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Featured researches published by Goyo Nagai.


Therapeutic Drug Monitoring | 2011

Effects of the CYP2D6*10 Allele on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

Takeshi Suzuki; Kazuo Mihara; Akifumi Nakamura; Goyo Nagai; Shoko Kagawa; Kenji Nemoto; Ikuya Ohta; Hajime Arakaki; Tsukasa Uno; Tsuyoshi Kondo

The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.


Therapeutic Drug Monitoring | 2009

Pharmacokinetic and pharmacodynamic interactions between carbamazepine and aripiprazole in patients with schizophrenia.

Akifumi Nakamura; Kazuo Mihara; Goyo Nagai; Takeshi Suzuki; Tsuyoshi Kondo

Pharmacokinetic and pharmacodynamic interactions between carbamazepine and aripiprazole were studied in 18 inpatients with schizophrenia being treated with aripiprazole. The daily dose of aripiprazole was 24 mg in 15 cases and 12 mg in 3 cases. Carbamazepine 400 mg/d was coadministered for 1 week, and blood samples were taken twice before the start of carbamazepine coadministration and then 1 week after completion. In addition, on these days, the severity of illness and side effects were evaluated using the Positive and Negative Syndrome Scale and the Udvalg for Kliniske Undersøgelser side effects rating scale, respectively. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. Carbamazepine significantly decreased both plasma concentrations of aripiprazole and dehydroaripiprazole by 64% and 68%, respectively (P < 0.001). Despite these decreases in plasma concentrations, the total and negative scores in Positive and Negative Syndrome Scale, together with the neurological score in Udvalg for Kliniske Undersøgelser, decreased slightly but significantly (P < 0.05) after carbamazepine coadministration. The present study implies that carbamazepine augmentation may be effective for patients with schizophrenia treated with aripiprazole, although carbamazepine dramatically decreases plasma concentrations of aripiprazole and dehydroaripiprazole, by inducing the metabolism of these compounds.


Therapeutic Drug Monitoring | 2014

Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia.

Takeshi Suzuki; Kazuo Mihara; Akifumi Nakamura; Shoko Kagawa; Goyo Nagai; Kenji Nemoto; Tsuyoshi Kondo

Background: We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females). Methods: All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. The CYP2D6 (CYP2D6*5, CYP2D6*10, and CYP2D6*14), CYP3A5 (CYP3A5*3), and ABCB1 (C3435T and G2677T/A) genotypes were identified by PCR analyses. Results: The mean concentration/dose ratios of aripiprazole and the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with 1 (P < 0.01 and P < 0.01) or 2 (P < 0.001 and P < 0.05) mutated alleles for CYP2D6 than in those without mutated alleles. No differences were found in the values of dehydroaripiprazole among CYP2D6 genotypes. There were no differences in the values of aripiprazole, dehydroaripiprazole, and the sum of the 2 compounds among CYP3A5 or the 2 ABCB1 variants. Multiple regression analyses including these polymorphisms, age, gender, and smoking habit showed that only the number of mutated alleles for CYP2D6 was correlated with mean concentration/dose ratios of aripiprazole [standardized partial correlation coefficients (beta) = 0.420, P < 0.001] and the sum of the 2 compounds (standardized beta = 0.335, P < 0.01). Conclusions: The findings of this study suggest that CYP2D6 genotypes play an important role in controlling steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects, whereas CYP3A5 and ABCB1 genotypes seemed unlikely to have an impact.


Therapeutic Drug Monitoring | 2009

Formulations of Valproate Alter Valproate Metabolism: A Single Oral Dose Kinetic Study

Goyo Nagai; Shingo Ono; Norio Yasui-Furukori; Akifumi Nakamura; Kazuo Mihara; Tsuyoshi Kondo

The risk for teratogenicity of valproate (VPA) increases in a dose- or concentration-dependent manner. It has been also suggested that an increased metabolic conversion of VPA to its toxic metabolites including 2-propyl-4-pentenoic acid (4-en) is involved in the mechanism of VPA toxicity at higher doses and concentrations. This study aimed to examine whether formulations of VPA alter metabolism of VPA itself. Seven healthy male volunteers received an oral dose (800 mg) of conventional and slow-release formulations of VPA on 2 separate days, consisting of 2 phases of single-dose kinetic trials. Blood sampling for determination of VPA and its monounsaturated (2-en, 3-en, and 4-en) and hydroxylated (3-OH, 4-OH, and 5-OH) metabolites by gas chromatography-mass spectrometry were performed up to 60 hours after dosing. In subjects receiving the slow-release formulation of VPA, decreased Cmax, prolonged Tmax, and reduced area under the curve of metabolites by microsomal oxidation (4-en, 4-OH, and 5-OH) were observed. In contrast, aforementioned kinetic parameters of beta-oxidative metabolites (2-en, 3-en, and 3-OH) were unchanged irrespective of VPA formulations. These results suggest that the slow-release formulation may be safer with regard to pharmacokinetic and metabolic aspects, which is characterized by decreased formation of 4-en, the most toxic metabolite, together with reduced peak concentrations of the parent compound.


