Aripiprazole for schizophrenia

El-Sayeh, HG; Morganti, Carla; Adams, Clive E

doi:10.1192/bjp.189.2.102

Cited by 59 publications

(29 citation statements)

References 8 publications

(9 reference statements)

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“…1,2) The action of aripiprazole is different from that of other typical and atypical antipsychotics; that is, aripiprazole is a potent partial agonist at dopamine D2 and serotonin (5-HT 1A ) receptors and antagonist at 5-HT 2A receptor. 3,4) The results of in vitro studies indicated that aripiprazole is mainly metabolized by human cytochrome P450 isozymes CYP3A4 and CYP2D6.…”

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confidence: 99%

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Koue

Kubo

Funaki

et al. 2007

Biological & Pharmaceutical Bulletin

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Aripiprazole is a new antipsychotic developed in Japan, and is prescribed for schizophrenia as a dopamine-serotonin system stabilizer.1,2) The action of aripiprazole is different from that of other typical and atypical antipsychotics; that is, aripiprazole is a potent partial agonist at dopamine D2 and serotonin (5-HT 1A ) receptors and antagonist at 5-HT 2A receptor.3,4) The results of in vitro studies indicated that aripiprazole is mainly metabolized by human cytochrome P450 isozymes CYP3A4 and CYP2D6.5) It has been reported that CYP3A4 and CYP2D6 are metabolic enzymes for numerous compounds, and also that there are many compounds that inhibit these enzymes. Although individual differences in hepatic levels of CYP3A4 enzyme protein have been reported to vary as much as 40-fold, 6) almost no gene mutations affecting CYP3A4 metabolic activity or ethnic differences have been reported. For CYP2D6, however, a number of polymorphisms and the existence of ethnic differences in the types and distribution of polymorphisms have been reported.6,7) The purpose of the present study was to estimate the population pharmacokinetic parameters of aripiprazole in healthy Japanese males, and to evaluate the effects of CYP2D6 polymorphisms and CYP3A4 inhibition on the pharmacokinetics of aripiprazole, and also its unknown (residual) interindividual variability.In the present study, we used the nonlinear mixed-effects model (NONMEM) method designed for the estimation of population pharmacokinetic parameters.8) This method pools data from all individuals but explicitly models and handles the complicated error structure arising from proper accounting of interindividual (h) and intraindividual (e) random effects. The first-order estimation method is the first estimation method available with NONMEM: it handles the error structure of data using first-order Taylor-series expansion in the random effect h, evaluated at the expected values (i.e. hϭ0).9) On the other hand, a newer analysis method designed for the estimation of population parameters, the firstorder conditional estimation (FOCE) method, is available with NONMEM software. 9) That is, FOCE uses first-order expansions for values of the h, but these values are the conditional (Bayesian) estimates of the h, rather than zero. The FOCE method needs much (20-40-fold) longer computational time than the first-order method, but generally gives precise parameter estimates, especially for the analysis of multiple-dose pharmacokinetic data with multiple compartment models. [9][10][11][12] In the present study, therefore, we used the FOCE method to estimate the population pharmacokinetic parameters of aripiprazole, where a two-compartment model with first-order input was applied for data obtained from single-and multiple-dose clinical trials. MATERIALS AND METHODS Pharmacokinetic DataPlasma aripiprazole concentration data for population pharmacokinetic analysis were obtained in two previous studies. 13,14) Briefly, 68 healthy Japanese male subjects, aged 20-32 years old (mean: 23.1) and w...

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confidence: 99%

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Koue

Kubo

Funaki

et al. 2007

Biological & Pharmaceutical Bulletin

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“…It was associated with a low likelihood of inducing EPS, sedation, QTc prolongation, weight gain and metabolic abnormalities. However, evidence on its effectiveness and tolerability was still scant and its hypothetically different profile of therapeutic and adverse effects was not yet proven [26].…”

Section: Study Hypothesismentioning

confidence: 99%

“…Therefore we focused on two sound endpoints: metabolic syndrome and treatment discontinuation. As the tendency of haloperidol to cause more EPS was well known, and available findings did not suggest relevant differences in terms of EPS between olanzapine and aripiprazole, those neurological side-effects were adopted as secondary endpoints [2,4,26].…”

Section: Study Hypothesismentioning

confidence: 99%

The GiSAS study: Rationale and design of a pragmatic randomized controlled trial on aripiprazole, olanzapine and haloperidol in the long-term treatment of schizophrenia

Parabiaghi

D'Avanzo

Tettamanti

et al. 2011

Contemporary Clinical Trials

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Given the controversy about the comparative efficacy of first-compared with second-generation antipsychotics in the treatment of schizophrenia, more large-scale evidence is needed to guide clinicians in their prescriptions. Most randomized controlled trials (RCTs) were conducted in centers of excellence on highly selected samples, poorly representative of real-world patients, and often suffered conflicts of interest as they were sponsored by drug companies. The primary aim of the present study is to compare the effectiveness of haloperidol, olanzapine and aripiprazole in a representative sample of schizophrenia patients. The GiSAS trial is an open-label, independent, pragmatic RCT in Italian community-based public psychiatric services. At least 260 patients meeting the DSM-IV criteria for schizophrenia will be randomly allocated to one of the study drugs and followed up for one year. A two-year observational phase will follow. The primary outcome for tolerability will be the onset of metabolic syndrome. The primary endpoint for effectiveness will be discontinuation of antipsychotic monotherapy. Secondary measures include global functioning, time to discontinuation due to side-effects, change of lipid profile, extrapyramidal symptoms and other adverse effects. In the last four years, the GiSAS study group has been working to implement this multicenter RCT. The trial mechanism is now fully functional and working. As of end of February 2011, 260 subjects were randomized by 54 study investigators in 33 out of 43 participating centers.

