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

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.

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 or bipolar disorder

- Diagnosis of progressive or additional neurologic disease

- Clinical signs of active infection