The proposed research will replicate and extend our studies of cerebral asymmetry and depression. In the prior grant period, the investigator used PET measures of regional cerebral glucose metabolism, along with simultaneously recorded brain electrical activity (EEG) to examine patterns of conical and subcortical activity in melancholic and nonmelancholic depressives when they were acutely depressed and then after a course of treatment with nortriptyline. The research conducted during the prior phase was restricted to examining relations between measures of regional brain function and self-report or interview-based indices of symptomatology and emotion. The investigators findings indicated that PET and EEG measures of prefrontal activation asymmetry were significantly correlated and predicted depressive symptomatology. The analysis of the EEG data to date indicate robust differences between melancholic and nonmelancholic subtypes, with the former characterized by decreased left prefrontal activation, while the latter was characterized by increased right prefrontal activation. The PET measures further revealed a circuit that included the amygdala, hypothalamus, parietal cortex, along with medial prefrontal regions that distinguished between depressed and control subjects. Moreover, metabolic activity in these regions predicted the magnitude of response to antidepressant medication. The indices of cortical metabolism changed with treatment but amygdala metabolism did not. In the next phase of this research program, the investigator will address a number of questions that have emerged from the previous phase. He will examine the relation between EEG and PET measures of regional brain function and experimental measures of reactivity to and recovery from standardized positive and negative affective stimuli. These studies will utilize emotion-modulated startle and classical conditioning to make inferences about emotional reactivity and recovery. These methods provide important clues to the mechanisms which underlie affective differences among the investigator's groups. These measures will be obtained on four separate occasions. First during an acute episode when all patients are off medication. Second, patients will then be treated with paroxetine and will be retested after meeting criteria for recovery. Patients will be maintained on paroxetine for 12 months following recovery. A third testing session will be held 6 months after the second. The fourth testing session will be held when patients have had a recurrence or after 12 months have elapsed. During each assessment period, subjects will undergo an FDG-PET scan, and will be administered the emotion-modulated startle and conditioning protocols. This design will permit the investigator to separate the effects of medication versus symptom change in examining within subjects change in brain function and behavior. It will also enable him to rigorously examine those patterns of brain function that predict treatment response and recurrence and to identify the patterns of brain function associated with group differences in emotional reactivity and recovery.
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