Therapeutic Drug Monitoring | 2014

Relationship between plasma concentrations of lamotrigine and its early therapeutic effect of lamotrigine augmentation therapy in treatment-resistant depressive disorder.

Shoko Kagawa; Kazuo Mihara; Akifumi Nakamura; Kenji Nemoto; Takeshi Suzuki; Goyo Nagai; Tsuyoshi Kondo

Background: The relationship between plasma concentrations of lamotrigine and its therapeutic effects was prospectively studied on 34 (9 men and 25 women) inpatients with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation using an open-study design. Methods: The subjects were depressed patients who had already shown insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 12), bipolar I disorder (n = 7), and bipolar II disorder (n = 15). The final doses of lamotrigine were 100 mg/d for 18 subjects who were not taking valproate and 75 mg/d for 16 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed at week 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. Results: There was a significant linear relationship between the plasma concentrations of lamotrigine and percentage improvements at week 8 (r = 0.418, P < 0.05). A stepwise multiple regression analysis showed that plasma lamotrigine concentrations alone had a significant effect on the percentage improvements at week 8 (standardized partial correlation coefficients = 0.454, P < 0.001). The receiver operating characteristics analysis indicated that a plasma lamotrigine concentration of 12.7 &mgr;mol/L or greater was significantly (P < 0.001) predictive of response (50% or more reduction in the MADRS score). The proportion of the responders was significantly higher in the groups with a lamotrigine concentration >12.7 &mgr;mol/L (11/15 versus 4/19, P < 0.01). Conclusions: The present study suggests that an early therapeutic response to lamotrigine is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 &mgr;mol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder.


Psychiatry and Clinical Neurosciences | 2012

Prolactin concentrations during aripiprazole treatment in relation to sex, plasma drugs concentrations and genetic polymorphisms of dopamine D2 receptor and cytochrome P450 2D6 in Japanese patients with schizophrenia

Goyo Nagai; Kazuo Mihara; Akifumi Nakamura; Takeshi Suzuki; Kenji Nemoto; Shoko Kagawa; Ikuya Ohta; Hajime Arakaki; Tsuyoshi Kondo

The authors investigated the correlation between prolactin concentrations during aripiprazole treatment and various factors, including age, sex, plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, and genetic polymorphisms of dopamine D2 receptor (DRD2) and cytochrome P450(CYP)2D6.


Therapeutic Drug Monitoring | 2012

Effects of paroxetine on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia.

Kenji Nemoto; Kazuo Mihara; Akifumi Nakamura; Goyo Nagai; Shoko Kagawa; Takeshi Suzuki; Tsuyoshi Kondo

Background The effects of paroxetine coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 14 Japanese patients with schizophrenia. Methods The patients had been treated with aripiprazole (24 mg/d in 5 cases, 12 mg/d in 5 cases, and 6 mg/d in 4 cases) for at least 2 weeks. Paroxetine 10 mg/d was coadministered during the first week, and the dose was increased to 20 mg/d during the second week. Blood samples were taken 3 times, before the start of paroxetine and then 1 and 2 weeks after paroxetine coadministration. On the same days, the severity of illness and extrapyramidal adverse effects were evaluated by the clinical global impressions and the Drug-Induced Extra-Pyramidal Symptoms Scale, respectively. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. Results Plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during coadministration of paroxetine 10 and 20 mg/d were significantly (P < 0.05) higher (1.5-fold and 1.7-fold; 1.4-fold and 1.5-fold) than those before paroxetine coadministration. Those values during coadministration of paroxetine 20 mg/d were also significantly (P < 0.05) higher (1.1-fold and 1.1-fold) than those during coadministration of paroxetine 10 mg/d. Plasma concentrations of dehydroaripiprazole were unchanged throughout the study period. The mean clinical global impression score was significantly (P < 0.05) higher during the paroxetine 10 mg/d than that before coadministration, whereas the Drug-Induced Extra-Pyramidal Symptoms Scale scores remained unchanged during the study. Conclusions This study suggests that lower doses (10–20 mg/d) of paroxetine coadministration increase plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole.


Therapeutic Drug Monitoring | 2016

Prediction of an Optimal Dose of Lamotrigine for Augmentation Therapy in Treatment-resistant Depressive Disorder From Plasma Lamotrigine Concentration at Week 2

Akifumi Nakamura; Kazuo Mihara; Goyo Nagai; Shoko Kagawa; Takeshi Suzuki; Kenji Nemoto; Tsuyoshi Kondo

Background: The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 &mgr;mol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. Methods: The subjects were 37 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. Results: There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. Conclusions: The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.


Therapeutic Drug Monitoring | 2014

Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia.

