Risperidone concentrations

Spina E, D Arrigo C, Miglardi G, Morgante L, Zoccali R, Ancione M, Madia A. Plasma risperidone concentrations during combined treatment with sertraline. Ther Drug Monit 2004 26 386-90. 

The effect of citalopram on plasma concentrations of risperidone has been prospectively studied in 15 patients with schizophrenia (32). The addition of citalopram did not alter plasma risperidone concentrations. 

Combined treatment with atypical neuroleptic drugs and SSRIs is common and case reports have suggested that SSRIs can increase risperidone concentrations and increase the risk of extrapyramidal disorders (SEDA-23, 18). 

In a systematic open study in 11 hospitalized patients taking a steady dose of risperidone (4-6 mg/day), fluoxetine (20 mg/day) increased plasma concentrations of active antipsychotic medication (combined concentrations of risperidone and 9-hydroxyrisperidone) by 50% after treatment for 25 days (42). Despite this, the treatment was well tolerated and there were improvements in rating scales of psychosis and depressed mood. Whether this was due to the introduction of fluoxetine or the higher plasma concentrations of risperidone is not clear. Fluoxetine and norfluoxetine would require at least a further 2 weeks to reach steady state, so additional increases in risperidone concentrations might be anticipated over this time. 

A pharmacokinetic interaction of risperidone with fluoxetine has been reported (SEDA-22, 71). When 10 schizophrenic patients stabilized on risperidone 4-6 mg/ day took fluoxetine 20 mg/day for concomitant depression the mean plasma risperidone concentration increased from 12 to 56 ng/ml at week 4 the concentration of 9-hydroxyrisperidone was not significantly affected (51). One patient dropped out after 1 week because of akathi-sia associated with a markedly increased plasma risperidone concentration. 

Mean plasma concentrations of risperidone and 9-hydroxyrisperidone (5 ng/ml and 35 ng/ml) fell significantly during carbamazepine co-administration (2.5 ng/ ml and 19 ng/ml) in 11 schizophrenic patients taking risperidone 6 mg/day and then carbamazepine 400 mg/day for 1 week the changes in risperidone concentrations... 

Drugs that inhibit CYP3A, such as the macrolides, can significantly alter risperidone concentrations, especially in patients with CYP2D6 deficiency (254). 

Fluoxetine and norfluoxetine would require at least a further 2 weeks to reach steady state, so additional increases in risperidone concentrations might be anticipated over this time. 

Plasma concentrations of risperidone and 9-hydroxyris-peridone were measured in 44 patients (aged 26-63 years) taking risperidone alone (n = 23) or co-medicated with sodium valproate (n = 10) (154). Valproate had no major effect on plasma risperidone concentrations. 

A therapeutic target range for serum risperidone concentrations has not been established, but in 20 of 22 patients taking 6 mg/day, which is considered the optimum dosage for most patients, risperidone serum concentrations were 50-150 nmol/1 (278). Steady-state serum concentrations of risperidone and 9-hydroxyrisperidone, the active moiety, were also measured in 42 patients there was no correlation between the serum concentration of the active moiety and adverse effects. 

Thioridazine 25 mg bd significantly increased the steady-state plasma concentration of risperidone (3 mg bd) and reduced 9-hydroxyrisperidone in 12 patients with schizophrenia (38). Since risperidone mainly undergoes 9-hydroxylation yielding an active metabolite, 9-hydroxyrisperidone, metabolic inhibition could account for this increase. Moreover, there was a greater rise in risperidone concentrations in subjects with more capacity for CYP2D6-dependent 9-hydroxylation of risperidone. 

Risperidone significantly increases serum carbamazepine concentrations (106) and carbamazepine significantly reduces serum risperidone concentrations (107). The clinical relevance of these changes is uncertain. 

The effects of paroxetine 20 mg/day for 4 weeks on steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone have been studied in 10 patients taking risperidone 4-8 mg/day (175). During paroxetine administration, mean plasma risperidone concentrations increased significantly, while... 

D Arrigo C, Migliardi G, Santoro V, Morgante L, Muscatello MR, Ancione M, Spina E. Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia. Pharmacol Res (2005) 52, 497-501. 

---