btn02 獨協医科大学 精神神経科へようこそ │ 研究と業績 Research activity

研究と業績 Research activity

渡邊 崇 上田幹人 佐伯吉規 石黒 慎 林 有希 青木顕子 下田和孝
薬理遺伝学・ゲノム薬理研究グループ

渡邊 崇 上田幹人 佐伯吉規 石黒 慎 林 有希 青木顕子 下田和孝


精神疾患の原因は、まだまだ未知の部分が多いため、がんを手術したり、細菌感染を抗生物質で治したりというような病気の原因そのものに対する治療は難しいのが現状です。

現在の精神科治療の主体は薬物療法であり私たちのグループは、この精神科薬物療法に関連したことを研究しています。

とくに近年は臨床薬理遺伝学 (clinical pharmacogenetics)・ゲノム薬理学(pharmacogenomics) 、つまり簡単に言うと薬物の効果や副作用の個体差・人種差や各種の薬物や物質との交互作用に関する研究をしています。

例:その1

「Aさんは、抗うつ薬を一日50mg服用すると効果がでた。Bさんは同じ量を服用したがまったく効かない」

例:その2

「Cさんはこの薬で副作用が出やすい。しかし、Dさんはほとんど副作用は出ていない」

例:その3

「日本人のEさんはアメリカ人の友人のFさんの飲んでいる安定剤を服用してみた。Fさんと同じ量を服用するとかなり副作用が出て、結局使えなかった」

例:その4

「Gさんはいつもと同じ睡眠剤をグレープフルーツジュースで飲んだら次の日、起きられなかった」などという実際に日常遭遇する事実と関連したことについて調べています。人間は一人一人、その顔や体つきが違うように体の中のいろいろな働きにも違いがあります。


例1、例2はこのような個体差について述べているもので、実際に私たちの研究結果からは、同じ量の薬を飲んでいてもその薬の血液中の濃度には人によってかなりの差が存在することがわかっています。

例3は薬物代謝の人種差について述べており、実際にアジア人とヨーロッパ人を比較した場合、アジア人では薬物の代謝能力が低いことがわかっている薬物がいくつか存在します。

例4は薬物と併用物質 (他の薬やたばこ、アルコール、グレープフルーツジュースなど) の交互作用について述べています。この例にあるグレープフルーツジュースはある酵素を阻害し、その結果としてその酵素によって分解される薬物(例えば、ある種の降圧薬や睡眠薬)の血液中の濃度を上昇させるので、薬の副作用が出やすくなることが知られています。

現在の主な研究テーマは不安性障害、特にパニック障害の治療に関するゲノム薬理学的研究です。「研究は患者さんの役に立つこと目指して」というポリシーのもとに進めており、パニック障害を診療する専門外来を2004年6月より稼動しております。

上へ戻る

主な業績

T. Watanabe, Y. Hayashi, A. Aoki, S. Ishiguro, M. Ueda, K. Akiyama, K. Kato, Y. Inoue, S. Tsuchimine, N. Yasui-Furukori, K. Shimoda.
Impact of CYP2D6*10 polymorphism on the pharmacokinetics of mirtazapine and its desmethylated metabolite in Japanese psychiatric patients treated with mirtazapine
Clinical Neuropsychopharmacology and Therapeutics  6:5-15, 2015

A. Aoki, S. Ishiguro, T. Watanabe, M. Ueda, Y. Hayashi, K. Akiyama, K. Kato, Y. Inoue, S. Tsuchimine, N. Yasui-Furukori, K Shimoda
Factors affecting discontinuation of initial treatment with paroxetine in panic disorder and major depressive disorder 2014 Sep 18;10:1793-8. doi: 10.2147/NDT.S68670. eCollection 2014

T. Ishikawa, T. Shinozaki, K. Shimoda.
Rhabdomyolysis After the Administration of Clarithromycin in a Japanese Schizophrenic Patient Receiving Aripiprazole: A Possible Impact of CYP2D6 Genotype
Clinical Neuropsychopharmacology and Therapeutics 5:18:22, 2014

N. Sugawara, N. Yasui-Furukori, M. Yamzaki, K. Shimoda, T. Mori, T. Sugai, Y. Suzuki , T. Someya.
Psychiatrists' attitudes toward metabolic adverse events in patients with schizophrenia
Plos one 2014 Jan 23;9(1):e86826. doi: 10.1371/journal.pone.0086826. eCollection 2014.

H. Okayasu, T. Shinozaki, A. Osone, Y. Ozeki and K. Shimoda.
Development of acute pancreatitis caused by sodium valproate in a patient with bipolar disorder on hemodialysis for chronic renal failure: a case report
BMC Psychiatry 2014 Mar 29;14:93. doi: 10.1186/1471-244X-14-93.

