Effects of metabolic perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume.

OBJECTIVE

Several recent hypotheses suggest that deficits in normal prefrontal cortical inhibition of subcortical dopamine activity result in dysregulated dopamine function and may contribute to the pathophysiology of schizophrenia. These effects seem to be more consistently demonstrable during stressful perturbation of the dopamine system, as opposed to during the resting state. We have developed a novel paradigm involving infusion of the glucose analog, 2-deoxyglucose (2DG), to examine the effects of perturbation on the dopamine metabolite, plasma homovanillic acid (HVA), in schizophrenics and healthy controls.

DESIGN

Pharmacologic doses of 2DG (50 mg/kg) and placebo were infused in a double-blind manner. 2-Deoxyglucose-induced effects on plasma HVA were related to magnetic resonance imaging-derived prefrontal cortex volumes.

SUBJECTS

Schizophrenic outpatients (N = 18) and healthy volunteers (N = 11) participated in the study.

RESULTS

Schizophrenic patients, as compared with controls, had significantly greater 2DG-induced plasma HVA elevations. These effects were observed in subgroups of neuroleptic-free and neuroleptic-treated patients. Other neuroendocrine (plasma cortisol), physiologic (heart rate, diastolic blood pressure, temperature) and behavioral (self-ratings of stress, fatigue) variables were significantly effected by 2DG but did not differeniate schizophrenics and controls suggesting that the effects on plasma HVA may be relatively specific. Magnetic resonance imaging-derived volumes of the prefrontal cortex were significantly and inversely correlated to 2DG-related peak changes in plasma HVA levels in the schizophrenics.

CONCLUSION

These data support the hypothesis that schizophrenia is associated with abnormal regulation of dopamine and that this deficit may be related to reduced frontal cortical inhibitory influences.