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“…Aripiprazole appears to exert its effects, in principle, on the D2 receptor partial agonist, which modulates dopaminergic activity in areas where dopamine activity may be increased or decreased, like the mesolimbic brain area. 9 In addition to its partial agonist action on D2 receptors, aripiprazole is also a partial agonist of the 5-HT1A receptor. 9 Two Cochrane systematic reviews have evaluated the use of aripiprazole for treating schizophrenia.…”

Section: Aripiprazole For Treating Refractory Schizophreniamentioning

confidence: 99%

“…9 In addition to its partial agonist action on D2 receptors, aripiprazole is also a partial agonist of the 5-HT1A receptor. 9 Two Cochrane systematic reviews have evaluated the use of aripiprazole for treating schizophrenia.…”

Section: Aripiprazole For Treating Refractory Schizophreniamentioning

confidence: 99%

Efficacy and safety of atypical antipsychotic drugs (quetiapine, risperidone, aripiprazole and paliperidone) compared with placebo or typical antipsychotic drugs for treating refractory schizophrenia: overview of systematic reviews

et al. 2010

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Efficacy and safety of atypical antipsychotic drugs (quetiapine, risperidone, aripiprazole and paliperidone) compared with placebo or typical antipsychotic drugs for treating refractory schizophrenia: overview of systematic reviewsEficácia e segurança dos antipsicóticos atípicos (quetiapina, risperidona, aripiprazol, paliperidona) ABSTRACTCONTEXT AND OBJECTIVE: According to some cohort studies, the prevalence of refractory schizophrenia (RS) is 20-40%. Our aim was to evaluate the effectiveness and safety of aripiprazole, paliperidone, quetiapine and risperidone for treating RS. METHODS:This was a critical appraisal of Cochrane reviews published in the Cochrane Library, supplemented with reference to more recent randomized controlled trials (RCTs) on RS. The following databases were searched: Medical Literature Analysis and Retrieval System Online (Medline) RESULTS: Seven Cochrane systematic reviews and 10 additional RCTs were included in this review. The data generally showed minor differences between the atypical antipsychotics evaluated and typical antipsychotics, regarding improvement in disease symptoms, despite better adherence to treatment with atypical antipsychotics. Risperidone was specifically evaluated in patients with RS in one of the systematic reviews included, with favorable outcomes, but without definitive superiority compared with other drugs of proven efficacy, like amisulpride, clozapine and olanzapine. CONCLUSIONS:The findings underscore the difficulty in treating these patients, with high dropout rates and treatment patterns of modest improvement in assessments of effectiveness. Atypical antipsychotics have advantages over typical antipsychotics mainly through their better safety profile, which leads to better adherence to treatment. A combination of antipsychotics may also be an option for some refractory patients. RESUMOCONTEXTO E OBJETIVO: De acordo com alguns estudos de coorte, a prevalência da esquizofrenia refratária (ER) está entre 20-40%. Nosso objetivo foi avaliar a efetividade e segurança de aripiprazol, paliperidona, quetiapina e risperidona no tratamento da esquizofrenia refratária. RESULTADOS: Sete revisões sistemáticas Cochrane e 10 ECRs complementares foram incluídos nessa revisão. No geral os dados demonstram pequenas diferenças entre os antipsicóticos atípicos avaliados e os típicos na melhora dos sintomas da doença, apesar da melhor adesão ao tratamento com os atípicos. A risperidona foi avaliada especificamente em pacientes com esquizofrenia refratária em uma das revisões sistemáticas incluídas, a qual demonstrou desfechos favoráveis, porém não definitivos quando comparada a drogas também com eficácia comprovada como amisulprida, clozapina e olanzapina. MÉTODOS: Avaliação crítica das revisões Cochrane publicadas na CONCLUSÕES:Os dados reforçam a dificuldade de tratar esses pacientes, com elevadas taxas de desistência do tratamento e padrões de melhora modestos nas avaliações de eficácia. Os antipsicóticos atípicos têm vantagens sobre os típicos principalmente pelo melh...

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Aripiprazole for schizophrenia

Abstract: Aripiprazole has been licensed despite the fact that few reliable data on this drug are publicly available. It may be effective for treatment of schizophrenia, but in terms of tolerability and global outcomes it shows little difference from existing antipsychotics.

Cited by 59 publications

References 8 publications

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

The GiSAS study: Rationale and design of a pragmatic randomized controlled trial on aripiprazole, olanzapine and haloperidol in the long-term treatment of schizophrenia

Efficacy and safety of atypical antipsychotic drugs (quetiapine, risperidone, aripiprazole and paliperidone) compared with placebo or typical antipsychotic drugs for treating refractory schizophrenia: overview of systematic reviews

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