurologic disease
• Clinical signs of active infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Buspirone Treatment; starting at 15 mg/day and ending at 60 mg/day as prescribed	Drug: Buspirone; Buspirone/placebo will be given in increasing increments of 15 mg as needed. Subjects will start with 15 mg on day one and end with 60 mg on day 91 or placebo equivalent. Dose is titrated based on treatment response.; Other Names: Buspar
Placebo Comparator: Buspirone Placebo; placebo tablets as prescribed	Drug: Placebo; The placebo tablets taste and look identical to buspirone.; Other Names: Inactive

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychiatric Inventory-Irritability Domain - Observer-rated Proportion Improved ≥ 3 Points Baseline to Day-91	Neuropsychiatric Inventory (NPI) is a 40-item instrument evaluating 12 behavioral domains with prior use in TBI. NPI-Irritability domain (NPI-I) encompasses temper outbursts, mood fluctuations, abrupt anger, impatience, irritable disposition, and argumentative behavior. Assessment involves identifying if these behaviors are present and then scoring the most concerning manifestation on severity (1=mild to 3=severe) and frequency (1-4 scale, higher=greater occurrence). Domain totals (0-12 range) represent the product of severity and frequency ratings for the predominant symptom.	Day 91

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychiatric Inventory-Aggression Domain - Observer-rated Proportion Improved ≥ 3 Points Baseline to Day-91	Neuropsychiatric Inventory (NPI) is a 40-item instrument evaluating 12 behavioral domains with prior use in TBI. NPI-Aggression domain (NPI-A) captures emotional reactivity, resistance to activities, obstinate conduct, lack of cooperation, verbal outbursts, profanity, and physical aggression. Assessment involves identifying if these behaviors are present and then scoring the most concerning manifestation on severity (1=mild to 3=severe) and frequency (1-4 scale, higher=greater occurrence). Domain totals (0-12 range) represent the product of severity and frequency ratings for the predominant symptom.	Day 91
Neuropsychiatric Inventory-Distress Irritability Domain - Observer-rated	Neuropsychiatric Inventory (NPI) is a 40-item instrument evaluating 12 behavioral domains with prior use in TBI. NPI-Irritability domain (NPI-I) encompasses temper outbursts, mood fluctuations, abrupt anger, impatience, irritable disposition, and argumentative behavior. Assessment involves identifying if these behaviors are present and then scoring the most concerning manifestation on severity, frequency, and distress. The NPI-I Distress quantifies the emotional burden experienced by the rater regarding the most troublesome behavior using a 6-point rating system 0 to 5 (lower scores=lower distress).	Day 91
Neuropsychiatric Inventory-Distress Aggression Domain - Observer Rated	Neuropsychiatric Inventory (NPI) is a 40-item instrument evaluating 12 behavioral domains with prior use in TBI. NPI-Aggression domain (NPI-A) captures emotional reactivity, resistance to activities, obstinate conduct, lack of cooperation, verbal outbursts, profanity, and physical aggression. Assessment involves identifying if these behaviors are present and then scoring the most concerning manifestation on severity (1=mild to 3=severe) and frequency (1-4 scale, higher=greater occurrence). Domain totals (0-12 range) represent the product of severity and frequency ratings for the predominant symptom. The NPI-A Distress quantifies the emotional burden experienced by the rater regarding the most troublesome behavior using a 6-point rating system 0 - 5 (lower scores=lower distress).	Day 91
St. Andrews-Swansea Neurobehavioural Outcome Scale - Observer-rated	A self-report measure of overall neurobehavioral function. St Andrew's-Swansea Neurobehavioural Outcome Scale (SASNOS) is a 49-item observer-rated measure of neurobehavioral dysfunction in acquired brain injury. This study utilized the 15-item aggression subscale (overt aggression, irritability, and provocative behavior). The scale uses a 7-point Likert scale ("never" to "always") for items, and raw total scores are converted into standardized T-scores (M=50),(SD=10). Higher score reflects less aggression with a clinically relevant range usually extending from below (30) (indicating significant disability/high aggression) to (70) or higher (fewer symptoms).	Day 91
