This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This project proposes to test the effects of guanfacine hydrochloride, a Food and Drug Administration (FDA)-approved alpha-2 adrenergic agonist, in borderline personality disorder (BPD), a prevalent and disabling disorder characterized by affective lability, impulsive aggression, cognitive-perceptual disturbances and unstable interpersonal relationships. The available treatments for BPD are notorious for their variable and limited efficacy, and many of these treatments carry significant risks of somatic toxicity and/or psychiatric deterioration. Guanfacine is a safe agent that has been used in physically vulnerable populations including children (for attention-deficit hyperactivity disorder) and medically compromised adults (for hypertension, for which it is FDA-approved). By stimulating alpha-2 adrenoreceptors in prefrontal cortex, guanfacine has been shown to enhance attention and reduce behavioral dysregulation. We believe that guanfacine represents an important, novel and promising treatment for BPD in that it has the potential to ameliorate one of the core disturbances of the disorder - relatively hypoactive or ineffective modulation of affect and behavior by the prefrontal cortex (particularly orbital frontal cortex), resulting in an imbalance between emotions arising from the amygdala/limbic system and 'top-down' control in higher brain centers. Hypotheses: 1) Guanfacine will decrease impulsive aggressive symptoms and improve emotional lability in borderline personality disorder compared to placebo.2) Borderline patients will show decreased activity at baseline in OFC and increased activity in amygdala compared to healthy comparison subjects. Borderline patients will show enhanced startle eyeblink modification in response to negative pictures compared to controls. Borderline patients will show deficits in cognitive tasks that particularly tap OFC function (e.g. the time perception task) compared to other frontal lobe function (e.g. a spatial working memory task). 3) Healthy control subjects will show stable responses in the regions of interest we are studying (OFC, amygdala) to emotional pictures over an 8 week period. 4) Guanfacine will increase activation in orbital frontal cortex and decrease amygdala activation as measured by BOLD response with fMRI in response to negative emotional pictures and decrease subjective ratings of the aversiveness of the negative pictures compared to placebo. Guanfacine will decrease the amplitude of the startle eyeblink enhancement to emotional pictures in borderline subjects, reflecting improved top-down control of amygdala activation compared to placebo. 5) Guanfacine compared to placebo will specifically improve function on those cognitive tasks that test orbital frontal activity (e.g. the time perception task) more than it will improve performance on tests of cognitive function that tap other brain regions such as dorsolateral prefrontal cortex (e.g. a spatial working memory task). Exploratory Hypothesis: (see Protocol, p. 7) 1) BPD subjects with the lowest activity in OFC in response to negative emotional stimuli and the highest enhancement of startle response to negative stimuli will be less likely to respond to guanfacine than those with responses that more closely resemble our healthy controls (e.g. more robust OFC response to negative emotional stimuli and more modest enhancement of startle response to negative stimuli).
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