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

Abstract

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 ( 3 H-NE) in risperidone-Clozapine is an atypical antipsychotic drug (APD) with efficacy superior to that of conventional agents and with little or no extrapyramidal signs or symptoms (EPS) (Kane et al. 1988;Lieberman et al. 1989;Breier et al. 1994a;Meltzer 1995;Meltzer et al. 1996). Because these advantageous therapeutic properties are accompanied by unusually severe side effects, scientists have been searching for clozapine-like APDs that would share its beneficial features but not induce bone marrow toxicity, seizures, or hypotension. 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. 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.We have reported previous data suggesting that high plasma NE levels in clozapine-treated patients result from increases in the appearance rate of the endogenously released NE in the plasma (spillover) rather than from decreased neuronal uptake of NE, inhibition of intraneuronal monoamine oxidase (MAO), or adrenoceptor antagonism . Risperidone, the next atypical antipsychotic drug marketed in the United States after clozapine, is associated with a low incidence of EPS and may have improved efficacy compared with conventional agents (Kane and McGlashan 1995;Pickar 1995;Campbell et al. 1999). Interestingly, risperidone has also recently been observed in a clinical study to produce a modest (i.e., 58%) inc...

Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics

“…Briefly, mRNA of the DA receptors peaked at week 2 after taking antipsychotics, after which it decreased but was above baseline at week 8 [76,77] . Finally, it has been reported that both risperidone and clozapine elevate plasma NE levels, with risperidone producing a smaller effect [85] . Logically, considering their close ties with the pharmacological properties of antipsychotics, peripheral monoamine related molecules might be a good indicator for treatment response but current evidence to support this posit is lacking.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Likewise, potential contributions to weight gain of norepinephrine (Elman et al, 2002(Elman et al, , 2004 and prolactin (Melkersson, 2005;Mann et al, 2006) increases associated with SGA treatment are still unclear. The findings of SGA effects on the brain BDNF (Bai et al, 2003;Luo et al, 2004;Angelucci et al, 2005) and orexin in preclinical literature may be also of potential importance as both neurochemicals are involved in reward and appetitive functions; however, their precise role and how they are influenced by SGAs in humans (Dalal et al, 2003;Weickert et al, 2005) are intriguing topics for future research.…”

Clinical Assessment of Norepinephrine Transporter Blockade Through Biochemical and Pharmacological Profiles

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