Global Impressions of Change - Observer-rated	A self-report measure of overall change. Global Impression of Change (GIC) employs a 5-point Likert scale whereby observers rate perceived changes in the participant from significant improvement to substantial deterioration. High score reflects worsening. Score ranges 1 to 5: 1-much improved, 2-mildly improved, 3-unchanged, 4-mildly worsened, 5-much worsened.	Day 91
Personal Health Questionnaire - Participant-rated	A measure of depression that maps on to Diagnostic and Statistical Manual (DSM) criteria for depression. Personal Health Questionnaire-9 (PHQ-9) is a 9-item self-report depression screening based on DSM-V criteria with validity and reliability in TBI populations. Higher scores indicate greater presence of recent depression symptoms. PHQ-9 has a total score range of 0 to 27, based on 9 items scored from 0 ("not at all") to 3 ("nearly every day"). It is a validated tool for assessing depression severity in various populations, including those with traumatic brain injury.	Day 91
Generalized Anxiety Disorder - Participant-rated	A self-report measure of anxiety. Generalized Anxiety Disorder-7 (GAD-7) is a 7-item self-report questionnaire assessing generalized anxiety disorder symptoms based on DSM-V criteria. Total score ranges from 0 to 21, where higher scores indicate greater severity of anxiety. Scores are categorized as: 0-4 (Minimal), 5-9 (Mild), 10-14 (Moderate), and 15-21 (Severe). A score of 10 or higher is commonly used as the cutoff for clinical screening.	91 day
Traumatic Brain Injury-Quality of Life Anger - Participant-rated	A self-report measure of overall impact of anger on quality of life. TBI-Quality of Life (TBI-QOL) Anger is a 10-item measure of the continuum of anger in TBI populations that is calibrated with the Patient Reporter Outcome Measurement Information System (PROMIS) scales. The measure assesses self-reported frequency and intensity of anger symptoms-including irritability, frustration, and outward aggression-in individuals with traumatic brain injuries. A T-score metric is used, typically ranging from roughly 30 to 80+, where a mean of 50 and a standard deviation (SD) of 10 represent the general population. Higher scores indicate more severe anger.	Day 91
Clinical Global Impressions -- Global Improvement -- Clinician Rated.	Clinician rating of overall change. The Clinical Global Impressions (CGI) scale is a 3-item, 7-point observer-rated instrument used in psychiatry to assess treatment response. It measures severity of illness (1-7), global improvement (1-7), and the efficacy index (0-4) or specific combinations of therapeutic/side effects). Lower scores generally indicate better outcomes (e.g., 1="Very much improved"). CGI-Improvement (CGI-I) (1-7): Assesses change from baseline, with 1 indicating "very much improved" and 7 indicating "very much worse".	Day 91

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Flora Hammond, MD, Indiana University/Rehabilitation Hospital of Indiana

Publications and helpful links

Helpful Links

• Rehabilitation Hospital of Indiana
• Indiana University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2013
• Primary Completion (Actual): September 26, 2025
• Study Completion (Actual): September 26, 2025

Study Registration Dates

• First Submitted: March 27, 2013
• First Submitted That Met QC Criteria: March 27, 2013
• First Posted (Estimated): April 1, 2013

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Behavior; Aggression; Traumatic Brain Injury; Irritability; Buspirone
• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Behavioral Symptoms; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Social Behavior; Brain Injuries, Traumatic; Aggression; Behavior; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Compounds; Pyrimidines; Piperazines; Spiro Compounds; Buspirone
• Other Study ID Numbers: 1210009885; CFDA #: 84.133A-120035 (Other Grant/Funding Number: National Institute on Disability and Rehabilitation Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: De-identified data will be available upon request 24 months after completion of the project. Data requests should be submitted to the principal investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No