K. Fujii, Y. Ozeki, H. Okayasu, Y. Takano, T. Shinozaki, H. Hori, M. Orui, M. Horie, H. Kunugi, K. Shimoda QT is longer in drug-free patients with schizophrenia compared with age-matched healthy subjects. PLOS one 2014 Jun 2;9(6):e98555. doi: 10.1371/journal.pone.0098555. eCollection 2014.

H. Okayasu, Y. Ozeki, M. Chida, S. Miyoshi, K. Shimoda
Lung transplantation in a Japanese patient with schizophrenia from brain-dead donor.
General Hospital Psychiatry 102:e11-13, 2013

H. Okayasu, Y. Ozeki, K. Fujii, Y.Takano, Y. Saeki, H. Hori, M. Horie, T. Higuchi, H. Kunugi, K. Shimoda
Pharmachotherapeutic determinants for QTc interval prolongation in Japanese patients with mood disorder. Pharmacopsychiatry 47:279-283, 2012

S Ishiguro, T Watanabe, M Ueda, Y Saeki, Y Hayashi, K Akiyama, A Saito, K Kato, Y Inoue, K Shimoda
Determinants of pharmacodynamic trajectory of the therapeutic response to paroxetine in Japanese patients with panic disorder
European Journal of Clinical Pharmacology 67:1213-21, 2011

Morita S, Roh H-K, Shimoda K, Someya T, Shibasaki M, Hirokane G, Svensson JO, Bertilsson L.
A comparison of haloperidol plasma levels between Japanese, Korean and Swedish psychiatric patients Clinical Neuropsychopharmacology and Therapeutics 1:24-30, 2010

Y Saeki, T Watanabe, M Ueda, A Saito, K Akiyama, Y Inoue, G Hirokane, S Morita, N Yamada, K Shimoda
Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder.
European Journal of Clinical Pharmacology 65(7):685-91, 2009

T Watanabe, M Ueda, Y Saeki, G Hirokane, S Morita, M Okawa, K Akiyama, and K Shimoda
High plasma concentrations of paroxetine impede clinical response in patients with panic disorder Therapeutic Drug Monitoring  29(1):40-44, 2007

M Ueda, G Hirokane, S Morita, M Okawa, T Watanabe, K Akiyama, K Shimoda
The impact of CYP2D6 genotypes on the plasma concentration of paroxetine in Japanese psychiatric patients, Progress in Neuropsychopharmacology & Biological Psychiatry;30(3):486-91, 2006

C Reist, LJ. Albers, SR. Marder, B Williams-Jones, JC. Wu, S Mee, K Shimoda, T Someya, V Ozdemir
A Candidate Pathway Strategy for Integration of Pharmacogenomic Components of Variability in Antipsychotic Treatment Outcomes: A Focus on Aripiprazole
Current Pharmacogenomics, 3:305-317, 2005

T. Someya, K. Shimoda, Y. Suzuki, S. Sato, Y. Kawashima, G. Hirokane, S. Morita, A. Yokono. Y. Inoue, S. Takahashi.
The effect of CYP2D6 genotypes on haloperidol metabolism in a Japanese psychiatric population. Neuropsychopharmaology
28:1501-5、2003

Y Suzuki, T Shioiri, T Muratake, T., Y Kawashima, K Shimoda, T Someya: Effects of concomitant fluvoxamine on metabolism of alprazolam in Japanese psychiatric patients: Interaction with CYP2C19 mutated alleles. European Journal of Clinical Pharmacology,
58, 12:829-833, 2003.

K. Shimoda, T. Someya, S.Morita, G. Hirokane, A. Yokono, M. Okawa, S. Takahashi.
Lack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position –2964 in the 5’-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 26:261-265, 2002.

K. Shimoda, T. Someya, A. Yokono, S. Morita, G. Hirokane, S. Takahashi and M.Okawa.
The impact of CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline in Japanese psychiatric patients. Journal of Clinical Psychopharmacology, 22:371-378, 2002

Y. Suzuki, T. Someya, K. Shimoda, G. Hirokane, S. Morita, A. Yokono, Y. Inoue, S.Takahashi
Importance of the cytochrome P450 2D6 genotype for the drug metabolic interaction between chlorpromazine and haloperidol. Therapeutic Drug Monitoring 23:363-368, 2001

A. Yokono, T Someya, S. Morita, G. Hirokane, M. Okawa and K Shimoda
The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramne in Japanese psychiatric patients. Journal of Clinical Psychopharmacology, 21:549-555, 2001.

