Blood biogenic amines during clozapine treatment of early-onset schizophrenia

Abstract

The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14-22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 +/- 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11-20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n = 7) and nonresponders (n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therape...

Serotonin and Schizophrenia

“…The increase in peripheral 5-HT concentrations reported in the early studies was apparently not an artifact of medication, as no in vivo effect of antipsychotics on platelet 5-HT could be demonstrated (Bleich et al, 1991). On the contrary, accumulating evidence suggests that treatment with clozapine and other atypical and typical antipsychotics increases 5-HT plasma levels in schizophrenia patients (Joseph et al, 1977;Schulz et al, 1997;Fleischhaker et al, 1998;van der Heijden et al, 2004;Ertugrul et al, 2007). These findings suggest that antipsychotics still have an impact on peripheral 5-HT concentrations and indicate that medication may have indeed influenced previous results.…”

Predictors and markers of clozapine response

“…Higher baseline plasma HVA corresponded to better improvement in BPRS positive scores at 6 weeks in responders, but not in nonresponders Schulz et al 1997 15…”

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.…”

“…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 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.…”