Maria Ancione

Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics

Abstract Rationale: Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial. Objective: The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics. Methods: Forty-five patients, 35 males and ten females, aged 19–65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less. Results: Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472±220 versus 328±128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201±104 versus 156±64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (rs=0.371, P<0.02), but not for norclozapine (rs=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%). Conclusions: These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350–400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations.

Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: A clinically relevant pharmacokinetic drug interaction

The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4–6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 ± 9 ng/mL at baseline to 56 ± 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9–204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-OH-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine.

Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients

The effect of adjunctive fluoxetine on negative schizophrenic symptoms was evaluated in 34 chronic schizophrenic in-patients on maintenance therapy with neuroleptics. They received randomly, on a double-blind basis, fluoxetine (20 mg/day) or placebo for 12 weeks. In the fluoxetine group, three patients dropped out because of side effects. Negative symptoms, as measured by change on the Scale for Assessment of Negative Symptoms at the end point compared to baseline values, were significantly improved in fluoxetine-treated patients (p < 0.001), but not in the placebo group. Fluoxetine treatment did not influence positive schizophrenic symptoms, while it induced a slight, but statistically significant, decrease (p < 0.05) in depressive symptoms, as measured by the Hamilton Rating Scale for Depression. Unwanted effects were more common among patients receiving fluoxetine. These data suggest that the addition of fluoxetine to neuroleptic treatment may be beneficial in some schizophrenic patients with negative symptoms.

Plasma risperidone concentrations during combined treatment with sertraline.

The effect of sertraline on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was studied in 11 patients with schizophrenia or schizoaffective disorder. To treat concomitant depressive symptoms, additional sertraline, at the dose of 50 mg/d, was administered for 4 weeks to patients stabilized on risperidone (4–6 mg/d). Mean plasma concentrations of risperidone, 9-OH-risperidone, and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) did not change significantly during combined treatment with sertraline. At the end of week 4, sertraline dosage was adjusted in some patients on the basis of the individual response and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the 4 patients who were still receiving the initial sertraline dose, but concentrations were slightly but not significantly increased (by a mean 15% over pretreatment) in the subgroup of 5 subjects treated with a final dose of 100 mg/d. In the 2 patients receiving the highest dose of sertraline, 150 mg/d, at week 8 total plasma risperidone concentrations were increased by 36% and 52%, respectively, as compared with baseline values. Sertraline coadministration with risperidone was well tolerated, and no patient developed extrapyramidal symptoms. These findings indicate that sertraline at dosages up to 100 mg/d is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of sertraline may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of sertraline on CYP2D6-mediated 9-hydroxylation of risperidone.

Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions

To evaluate the role of defective drug oxidation as a predisposing factor for neuroleptic‐induced dystonic reactions, 26 patients who developed the reaction and 53 with no history of dystonia were phenotyped by the debrisoquine hydroxylation test. The percentage of poor debrisoquine metabolizers was similar in patients with dystonic reactions (11.5%) and in the control group (9.4%). These results suggest that there is no association between the individuals drug oxidative status and the occurrence of neuroleptic‐induced dystonia.

No effect of reboxetine on plasma concentrations of clozapine, risperidone, and their active metabolites

The effect of reboxetine on steady-state plasma concentrations of the atypical antipsychotics clozapine and risperidone was studied in 14 patients with schizophrenia or schizoaffective disorder with associated depressive symptoms. Seven patients stabilized on clozapine therapy (250–500 mg/day) and seven receiving risperidone (4–6 mg/day) were given additional reboxetine (8 mg/day). After 4 weeks of reboxetine therapy, mean plasma concentrations of clozapine, norclozapine, and risperidone active moiety (sum of concentrations of risperidone and 9-hydroxyrisperidone) increased slightly but not significantly by 5%, 2%, and 10%, respectively. The mean plasma clozapine/norclozapine and risperidone/9-hydroxyrisperidone ratios were not modified during reboxetine treatment. Reboxetine coadministration with either clozapine or risperidone was well tolerated. These findings indicate that reboxetine has minimal effects on the metabolism of clozapine and risperidone and may be added safely to patients receiving maintenance treatment with these two antipsychotics.

Prevalence of acute dystonic reactions associated with neuroleptic treatment with and without anticholinergic prophylaxis.

The occurrence of acute dystonic reactions was intensively monitored in a population of 646 patients, 379 males and 267 females. aged 18–87 years, consecutively admitted to different psychiatric units and treated with neuroleptics alone or in combination with anticholinergic drugs. Thirty-four patients experienced acute dystonic reactions yielding a total incidence of 5.3%. There wasa tendency towards a higher frequency of dystonia in males than in females, and in young patients than in older ones. Patients without anticholinergic medication had a higher frequency of the reaction than those receiving anticholinergic drugs (8.5% vs. 2.8%; p < 0.02). Neuroteptic-induced dystonia was more common in patients treated with buthyrophenones than in those receiving phenothiazines or substituted benzamides.

Iron status in schizophrenic patients with acute neuroleptic-induced dystonic reactions

1. Serum iron parameters were measured in a group of schizophrenic patients who had developed acute neuroleptic-induced dystonia (N = 17) and in control patients with no history of extrapyramidal disorders (N = 16). No differences were found between the two groups for iron, ferritin or transferrin levels. 2. Iron status was estimated in 44 schizophrenic patients starting treatment with high-potency neuroleptics before and after 3 weeks of medication. In the 6 patients developing dystonia serum iron levels as well as other iron parameters did not differ from the values observed in the remaining 38 patients either on admission or after neuroleptic treatment. In each group the haematological profile was not modified by neuroleptic medication. 3. These results do not support an association between low serum iron and the occurrence of neuroleptic-induced dystonic reactions.