T. Someya, K. Shimoda, T. Muratake,E. Nakajima, A. Shirai, H. Funaoka, T. Yashiki, H. Ishii, N. Sunahara and S. Takahashi
Establishment of enzyme immuno-assay for measuring serum sultopride level. Therapeutic Drug Monitoring, 23:277-81, 2001.

T. Someya, T. Muratake, G. Hirokane, M. Shibasaki, K. Shimoda and S. Takahashi
Interindividual variation in bromperidol metabolism and relationship with therapeutic effects
Journal of Clinical Psychopharmacology 20:175-180, 2000.

S. Morita, K. Shimoda, T. Someya, Y. Yoshimura, K. Kamijima, N. Kato.
Steady-state plasma levels of nortriptyline and its hydroxylated metabolites: The impact of CYP2D6 genotype on the hydroxylation of nortriptyline. Journal of Clinical Psychopharmacology 20:141-149, 2000.

K. Shimoda, S. Morita, G. Hirokane, A. Yokono, T. Someya, S. Takahashi.
Metabolism of desipramine in Japanese psychiatric patients: The impact of CYP2D6 genotype on the hydroxylation of desipramine. Pharmacology & Toxicology, 86:245-249, 2000.

K. Shimoda, S. Morita, A. Yokono, T. Someya, G. Hirokane, N. Sunahara, S. Takahashi
CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Oriental patients. Therapeutic Drug Monitoring  22:392-396, 2000.

G. Hirokane, T. Someya, S. Takahashi, S. Morita, K. Shimoda
Interindividual variation of plasma haloperidol concentrations and the impact of concomitant medications: the analysis of therapeutic drug monitoring data.
Therapeutic Drug Monitoring, 21: 82-86, 1999.

K. Shimoda, T. Someya, S. Morita, G. Hirokane, T. Noguchi, A. Yokono, M. Shibasaki, S. Takahashi.
Lower plasma levels of haloperidol in smoking than in non-smoking schizophrenic patients. Therapeutic Drug Monitoring 21:293-296, 1999.

K. Shimoda, M. Jerling, Y. Böttiger, S. Yasuda, S. Morita, L. Bertilsson.
Pronounced differences in the disposition of clomipramine between Japanese and Swedish patients. Journal of Clinical Psychopharmacology, 19:393-400, 1999.

T. Someya, Y. Suzuki, K. Shimoda, G. Hirokane, S. Morita, A. Yokono, Y. Inoue, S. Takahashi.
The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism in Japanese psychiatric patients. : A preliminary study in a psychiatric population.
Psychiatry and Clinical Neuroscience, 53:593-597, 1999.

K. Shimoda, M.Shibasaki, T. Inaba, T. Someya, S.W. Cheung, S. Takahashi
Carbonyl reduction of timiperone in human liver cytosol.
Pharmacology & Toxicology 83: 164-168, 1998.

K. Shimoda, T. Someya, S. Morita, G. Hirokane, A. Yokono, M. Shibasaki, S. Takahashi
Plasma concentrations of timiperone and its reduced metabolite in the patients on timiperone.
Psychiatry and Clinical Neuroscience, 52:535-540, 1998.

K. Shimoda, S. Yasuda, S. Morita, M. Shibasaki, T. Someya, L. Bertilsson, S. Takahashi
Significance of monitoring plasma levels of amitriptyline, its hydroxylated and desmethylated metabolites in prediction of clinical outcome of depressive state. Psychiatry and Clinical Neuroscience, 51:35-41, 1997.

K. Shimoda, T. Noguchi, Y. Ozeki, S. Morita, M. Shibasaki, T. Someya, S. Takahashi
Metabolism of clomipramine in a Japanese population: Significance of hydroxylation, desmethylation and glucuronidation. Neuropsychopharmacology, 12:323-333, 1995.

K. Shimoda, T. Noguchi, S. Morita, Y. Ozeki, M. Shibasaki, T. Someya, S. Takahashi
Interindividual variations of desmethylation and hydroxylation of amitriptyline in a Japanese psychiatric population. Journal of Clinical Psychopharmacology 15:175-181, 1995.

K. Shimoda, T. Minowada, T. Noguchi, S. Takahashi
Interindividual variations of desmethylation and hydroxylation of clomipramine in an Oriental psychiatric population.
Journal of Clinical Psychopharmacology, 13:181-188, 1993.

T. Noguchi, K. Shimoda, S. Takahashi
Clinical significance of plasma levels of clomipramine and its hydroxylated and desmethylated metabolites : Prediction of clinical outcome in mood disorders using discriminant analysis of therapeutic drug monitoring data.
Journal of Affective Disorders, 29: 267-279, 1993.

上へ戻る