Chronic neuroleptic treatment is associated with various tardive and withdrawal manifestations in the human patient which are generally ascribed to dopamine (DA) receptor supersensitivity. Although well studied in the experimental animal, little clinical biochemical or neuroanatomic data have been collected in the living human patient to explain human tardive or withdrawal syndromes. Therefore, we propose to study 30 schizophrenic patients (15 with and 15 without tardive dyskinesia) using positron emission tomography (PET) with fluoro-deoxyglucose (FDG) before, and during a one month course after neuroleptic withdrawal. The abrupt neuroleptic withdrawal design was chosen to stimulate or intensify the regional metabolic changes associated with chronic neuroleptic treatment. Patients with and without tardive dyskinesia were included to compare the regional metabolic changes associated with """"""""tardive,"""""""" as compared to """"""""non-tardive,"""""""" conditions. All individuals in this protocol will receive three PET/FDG scans: before, 3-5 days after, and one month after abrupt haloperidol withdrawal. In addition, clinical assessments of mental status (BPRS) and motor function (MPRC scale), and sleep and biochemical (plasma prolactin and homovanillic acid) measurements will be done before and throughout the withdrawal period. Changes in regional cerebral glucose uptake with abrupt neuroleptic withdrawal (3-3 day post withdrawal scan) will be compared with the regional glucose uptake during chronic treatment and at the """"""""drug-free"""""""" point (4 week post withdrawal scan). These PET/FDG changes will be correlated with maximum alterations in sleep characteristics and biochemical measures during the withdrawal period. In a pilot study, sleep characteristics, prolactin concentrations, and dyskinesia scores changed in a predicted """"""""supersensitive"""""""" pattern with abrupt neuroleptic withdrawal; mental status responses have been more individualistic. These data have provided the impetus for studying PET/FDG alterations over the course of neuroleptic withdrawal in patients with and without tardive manifestations. In the future, we would hope to study the biochemical basis of the PET/FDG withdrawal changes more precisely as they might explain these tardive phenomena.
