THE EFFECT OF CLOZAPINE ON PLASMA NOREPINEPHRINE - RELATIONSHIP TO CLINICAL EFFICACY

Clozapine is an atypical neuroleptic medication with superior efficacy to conventional antipsychotic agents for patients with chronic, sympt omatic schizophrenia. Neurochemical characteristics that distinguish c lozapine from other neuroleptics and contribute to its differential ef ficacy are not known. We assessed the effects of clozapine on plasma l evels of norepinephrine (NE) in a double-blind, parallel groups compar ison of clozapine (n = 11) and haloperidol (n = 15) in chronic schizop hrenic outpatients who had been previously treated with fluphenazine. Simultaneous measurements were obtained for plasma levels of the catec holamine precursor dopa, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), the NE metabolite 3,4-dihydroxyphenylglycol (DHPG), adr enocorticotropin (ACTH), cortisol, and hemodynamic parameters. Clozapi ne produced marked increases (471%) in plasma NE levels, whereas halop eridol had no significant effects on plasma NE levels. Clozapine also increased dopa and tended to increase DOPAC levels, without effects on DHPG, ACTH, or cortisol levels and without consistent changes in bloo d pressure. Across patients, the magnitude of clozapine-induced increm ents in plasma NE levels was positively related to improvement in posi tive symptoms and global symptomatology and was unrelated to the occur rence of extrapyramidal symptoms. The results suggest that clozapine d iffers importantly from other neuroleptics in increasing plasma NE lev els, with the peripheral noradrenergic stimulation related to its supe rior efficacy profile. The unchanged DHPG levels and absence of hypert ension suggest a more complex mechanism of action of clozapine than he ightened NE release alone.