研究者詳細 - 内田　裕之

論文 - 内田　裕之

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Absence of evidence that the pro re nata regimen confers benefit: A review of the studies

Yoshida K., Suzuki T., Uchida H., Mimura M.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 28 （ 5 ） 228 - 237 2013年09月

ISSN 02681315

Studies were sought that evaluated the prevalence, effectiveness, and safety of pro re nata (p.r.n.) medications in psychiatric practice for which evidence has been scarce despite their wide application. To this end, a systematic literature search was performed using various search engines (last search: October 2012) with cross-referencing. A total of 34 studies were identified: 16 studies on epidemiological usage, 16 retrospective studies on effectiveness/safety as well as reasons, and only two prospective studies on the effectiveness/safety of p.r.n. medications. All the patients studied were inpatients, and the reasons for p.r.n. were acute behavioral dyscontrol in 29 studies. Psychiatric diagnoses and outcome measures to assess effectiveness/safety varied and were described in 27 and 20 studies, respectively. Medications under study included antipsychotics (mainly chlorpromazine, haloperidol, olanzapine, risperidone, or quetiapine), benzodiazepines (mainly diazepam and lorazepam), and antihistamines (mainly diphenhydramine). Altogether, 17 studies reported that p.r.n. medications were effective in psychiatric inpatients. Those two prospective studies targeted solely a child/adolescent population with small sample sizes. Currently available data are limited in number, quality, and scope; there has been only equivocal evidence to guide the choice of p.r.n. medications for psychiatric patients, hence there is a need for more investigations on this important clinical topic. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: An open-label, randomized, controlled, pilot study

Takeuchi H., Suzuki T., Remington G., Bies R., Abe T., Graff-Guerrero A., Watanabe K., Mimura M., Uchida H.

Schizophrenia Bulletin （Schizophrenia Bulletin） 39 （ 5 ） 993 - 998 2013年09月

ISSN 05867614

Impact of dose reduction of atypical antipsychotics on cognitive function has not been investigated in stable patients with schizophrenia. In this open-label, 28-week, randomized controlled trial, stable patients with schizophrenia treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50% in 4 weeks and then maintained) or maintenance group (dose kept constant). Assessments at baseline and week 28 included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Sixty-one patients were enrolled; 2 of 31 (6.5%) and 5 of 30 (16.7%) patients prematurely withdrew from the study in the reduction and maintenance groups, respectively. While no significant differences in change in the PANSS total score were observed between the 2 groups, the reduction group showed significantly greater improvements in the RBANS and DIEPSS total scores compared with the maintenance group (mean ± SD, +7.0±7.1 vs -0.1±8.0, P <. 001; -0.9±1.7 vs +0.1±1.2, P =. 010, respectively). This 6-month pilot study suggests that risperidone or olanzapine dose reduction of 50% can improve cognitive function for stable patients with schizophrenia. Due to the open-label design, small sample size, and short study duration, however, there is a need to confirm the finding through double-blind, larger scale trials with longer follow-up periods. Moreover, potential risks of relapse following antipsychotic dose reduction should be thoroughly investigated in longer term studies. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

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C-terminus of the Sgf73 subunit of SAGA and SLIK is important for retention in the larger complex and for heterochromatin boundary function.

Kamata K, Hatanaka A, Goswami G, Shinmyozu K, Nakayama J, Urano T, Hatashita M, Uchida H, Oki M

Genes to cells : devoted to molecular & cellular mechanisms 18 （ 9 ） 823 - 37 2013年09月

ISSN 1356-9597

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Ten year outcomes of outpatients with schizophrenia on conventional depot antipsychotics: A systematic chart review

Uchida T., Suzuki T., Sakurai H., Tsutsumi C., Den R., Mimura M., Uchida H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology） 28 （ 5 ） 261 - 266 2013年09月

