Carbamazepine for the Treatment of Chronic Post-Traumatic Brain Injury Irritability and Aggression

It is anticipated that 74 subjects with 74 corresponding subject informants will be
recruited at Carolinas Rehabilitation. Subjects will be recruited from the clinic at
Carolinas Rehabilitation. Subjects will also be referred by psychiatrists at North Carolina
Neuropsychiatry.

Subjects who consent and qualify will be randomized in a 1:1 ratio to Tegretol® or placebo.
Stratification to randomization group will occur based on the presence of depression defined
by a BDI-II score ≥ 13. Subjects randomized to active drug will be titrated up in dose, as
tolerated, over a period of 3 weeks. Starting dose is 200mg twice daily to 200mg three times
daily to 200mg, 2 tabs, twice daily. There will be 3 clinic visits. Visits will occur at
baseline for consenting and screening, day 28, and day 42. Follow up phone calls will occur
each week that the subject is not seen in the clinic until the end of the study. Follow up
phone calls will assess for study medication compliance, adverse events and concomitant
medication changes. Day 42 ends the period of the Randomized Clinical Trial phase of the
study and the subjects will begin the 1 week of taper of Tegretol® at 400mg daily and then
stop drug. A safety phone call will be made at day 49.

The following questionnaires will be used as measures of irritability for the subject and
the informant: Neuropsychiatric Inventory (NPI), State Trait Anger Expression Inventory
(STAXI-2), and Global Impression of Change. The following 3 questionnaires will be dispensed
to the subject only: Beck Depression Inventory, Brief Symptom Inventory, and Fatigue Impact
Scale. The Investigator will complete the Clinical Global Impression of change at Visits 2
and 3.

History and Physical Exam, hematology, chemistry, including renal and liver function studies
will be obtained for safety and tolerability. Serum pregnancy tests will be drawn at
screening for females of childbearing potential. Carbamazepine levels will be drawn at
visits 2 and 3.

Inclusion Criteria:

- Closed head injury (defined as impaired brain function resulting from externally
inflicted trauma without penetrating injury) at least 6 months prior to enrollment

- Age at time of enrollment: 16 to 70 years

- Voluntary informed consent of patient and informant

- Subject and informant willing to comply with the protocol

- Informant-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 42-day participation No surgeries planned during the
42-day participation Vision, hearing, speech, motor function, and comprehension
sufficient for compliance with all testing procedures and assessments

- Informant (e.g. family member or close friend) with daily interaction in order to
observe occurrences of irritability

Exclusion Criteria:

- Potential subject without a reliable informant

- Penetrating head injury

- Injury < 6 months prior to enrollment

- Ingestion of CBZ during the month prior to enrollment

- Inability to interact sufficiently for communication with caregiver

- Acute and rehabilitation records unavailable or incomplete

- DSM-IV diagnosis of schizophrenia or psychosis

- Diagnosis of progressive or additional neurologic disease

- Clinical signs of active infection

- Creatinine clearance <60 mL/min

- Liver function tests > 2x normal values

- Pregnancy (Beta-HCG + females of child-bearing potential); lactating females;
sexually active females who do not agree to use birth control

- Hormonal birth control as only means of birth control if sexually active and of child
bearing age potential due to CBZ effect of lowering hormone levels, and potentially
effectiveness

- Concurrent use of the following medicines due to potential for drug interaction:
macrolides, rifabutin, doxycycline, nicoumalone, warfarin, fluoxetine, fluvoxamine,
viloxazine, nefazodone, tricyclic and tetracyclic antidepressants, clobazam,
clonazepam, lamotrigine, phenytoin, sodium valproate, tigabine and topiramate,
phenobarbitone, primidone, chloroquine and mefloquine, antipsychotics, indinavir,
nelfinavir, saquinavir, ritonavir, diltiazem, verapamil, felodipine, isradipine,
nicardipine, nifedipine, cimetidine, cyclosporins, corticosteroids, gestrinone and
toremifene, danazol, tibolone

- Suicidal ideation

- Concurrent use of Monoamine Oxidase Inhibitors (MAOIs) or ingestion of MOAI within 2
weeks before starting study

- Hypersensitivity/allergy to CBZ, any of the ingredients in CBZ, or any structurally
related drugs (e.g. the tricyclic antidepressants)

- History of liver failure or hepatitis

- History of renal failure

- History atrio-ventricular (AV) conduction abnormalities unless paced

- History of bone marrow depression

- History of porphyria