Pharmacokinetic Interaction of Fluvoxamine and Thioridazine in Schizophrenic Patients

Carrillo, Juan Antonio; Ramos, Sara I.; Herraiz, Angustias G.; LLerena, Adrián; Agúndez, José A.G.; Berecz, Roland; Duran, Marisol; Benı́tez, Julio

doi:10.1097/00004714-199912000-00002

Cited by 60 publications

(25 citation statements)

References 44 publications

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“…An increase in thioridazine plasma concentrations may occur when the enzyme activity is impaired genetically in PMs (7% of Caucasians) (LLerena et al, 1996). Notwithstanding, CYP2D6 enzyme impairment may also result from a dose-dependent inhibition by thioridazine (LLerena et al, 2001) or from concomitant medications which are inhibitors or substrates of CYP2D6 (Carrillo et al, 1999). Considering that thioridazine is frequently used among elderly patients (Schneider, 1993), and that this population is usually comedicated with several drugs, the risk of drug interactions and sudden death is higher.…”

Section: Resultsmentioning

confidence: 99%

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients

et al. 2002

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Thioridazine cardiotoxicity has been associated with a prolonged heart-rate corrected QT (QTc) interval. However, no systematic studies have been performed on patients at therapeutic doses. The present study aimed to evaluate the influence of dose and plasma concentration of thioridazine and CYP2D6 enzyme status on the QTc interval in psychiatric patients. Sixty-five Spanish European psychiatric patients receiving thioridazine antipsychotic monotherapy were studied. The plasma levels of thioridazine and its metabolites were determined by high-performance liquid chromatography. All patients were phenotyped for CYP2D6 activity with debrisoquine during treatment. Thirty-five patients (54%) had a QTc interval over 420 ms. The lengthening of QTc interval was correlated with plasma concentration (p < 0.05) and daily dose (p < 0.05) of thioridazine. CYP2D6 enzyme hydroxylation capacity, evaluated by debrisoquine metabolic ratio (MR) (p < 0.05) and thioridazine/mesoridazine ratio (p < 0.05), was also correlated with QTc intervals. The present study shows the relationship between QTc interval lengthening among psychiatric patients treated at therapeutical doses with the dose and the plasma concentration of thioridazine. Since debrisoquine MR has been shown to be correlated with the QTc intervals, CYP2D6 enzyme hydroxylation capacity might be relevant in determining the risk for QTc interval lengthening. Patients with impaired CYP2D6 enzyme activity due to enzyme inhibition by thioridazine might be more prone to increased risk of sudden death due to torsade de pointes type cardiac dysrhythmia.

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Section: Resultsmentioning

confidence: 99%

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients

et al. 2002

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“…[155,158] Clomipramine Yes ? [156,158,231,232] Fluvoxamine (*) ( †) NA Yes [148,149,233] Imipramine Yes Yes [153,157,234] Mirtazapine Yes Yes [161][162][163] Antipsychotics Chlorpromazine Yes NA [235] Clozapine (*) Yes Yes [42,44,178,236] Haloperidol Yes Yes [237,238] Olanzapine (*) Yes Yes [17,54] Perphenazine Yes NA [239] Thioridazine (*) NA Yes [164] Zotepine Yes NA [240] ?= not fully elucidated; NA = data not available. The asterisk (*) indicates the drugs for which the enzyme is of major clinical importance.…”

Section: Antidepressantsmentioning

confidence: 99%

“…Fluvoxamine markedly interferes with the metabolism of typical and atypical antipsychotics in schizophrenic patients [164]. Thioridazine has been frequently implicated in arrhytmias and sudden death.…”

Section: Fluvoxamine: the Paradigm Of Cyp1a2-related Drug Interactionmentioning

confidence: 99%

Pharmacogenetics of Cytochrome P450 (CYP) 1A2 and Variability in Psychotropic Drug Response

Carrillo¹

2006

CPSR

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Despite the availability of a wide range of different drug classes for the management of psychiatric disorders, the efficiency of drug treatment is far from optimal. Regardless of the initial choice and dose of standard psychiatric medication, about 30-50% of patients will not respond sufficiently to acute treatment while others suffer from severe adverse drug reactions. The patient-to-patient differences in drug response can be explained on the basis of variability in drug pharmacokinetic and pharmacodynamic processes. The involvement of the human polycyclic aromatic hydrocarbon (PAH)-inducible CYP1A2 in the metabolism of several psychotropic drugs is increasingly acknowledged. Currently, it is well-known that this enzyme shows a wide interindividual variability, but controversy has long surrounded the issue of a polymorphic distribution of the enzyme activity leading to pronounced differences in drug response. Moreover, whether genetic polymorphism and/or environmental factors play a definitive role has not yet unequivocally established. On the other hand, combination pharmacotherapy is commonly used in clinical psychiatry, and the CYP1A2 enzyme is the target of many clinically relevant drug interactions.This review is dealing with factors that could better explain patient-to-patient differences in drug response to psychotropic drugs, including CYP1A2 genetic polymorphisms, environmental factors as well drug interactions modulating the CYP1A2 enzyme activity.

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“…Several reports have shown that fluvoxamine coadministration increases plasma concentrations of the antipsychotic drugs clozapine (Markowitz et al 1996;Armstrong et al 1997;Heeringa et al 1999;Fabrazzo et al 2000), olanzapine (de Jong et al 2001;Weigmann et al 2001;Hiemke et al 2002), and thioridazine (Carrillo et al 1999). In addition, Daniel and coworkers (1994) reported a pharmacokinetic interaction of relatively highdose fluvoxamine (100-300 mg/day) with haloperidol, which is still one of the most widely used antipsychotic drugs in the treatment of schizophrenia and other psychiatric disorders (Santamaria et al 2002), in a small-sized study with three schizophrenic patients.…”

Section: Introductionmentioning

confidence: 99%

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

et al. 2004

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Augmentation with low-dose fluvoxamine (50-100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114-127%), 139% (95%CI; 130-149%), and 160% (95%CI; 142-178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

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Pharmacokinetic Interaction of Fluvoxamine and Thioridazine in Schizophrenic Patients

Cited by 60 publications

References 44 publications

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients

Pharmacogenetics of Cytochrome P450 (CYP) 1A2 and Variability in Psychotropic Drug Response

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

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