Correlated Changes in Symptoms and Neurotransmitter Indices during Maintenance Treatment with Clozapine or Conventional Neuroleptics in Adolescents and Young Adults with Schizophrenia

Abstract

A study of 40 young patients (age 14-22 years) with DSM-III-R schizophrenia (without substance abuse) was conducted following a mean of 3.4 years of neuroleptic treatment. After failing on conventional agents in clinical trials lasting a mean of 2 years, 20 patients were prospectively maintained on open-label clozapine (mean 324 mg daily), and another 20 patients continued on typical neuroleptics (mean 465 mg chlorpromazine-equivalents daily). Patients were then sampled for biochemical measures and assessed for psychopathology (Brief Psychiatric Rating Scale, Scales for the Assessment of Positive/ Negative Symptoms) on six occasions at consecutive 6-week intervals-during maintenance treatment on clozapine or conventional neuroleptics. There were 22-fold interindividual differences in clozapine levels and also high intraindividual differences over time. Maintenance dosage was linearly related to plasma levels of clozapine and its metabolites. Prolactin levels were elevated with typical neuroleptics but not clozapine. Blood levels of serotonin, methoxyhydroxyphenylglycol (MHPG), norepinephrine, and epinephrine (but not dopamine) were significantly higher in clozapine-treated patients than in conventionally treated patients. Higher serotonin levels were associated with significantly fewer negative symptoms, whereas higher MHPG levels were correlated with less depression. These findings suggest involvement of norepinephrine and serotonin in the pathophysiology of schizophrenia (with depression associated with lower MHPG levels and negative symptoms associated with lower serotonin levels) and in the therapeutic actions of clozapine. Speculatively, a treatment strategy of targeting specific neurotransmitter systems might be based on the presence of specific symptoms in adolescents and young adults with schizophrenia.

Blood biogenic amines during clozapine treatment of early-onset schizophrenia

“…In agreement with our previous report including 40 adolescent patients with a one-year follow-up (Schulz et al, 1996), this six-week study confirmed that over the course of treatment the serum levels of serotonin increased during clozapine medication as compared to pretreatment levels. B anki (1978) first described elevated total blood serotonin concentrations due to clozapine treatment in adults.…”

“…The finding of markedly increased plasma norepinephrine levels is in agreement with our results on long-term clozapine treatment (Schulz et al, 1996) and concurs with studies in adult patients, which report clozapine-induced increases in plasma and/or CSF levels of norepinephrine in adults with schizophrenia (Breier et al, 1994;Green et al, 1993;Lieberman et al, 1991;Pickar et al, 1992). Breier et al (1994) reported that clozapine produced a significant increase in plasma norepinephrine levels and that this increase was positively correlated with a reduction in symptoms as assessed with BPRS total scores and positive symptom scores.…”

“…Plasma catecholamines, plasma level of 3-methoxy-4-hydroxyphenylglycol (MHPG), and serum serotonin concentrations were measured as previously described (Schulz et al, 1996) by HPLC kits (Catechol-Kit No. 5000, Serotonin-Kit No.…”

Predictors and markers of clozapine response

“…Responders showed increased plasma MHPG and epinephrine during clozapine treatment compared to pretreatment with typical antipsychotics, whereas nonresponders did not. Plasma NE and 5-HT increased following clozapine treatment, but did not differentiate responders and nonresponders Schulz et al 1996 40…”

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

“…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.…”