Traumatic Brain Injury
Conditions
Keywords
Traumatic Brain Injury, Buspirone, Behavior, Irritability, Aggression
Brief summary
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.
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.
Interventions
DRUGBuspirone
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.
DRUGPlacebo
The placebo tablets taste and look identical to buspirone.
Sponsors
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychiatric Inventory-Irritability Domain - Observer-rated Proportion Improved ≥ 3 Points Baseline to Day-91 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychiatric Inventory-Aggression Domain - Observer-rated Proportion Improved ≥ 3 Points Baseline to Day-91 | 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. |
| Neuropsychiatric Inventory-Distress Irritability Domain - Observer-rated | 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, 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). |
| Neuropsychiatric Inventory-Distress Aggression Domain - Observer Rated | 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. 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). |
| St. Andrews-Swansea Neurobehavioural Outcome Scale - Observer-rated | Day 91 | 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). |
| Global Impressions of Change - Observer-rated | Day 91 | 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. |
| Personal Health Questionnaire - Participant-rated | Day 91 | 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. |
| Generalized Anxiety Disorder - Participant-rated | 91 day | 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. |
| Traumatic Brain Injury-Quality of Life Anger - Participant-rated | Day 91 | 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. |
| Clinical Global Impressions -- Global Improvement -- Clinician Rated. | Day 91 | 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". |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFlora Hammond, MD
Indiana University/Rehabilitation Hospital of Indiana
Participant flow
Recruitment details
Recruitment occurred from May 2013 through September 2025 via support groups, physician correspondence, clinical referrals, and newsletters.
Pre-assignment details
Subject's observers were not enrolled.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 14 |
| General Anxiety Disorder (GAD-7) - Participant-rated | 8.7 Score STANDARD_DEVIATION 6.3 |
| Neuropsychiatric Inventory-Aggression (NPI-A) -- Observer-rated | 6.7 Score STANDARD_DEVIATION 3.5 |
| Neuropsychiatric Inventory-Aggression (NPI-A) -- Participant-rated | 4.8 Score STANDARD_DEVIATION 3.7 |
| Neuropsychiatric Inventory-Irritability (NPI-I) -- Observer-rated | 7.9 Scores on a scale STANDARD_DEVIATION 2.6 |
| Neuropsychiatric Inventory-Irritability (NPI-I) -- Participant-rated | 6.2 Scores on a scale STANDARD_DEVIATION 3.4 |
| Personal Health Questionnaire (PHQ)-9 - Participant-rated | 9.8 Score STANDARD_DEVIATION 5.6 |
| Race/Ethnicity, Customized Black | 6 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 35 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 28 Participants |
| TBI-Quality of Life -- Participant-rated | 59.9 T-score STANDARD_DEVIATION 7.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 40 |
| other Total, other adverse events | 24 / 41 | 22 / 40 |
| serious Total, serious adverse events | 0 / 41 | 1 / 40 |
Outcome results
None listed