Early childhood sexual abuse is an important public health problem that affects 16% of women before their 18th birthday and leads to chronic symptoms of posttraumatic stress disorder (PTSD) in as many as a third of women. Preclinical and clinical research has established a network of brain regions that are sensitive to stress and mediate PTSD symptoms, including decreased function in the hippocampus and anterior cingulate/medial prefrontal cortex, and increased function in the amygdala. During prior funding periods in women with early abuse related PTSD we have shown smaller hippocampal volume, a failure of hippocampal activation with declarative memory tasks, deficits in verbal declarative memory on neuropsychological testing, decreased anterior cingulate, medial prefrontal and hippocampal function, and increased amygdala function during fear acquisition, as well as smaller anterior cingulate volume. Little is known about the effects of treatment for PTSD on the brain. Such information may be useful in the development of better treatments for this disorder. Studies in animals have shown that treatment with antidepressants, including selective serotonin reuptake inhibitors (SSRI), promote neurogenesis in the hippocampus, which may even represent the mechanism of treatment response for these medications. Our pilot data has shown a 5% increase in hippocampal volume and improvements in neuropsychological testing of memory in patients with PTSD treated with paroxetine, as well as increases in medial temporal NAA. The current project assesses the effects of paroxetine on memory, brain structure and function in women with early childhood abuse related PTSD. Women with PTSD undergo baseline assessment with neuropsychological testing of memory, magnetic resonance imaging (MRI) for assessment of hippocampal volume and NAA, and high resolution positron emission tomography (PET) with PET O-15 water during verbal declarative memory and traumatic memory tasks. Women are then treated in a randomized double- blind fashion with paroxetine or placebo on a flexible dose schedule for three months, followed by a repeat of these assessments. All subjects then receive open label paroxetine for nine months followed by a repeat of all assessments. We hypothesize that paroxetine will result in an improvement in memory function, increased hippocampal volume and NAA, and increased frontal and hippocampal function ? ? ?
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