Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia

Spina, Edoardo; Avenoso, Angela; Facciolà, Gabriella; Salemi, Monica; Scordo, Maria Gabriella; Ancione, Maria; Madia, Aldo G.; Perucca, Emilio

doi:10.1007/s002130000576

Cited by 109 publications

(69 citation statements)

References 30 publications

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“…The half-lives of risperidone in our monkeys were similar to those in humans with the extensive metabolizer cytochrome P450 phenotype (Huang et al, 1993), consistent with an apparent lack of poor metabolizer phenotype monkeys (Wu et al, 1993). In humans (Spina et al, 2001), as in our monkeys, chronic risperidone treatment results in higher levels of the metabolite paliperidone than of the parent compound. Finally, the relationship between drug concentration and striatal D2R occupancy we find is strikingly similar to that in risperidone-treated humans (Uchida et al, 2011).…”

Section: Discussionsupporting

confidence: 55%

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Muly¹,

Votaw²,

Ritchie³

et al. 2012

J Pharmacol Exp Ther

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Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [ 18 F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.

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Section: Discussionsupporting

confidence: 55%

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Muly¹,

Votaw²,

Ritchie³

et al. 2012

J Pharmacol Exp Ther

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“…However, it should be underlined that the concentrations of risperidone active fraction reached at final evaluation by one of the patients on the highest fluvoxamine dose were close to the threshold values (around 70-80 ng/mL) more frequently associated with parkinsonian side effects [36].…”

Section: Discussionmentioning

confidence: 81%

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

D'Arrigo

Migliardi

Santoro

et al. 2005

Pharmacological Research

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The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.

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“…Moreover, risperidone TDM should be particularly useful when medication is switched from the oral to injectable depot form or vice versa (15). In chronic schizophrenic patients experiencing an acute exacerbation of the disorder, plasma levels of risperidone and its active metabolite correlate with the occurrence of parkinsonian side effects (40). Risperidone plasma concentration/ dose ratio (C/D) accumulation peaks of 49 % at 2 months (from baseline concentration) and 9-hydroxy-risperidone and total moiety C/D accumulation peaks of 66 and 55 % above the 2-month level at 6 months were found (41).…”

Section: Tdm Of Particular Atypical Antipsychotic Drugsmentioning

confidence: 99%

Therapeutic drug monitoring of atypical antipsychotic drugs

2014

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Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic epi sodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM) of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

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Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia

Cited by 109 publications

References 30 publications

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

Therapeutic drug monitoring of atypical antipsychotic drugs

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