The Effect of Clozapine on Plasma Norepinephrine: Relationship to Clinical Efficacy

Abstract

Clozapine is an atypical neuroleptic medication with superior efficacy to conventional antipsychotic agents for patients with chronic, symptomatic schizophrenia. Neurochemical characteristics that distinguish clozapine from other neuroleptics and contribute to its differential efficacy are not known. We assessed the effects of clozapine on plasma levels of norepinephrine (NE) in a double-blind, parallel groups comparison of clozapine (n = 11) and haloperidol (n = 15) in chronic schizophrenic outpatients who had been previously treated with fluphenazine. Simultaneous measurements were obtained for plasma levels of the catecholamine precursor dopa, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), the NE metabolite 3,4-dihydroxyphenylglycol (DHPG), adrenocorticotropin (ACTH), cortisol, and hemodynamic parameters. Clozapine produced marked increases (471%) in plasma NE levels, whereas haloperidol 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 blood pressure. Across patients, the magnitude of clozapine-induced increments in plasma NE levels was positively related to improvement in positive symptoms and global symptomatology and was unrelated to the occurrence of extrapyramidal symptoms. The results suggest that clozapine differs importantly from other neuroleptics in increasing plasma NE levels, with the peripheral noradrenergic stimulation related to its superior efficacy profile. The unchanged DHPG levels and absence of hypertension suggest a more complex mechanism of action of clozapine than heightened NE release alone.

Effects of Risperidone on the Peripheral Noradrenegic System in Patients with Schizophrenia A Comparison with Clozapine and Placebo

“…On the other hand, as with clozapine, risperidone did not alter DOPA and DOPAC levels, or the time-related changes in the 3 H-DHPG/ 3 H-NE ratio following 3 H-NE infusion. Although some prior clinical studies support the noradrenergic system's involvement in the treatment response to clozapine (Breier et al 1994b;Schulz et al 1997;Fleischhaker et al 1998), no such data are available for risperidone (See et al 1999), and no inferences can be made about risperidone's therapeutic mechanisms of action from this investigation that was primarily focused on its pharmacokinetic effects. Nonetheless, peripheral NE measures are important because a considerable amount of animal data, where peripheral and central measures were collected simultaneously in the presence of an effective blood-brain barrier, suggest that plasma measures may reflect directionally similar changes in the brain (Ziegler et al 1977; Jimerson et al Figure 1.…”

“…Our previous work suggested that clozapine has complex effects on the noradrenergic system, producing a robust increase in NE, but without an expected proportional increase in DHPG (Breier et al 1994b;Elman et al 1999). We hypothesized, based on the receptor binding profile of risperidone, that patients treated with the drug would display different characteristics of the noradrenergic response than their clozapine-treated counterparts.…”

“…This search has resulted in the introduction of four "newer atypical APDs" (i.e., risperidone, olanzapine, quetiapine, and ziprasidone), all of which have important effects on both dopaminergic and serotonergic neurotransmitter systems. Because none of these compounds has been proven as efficacious as the prototype, clozapine, in the treatment of resistant cases, continued research is focusing on other neurotransmitter systems affected by clozapine.Clozapine profoundly increases norepinephrine (NE) levels in both CSF (Ackenheil 1989;Lieberman et al 1989;Lieberman et al 1991;Pickar et al 1992) and plasma (Pickar et al 1992;Green et al 1993;Davidson et al 1993;Breier 1994;Breier et al 1994b;Schulz et al 1996;Schulz et al 1997;Brown et al 1997;Fleischhaker et al 1998;Elman et al 1999), an effect not seen with typical APDs. In some (Breier et al 1994b;Schulz et al 1997;Fleischhaker et al 1998), but not all (Brown et al 1997) studies, plasma NE increases have been related to clinical improvement, suggesting that this pharmacological effect may play a role in clozapine's beneficial central actions.…”

“…Because formation of 3 H-dihydroxyphenylglycol (DHPG) from 3 H-NE requires both neuronal uptake and intraneuronal deamination by MAO, measurement of plasma 3 H-DHPG responses furnished the basis for examining the effects of risperidone. Plasma levels of the NE precursor, dihydroxyphenylalanine (DOPA), and of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), were also measured to provide information about NE synthesis (Goldstein et al 1987;Goldstein 1995) and about intraneuronal metabolism by monoamine oxidase (MAO; Goldstein 1995).Our previous work suggested that clozapine has complex effects on the noradrenergic system, producing a robust increase in NE, but without an expected proportional increase in DHPG (Breier et al 1994b;Elman et al 1999). We hypothesized, based on the receptor binding profile of risperidone, that patients treated with the drug would display different characteristics of the noradrenergic response than their clozapine-treated counterparts.…”

“…In some (Breier et al 1994b;Schulz et al 1997;Fleischhaker et al 1998), but not all (Brown et al 1997) studies, plasma NE increases have been related to clinical improvement, suggesting that this pharmacological effect may play a role in clozapine's beneficial central actions. In this context, findings implicating noradrenergic dysregulation in the pathophysiology of schizophrenia (Stein and Wise 1971;Sternberg 1984;Breier et al 1990; Rao and Moller 1994;Breier 1994;Yamamoto et al 1994;Litman et al 1996;Breier et al 1998;Goff and Evins 1998;Friedman et al 1999a;Friedman et al 1999b;Klimek et al 1999) further support inquiry into the relevance of noradrenergic mechanisms in the action of APDs.…”