Pilot Trial of Neural Correlates of Response to Treatment of PTSD-Associated Impulsive Aggression

Objective One: One study objective is to evaluate potential effect sizes of phenytoin and
cognitive behavioral therapy for PTSD-related impulsive aggression.

Hypothesis: Phenytoin and cognitive behavioral therapy are hypothesized to be effective in
the treatment of PTSD-related impulsive aggression based on studies previously outlined.

Plan: Patients enrolled in this pilot study will be randomized to receive an eight-week
course of treatment with phenytoin or cognitive behavioral therapy in the Trauma Recovery
Program at the Veterans’s Affairs Medical Center in Houston, Texas.

Objective Two: Another study objective is to begin to attempt to delineate potential neural
correlates of treatment-related reductions in PTSD-related impulsive aggression.

Hypothesis: Potential neural correlates of treatment-related reduction in intensity and/or
severity of impulsive-aggressive acts are hypothesized to include changes in: 1) thalamic
activation reflecting more effective thalamic sensory gating, with anticipation of increased
activation of the thalamus post-treatment 2) activation of brain regions associated with
verbal information processing, with the anticipation of increased activation of these
regions post-treatment 3) activation of prefrontal regions, including the anticipation of
increased activation of the medial and/or orbital prefrontal cortex post-treatment, 4)
amygdalar activation, with the anticipation of decreased activation of the amygdala
post-treatment 5) hippocampal activation, with the anticipation of increased activation of
the hippocampus post-treatment, and/or, 6) right-left hemispheric dissociation of brain
processing of stimuli, with the anticipation of greater degrees of bilaterality of brain
processing of stimuli post-treatment. Specifically, greater degrees of activation of left
hemispheric brain structures are anticipated in post-treatment fMRI scans.

Plan: Patients with PTSD-associated impulsive aggression will undergo an eight-week course
of treatment with phenytoin or CBT. Treatment-related changes in impulsive-aggressive acts
will be correlated with changes in brain activation comparing pre- and post-treatment fMRI
scans utilizing a standardized Go-No Go task which has been used in the study of impulsive
aggressive individuals.

Inclusion Criteria:

- Inclusion Criteria for both groups will be right-handed adult combat veterans over the
age of 18 who meet criteria for PTSD via Structured Clinical Interview (SCID-I, First,
2002) and Impulsive Aggression as the primary diagnoses. To be included in the study with
a designation of Impulsive Aggression, patients must have committed at least three
aggressive acts over the preceding three months meeting criteria for impulsive aggressive
acts by Impulsive/Premeditated Aggression Scales (IPAS) criteria (Stanford et al 2003)
based on a semi-structured interview of the patient and his/her significant other. An
impulsive aggressive act is defined as a hair-trigger, non-premeditated response to a
stimulus that results in an immediate aggressive act or an agitated state that culminates
in an aggressive act, which is clearly disproportionate to the triggering stimulus.
Inclusion criteria for both groups also includes the availability for participation of a
significant other who can participate in the study. The significant other will need to
accompany the study participant to the initial assessment interview and complete measures
of aggressive acts which have been committed by the study participants in the three months
prior to the start of the study, and aggressive acts during the previous two weeks at
two-week interval follow-up visits throughout the eight-week treatment period.

Exclusion Criteria:

- Exclusion Criteria for both groups will include exclusion criteria for MRI scanning,
and known claustrophobia requiring sedation in the past during MRI scanning. MRI
exclusion criteria will include metallic implants, implanted devices of any kind,
such as a cardiac pacemaker, cardiac defibrillator, insulin pump, vagal nerve
stimulator, cochlear implant, metallic splinters in the eye, ferromagnetic clips or
metal in the head or brain (as from previous injury or head/brain surgery including
brain aneurysm clipping), lead wires of any kind, clips or stints anywhere in the
body, such as clips for arterial aneurysm clipping, stints in cardiac arteries or
other arteries anywhere in the body, prosthetic heart valves, stapedial implants of
any kind (implants in the inner ear).