The proposed studies are designed to evaluate regional brain glucose metabolism in response to the administration of 0.4 mg/kg, 0.8 mg/kg of d-fenfluramine and placebo to test the hypothesis that fenfluramine-induced changes in brain metabolism of the orbital frontal cortex and adjacent ventral medial frontal cortex (primary hypothesis) as well as temporal and cingulate cortex (secondary hypotheses) are blunted in patients with impulsive/aggressive personality disorders. These studies build on a body of evidence that reduced serotonergic activity as reflected in reduced neuroendocrine responses to serotonergic challenges or diminished concentrations of serotonin metabolites is associated with impulsive aggression in personality disorder patients. They provide an opportunity to directly visualize serotonergic modulation of metabolism of key brain regions implicated in the regulation of aggression.
The specific aims of this proposal are to: 1) identify and clinically characterize 40 impulsive personality disordered patients (20 males, 20 females) (as defined by DSM-IV criteria in Methods) as well as 30 nonimpulsive personality disordered patients (15 males, 15 females) and 30 normal volunteer control subjects (15 males, 15 females) over four years, 2) administer d-fenfluramine at a dose of 0.4 mg/kg and placebo in a randomized double-blind placebo controlled design on two separate days before PET scanning, 3) administer a higher dose of fenfluramine (0.8 mg/kg) on a third day in half of the sample randomly assigned to the third day (20 impulsive aggressive patients, 15 nonimpulsive aggressive patients and 15 normal control subjects-- blind to the order of d-fenfluramine dose/placebo regimen), 4) obtain and analyze blood samples for prolactin, d-fenfluramine and d-norfenfluramine levels prior to and following fenfluramine and for prolactin following placebo administration, and 5) evaluate and compare brain glucose metabolism in the hypothesized regions of interest as well as prolactin following the fenfluramine dose(s) and placebo between the three groups.
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