Effects of risperidone on the peripheral noradrenegic system in patients with schizophrenia: a comparison with clozapine and placebo

Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in risperidone-treated patients and compared their data with those from patients treated with clozapine or placebo. NE levels in risperidone patients were significantly higher than in placebo patients, but lower than in clozapine patients. Neither drug, however, had significant effect on plasma levels of the main neuronal metabolite of NE, dihydroxyphenylglycol (DHPG), suggesting that adrenoceptors blockade alone would not explain the NE findings. The rate of release of endogenous NE into the bloodstream (spillover) was elevated in both risperidone and clozapine patients in a manner that paralleled their NE levels; the NE clearance in both groups did not differ from placebo. Following 3H-NE infusion in risperidone-treated individuals, production of 3H-DHPG was normal, as it was in the clozapine group, suggesting that risperidone does not impede neuronal uptake or intraneuronal metabolism of NE by monoamine oxidase. Our data suggest that both risperidone and clozapine elevate plasma NE levels via enhanced neurotransmitter spillover, with risperidone producing a smaller effect.