Noradrenergic and neuroradiological abnormalities in tardive dyskinesia.

Previous studies suggest that catecholaminergic overactivity and structural brain damage may contribute to the pathogenesis of tardive dyskinesia (TD). Although dopaminergic (DA) mechanisms, specifically postsynaptic receptor supersensitivity, have been extensively studied, equally plausible noradrenergic (NE) changes have been all but ignored. Likewise, the interaction of neurochemical and neuroradiological abnormalities has received little attention. Over the past 6 years, 111 inpatients were studied with a battery of neurological, behavioral, biochemical, and neuroradiological measures. Forty-one patients met specific diagnostic criteria for TD, based in part on global ratings on the Abnormal Involuntary Movement Scale. Subgroups of patients were also evaluated with the Brief Psychiatric Rating Scale and were assayed for plasma dopamine-beta-hydroxylase (DBH) activity, platelet 3H-dihydroergocryptine (3H-DHE)-alpha 2 adrenergic receptor binding, lumbar cerebrospinal fluid (CSF) monoamines and metabolites [NE, 3-methoxy-4-hydroxyphenylglycol (MHPG), DA-sulfate, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC)], and CT scan indices of brain atrophy, including ventricle/brain ratio (VBR), bifrontal/bicaudate ratio, and cortical atrophy. All patients were studied in the steady state, primarily when free of neuroleptics. Patients with TD had significantly greater DBH activity than those without TD. In addition, 3H-DHE binding and CSF NE were significantly correlated with the severity of TD when present. Finally, TD patients with low DBH activities (below the mean) had significantly larger ventricles than non-TD patients with low DBH activities. Other data suggested that subcortical, rather than cortical, atrophy was more likely to be responsible for the larger VBR in the low DBH TD group. These results suggest an association of NE overactivity and TD in a portion of patients. Moreover, the presence of neuroradiological abnormalities in TD patients with low DBH activity underscores the contribution of heterogeneous factors to the pathogenesis of this disorder and may provide one possible explanation for the discrepant biochemical findings in TD reported by earlier investigators.