The proposed studies are designed to better understand the etiologic role of serotonergic abnormalities in impulsive aggressive personality disordered patients and their prediction of response to and change with fluoxetine. We propose to evaluate 5-hydroxytryptophan transporter (5-HTT) binding of [11C] DASB binding in the anterior cingulate and 5-HT2A receptor binding of [11C] MDL100907 in the orbital frontal cortex in 60 patients with impulsive aggressive personality disorders with current physical aggression at baseline prior to a twelve week treatment trial of fluoxetine or placebo (4:1, active:placebo) and 20 normal volunteer healthy controls, and will perform a second evaluation of 5-HT2A receptor binding within the final two weeks of the fluoxetine/placebo trial in the patients. It is hypothesized that 5-HTT binding will be reduced in impulsive aggressive personality disorder patients with current physical aggression compared to normal controls and the degree of transporter reduction will be predictive of poorer response to fluoxetine. It is hypothesized that 5- HT2A binding in the orbital frontal cortex will be increased in patients with current physical aggression and that the 5-HT2A binding will significantly decrease from baseline following the twelve week treatment with fluoxetine compared to placebo (stratified 4:1, active:placebo) in 50 of the patients (40 fluoxetine and 10 placebo). It is hypothesized that reductions in 5-HT2A binding in the orbital frontal cortex will be correlated with reductions in OAS-M scores following fluoxetine treatment. The specific objectives of this proposal are to: 1) To characterize [11C] MDL100907 binding to the 5-HT2A receptor in orbital frontal cortex and to characterize [11C] DASB binding to the 5HTT in the anterior cingulate cortex in 60 IED-R patients with personality disorders and 20 matched healthy volunteer control subjects. 2) To characterize [11C] MDL100907 binding to the 5- HT2A receptor in the orbital frontal cortex in 50 IED-R patients following 12 weeks of treatment with fluoxetine or placebo.
Impulsive aggression is an important public health problem. These studies will help our understanding of an important brain chemical, serotonin, which is related to aggression, and how it is affected by antidepressants that increase serotonin.
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