Inhibition of Risperidone Metabolism by Fluoxetine in Patients With Schizophrenia: A Clinically Relevant Pharmacokinetic Drug Interaction

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

doi:10.1097/00004714-200208000-00014

Cited by 108 publications

(57 citation statements)

References 29 publications

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“…However, these combinations may result in clinically relevant pharmacokinetic interactions as a consequence of the differential inhibitory effects of SSRIs on CYP enzymes [25]. In this respect, formal kinetic studies in patients with schizophrenia have reported that paroxetine and fluoxetine increased plasma concentrations of risperidone active moiety by 45 and 75%, respectively, sertraline caused a minimal, dose-dependent elevation of total risperidone concentrations, while citalopram did not modify significantly the plasma levels of risperidone and its metabolite [10,11,26,27]. With regard to other newer antidepressants, reboxetine and mirtazapine do not cause significant modifications of plasma concentrations of risperidone active fraction [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…It is well documented that co-administration of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers may affect total plasma risperidone concentrations with potential clinical implications [9]. In this respect, it has been reported that concomitant treatment with fluoxetine or paroxetine, selective serotonin reuptake inhibitors (SSRIs) with potent inhibitory activity on CYP2D6, may cause a significant elevation in the plasma concentrations of the active fraction of risperidone, possibly associated with occurrence or worsening of extrapyramidal side effects [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

D'Arrigo

Migliardi

Santoro

et al. 2005

Pharmacological Research

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“…Plasma concentrations of risperidone were increased by fluoxetine co-administration to approximately fourfold of control, while the levels of 9-hydroxyrisperidone were not significantly affected (Spina et al 2002). The incidence of parkinsonian symptoms increased during longer-term therapy with fluoxetine.…”

Section: Risperidonementioning

confidence: 83%

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

Murray

2006

Journal of Pharmacy and Pharmacology

104

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Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence invivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5 0 -regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.

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“…Vários relatos confirmam que a prescrição de fluoxetina e amitriptilina/ nortriptilina pode aumentar os níveis plasmáticos da amitriptilina/nortriptilina e provocar toxicidade (delírios e convulsões). Caso não haja redução da concentração da fluoxetina − medida esta nem sempre eficaz pelo fato de a redução dos níveis de fluoxetina e norfluoxetina ocorrer de forma extremamente lenta em virtude da auto-inibição do seu metabolismo −, a redução e/ ou interrupção desse composto tende a não ser eficaz diante de uma emergência clínica (atribuiu-se morte à toxicidade crônica da amitriptilina causada pela fluoxetina) (Spina et al, 2002).…”

Section: Discussionunclassified

Detecção de risco de interações entre fármacos antidepressivos e associados prescritos a pacientes adultos

Campigotto¹,

Teixeira

Cano

et al. 2008

Rev. psiquiatr. clín.

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ResumoContexto: O uso de fármacos combinados para o tratamento de patologias diversas em psiquiatria tem aumentado progressivamente. Os antidepressivos estão envolvidos em diversas interações farmacológicas clinicamente importantes. Objetivo: Detectar risco de interações entre fármacos antidepressivos e associados prescritos a pacientes adultos. Métodos: Pesquisa retrospectiva e descritiva foi desenvolvida em uma farmácia magistral da cidade de Cascavel, Paraná. Os dados foram coletados de 151 receituários médicos de pacientes adultos (19 anos ou mais), envolvendo fármacos antidepressivos e associados entre outubro e novembro de 2005. O estudo limitou-se às variáveis registradas no receituário médico (sexo, idade, fármaco antidepressivo e associado prescrito). Resultados: A categoria de 31 a 40 anos de idade foi a mais freqüente (32,46%) e o sexo foi o feminino (64,90%). Os fármacos antidepressivos tricíclicos (ADT) e associados apresentaram um total de oito episódios de interações relativos ao grau de severidade, sendo quatro de grau moderado e quatro menor. Em relação aos fármacos antidepressivos inibidores seletivos da recaptura de serotonina (ISRS) e associados, o risco de ocorrência foi de 16 casos; quatro de severidade menor, dez moderada e dois maior. Conclusão: Os dados mostram que os pacientes com prescrição de fármacos ISRS e associados possuíam mais risco de interações de maior severidade, totalizando o dobro de interações em relação aos ADTs. Campigotto, K.F. et al. / Rev. Psiq. Clín 35 (1); 1-5, 2008Palavras-chave: Farmacoepidemiologia, interação de medicamentos, antidepressivo, farmácia, prescrição de medicamentos. AbstractBackground: The combination of drugs for the treatment of psychiatric disorders has become a relatively frequent practice. The antidepressants are involved in several clinically important pharmacological interactions. Objectives: To detect the risk of interactions between antidepressants and associated drugs prescribed for adults patients. Methods: Data on 151 medical prescriptions of antidepressants and other psychiatric drugs were retrospectively assessed at a teaching pharmacy in the city of Cascavel (state of Parana, Brazil), between October and November 2005. Only prescriptions provided for adults patients (19 years and older) were analyzed. Results: Prescriptions were most frequently provided for female patients (64.9%), and for patients in the 31 to 40 year-old age group (32.5%). Considering prescription information only, we identified a clinically relevant risk of drug-drug interactions in eight prescriptions of tricyclic antidepressants (TADs) and associated drugs; the putative consequence of such pharmacological interaction was considered moderately relevant in four of these. The co-prescription of selective serotonin reuptake inhibitors (SSRIs) with other related drugs bearing a putative risk of interaction was observed in 16 cases, two of which involved a significant risk, ten a moderate risk, and four a minor risk of

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Inhibition of Risperidone Metabolism by Fluoxetine in Patients With Schizophrenia: A Clinically Relevant Pharmacokinetic Drug Interaction

Cited by 108 publications

References 29 publications

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

Detecção de risco de interações entre fármacos antidepressivos e associados prescritos a pacientes adultos

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