Akifumi Nakamura; Kazuo Mihara; Kenji Nemoto; Goyo Nagai; Shoko Kagawa; Takeshi Suzuki; Tsuyoshi Kondo

Background: Both aripiprazole and haloperidol have been used in the treatment of schizophrenia, and are metabolized by the cytochrome P450 (CYP) 2D6 and CYP3A4. The authors studied the correlations between the steady-state plasma concentrations (Css) of aripiprazole and its active metabolite, dehydroaripiprazole, and those of haloperidol in 19 Japanese patients with schizophrenia, together with the effects of CYP2D6 genotypes on the steady-state kinetics of these compounds. Methods: All the patients received first 24 mg/d of aripiprazole for 3 weeks and later received 6 mg/d of haloperidol for 2 weeks. Blood samplings were performed at least 2 weeks after the initiation of each treatment. The Css values of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection, and those of haloperidol were measured by using an enzyme immunoassay. CYP2D6 genotypes were determined by using polymerase chain reaction analysis. Results: None of the correlations between the Css of aripiprazole (r = 0.286) or the sum of aripiprazole plus dehydroaripiprazole (r = 0.344) and those of haloperidol were significant. The mean Css of aripiprazole was significantly higher (P < 0.05) in the subjects with 1 *10 allele of CYP2D6 (n = 6) than in those with no mutated alleles (n = 13), whereas there were no significant differences in those of haloperidol between the 2 groups. Conclusions: This study suggests that the Css of aripiprazole and that of aripiprazole plus dehydroaripiprazole do not correlate with that of haloperidol in the same individual, because of the greater involvement of CYP2D6 in the metabolism of aripiprazole than in that of haloperidol.


Psychiatry and Clinical Neurosciences | 2016

Lamotrigine augmentation therapy in a case with treatment‐resistant unipolar depression that showed insufficient response to electroconvulsive therapy

Kazuo Mihara; Akifumi Nakamura; Kenji Nemoto; Goyo Nagai; Shoko Kagawa; Takeshi Suzuki; Tsuyoshi Kondo

IT HAS BEEN shown that lamotrigine may be useful as augmentation of antidepressants for treatment-resistant unipolar depression. A large trial suggested a great response to lamotrigine augmentation in more severely depressed and more refractory unipolar patients. We report a case with refractory unipolar depression that had failed to sufficiently respond to several antidepressants, three augmentation strategies and electroconvulsive therapy (ECT), but that successfully achieved remission with lamotrigine augmentation of fluvoxamine. The use of lamotrigine was approved by the Ethics Committee of the University of the Ryukyus. Informed written consent and a singed release from the patient authorizing publication have been obtained. His anonymity has been preserved. The patient was a 54-year-old male office worker with recurrent major depressive disorder according to DSM-5. He had suffered his first depressive episode at the age of 38 due to work burden. Four antidepressants (paroxetine, amoxapine, trazodone, and milnacipran) and augmentation therapies with lithium, valproate, and clonazepam had showed little response. Eleven sessions of first ECT and 12 sessions of second ECT with maintenance ECT had a transient effect on him, and his depressive symptoms had relapsed on the regimen of lithium 600 mg/day (0.60 mmol/L) and valproate 600 mg/day (80 μg/mL). He had shown no (hypo)manic episodes throughout the period. His depressive symptoms were moderate with his Montgomery–Åsberg Depression Rating Scale (MADRS) score of 24 on fluvoxamine 200 mg/day, which showed partial response. Lamotrigine 25 mg/day was coadministered, and the daily dose was increased at the rate of 25 mg/2 weeks without a change in fluvoxamine dose. At the 8th week (lamotrigine 100 mg/day), his MADRS score decreased to 11 with a plasma lamotrigine concentration of 10.12 μmol/L. The dose was increased to 150 mg/day, as the concentration was under the therapeutic range (above 12.7 μmol/L) suggested by the authors. By the 10th week, his condition had remitted, with a MADRS score of 4 and a plasma lamotrigine concentration of 14.11 μmol/L. The possibility that he suffered from latent bipolar depression was not ruled out. However, the addition of lamotrigine to fluvoxamine improved his depressive symptoms, and finally led to remission. Therefore, it is suggested that lamotrigine can be a pharmacotherapeutic option for such patients. At a plasma lamotrigine concentration level below the therapeutic range, the therapeutic response was limited. Due to the increased dose of lamotrigine, the patient’s condition remitted at the therapeutic range. This result supports the notion proposed by the authors that therapeutic drug monitoring is necessary to optimize lamotrigine dose in the treatment of refractory depression.

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Takeshi Suzuki

University of the Ryukyus

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Kenji Nemoto

University of the Ryukyus

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Shoko Kagawa

University of the Ryukyus

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Hajime Arakaki

University of the Ryukyus

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Ikuya Ohta

University of the Ryukyus

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Noboru Sakumoto

University of the Ryukyus

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