ISSN 02681315

Long-term follow-up data of patients with schizophrenia on depot antipsychotics have been few and the longest follow-up period has been up to 7 years. We carried out a systematic chart review to examine 10-year outcomes for outpatients with schizophrenia who were receiving a conventional depot antipsychotic. Maintenance of outpatient status for 10 years was considered as a favorable outcome. From the initial sample of 1587 outpatients, 90 patients who were receiving a depot antipsychotic were included in this study (mean±SD, age 44.0±13.0 years; men, N=54). Haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, and haloperidol decanoate plus fluphenazine enanthate were used in 53 (58.9%), 29 (32.2%), seven (7.8%), and one (1.1%) patients, respectively. These depot antipsychotics accounted for 36.9% of the total antipsychotic dosage on average. Seventeen patients (18.9%) successfully maintained outpatient status for 10 years. The most frequent reason for dropout was 'hospitalization' (N=49, 54.4%), followed by 'referral to another clinic/hospital' (N=9, 10.0%) and 'side effects' (N=7, 7.8%). As only 36.9% of the chlorpromazine equivalents were administered through depot antipsychotics, it is difficult to draw any firm conclusion. Still, the data suggest that even depot antipsychotics may not sufficiently prevent relapse in the treatment of schizophrenia. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia

Tsuboi Takashi, Bies Robert R., Suzuki Takefumi, Mamo David C., Pollock Bruce G., Graff-Guerrero Ariel, Mimura Masaru, Uchida Hiroyuki

Progress in Neuro-Psychopharmacology and Biological Psychiatry 45 178 - 182 2013年08月

ISSN 0278-5846

Background: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. Methods: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N= 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. Results: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.

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Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Tsuboi T., Bies R., Suzuki T., Mamo D., Pollock B., Graff-Guerrero A., Mimura M., Uchida H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 45 178 - 182 2013年08月

ISSN 02785846

Background: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. Methods: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N= 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. Results: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia. © 2013 The Authors.

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Acute lethal crush-injured rats can be successfully rescued by a single injection of high-dose dexamethasone through a pathway involving PI3K-Akt-eNOS signaling.

Murata I, Ooi K, Shoji S, Motohashi Y, Kan M, Ohtake K, Kimura S, Ueda H, Nakano G, Sonoda K, Inoue Y, Uchida H, Kanamoto I, Morimoto Y, Kobayashi J

The journal of trauma and acute care surgery 75 （ 2 ） 241 - 9 2013年08月

ISSN 2163-0755

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研究と報告　日本版乳幼児感覚プロフィールの標準化　信頼性および標準値の検討

平島太郎, 伊藤大幸, 岩永竜一郎, 萩原拓, 谷伊織, 行廣隆次, 松本かおり, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 原幸一, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 55 （ 8 ） 785 - 795 2013年08月

ISSN 0488-1281

抄録本研究では,感覚刺激への反応異常のアセスメントツールとして国際的に広く用いられている感覚プロフィールの日本版の標準化に関する研究の一環として,乳幼児306名のデータをもとに,日本版乳幼児感覚プロフィール(ITSP-J)の信頼性と標準値を検討した。分析の結果,ITSP-Jを構成する質問項目は全般的に高い修正済みItem-Total相関を示し,各項目はそれぞれの下位尺度において有効に機能していた。月齢帯ごとにα係数を検討した結果,ITSP-Jは尺度として十分な内的整合性を有していた。また,パーセンタイルに基づきカットオフ値を設定し,感覚刺激への反応の特徴の判定を行えるようにした。(著者抄録)

Effect of the state of distribution of supported Pt nanoparticles on effective Pt utilization in polymer electrolyte fuel cells.

Uchida M, Park YC, Kakinuma K, Yano H, Tryk DA, Kamino T, Uchida H, Watanabe M

Physical chemistry chemical physics : PCCP 15 （ 27 ） 11236 - 47 2013年07月

ISSN 1463-9076

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Structural variations of CO adlayers on a Pt(100) electrode in 0.1 M HClO4 solution: an in situ STM study.

Wakisaka M, Yoneyama T, Ashizawa S, Hyuga Y, Ohkanda T, Uchida H, Watanabe M

Physical chemistry chemical physics : PCCP 15 （ 26 ） 11038 - 47 2013年07月

ISSN 1463-9076

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The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia

Takahashi Tatsuichiro, Uchida Hiroyuki, John Majnu, Hirano Jinichi, Watanabe Koichiro, Mimura Masaru, Correll Christoph U., Kishimoto Taishiro

Schizophrenia Research 147 （ 2-3 ） 383 - 386 2013年07月

ISSN 0920-9964

To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received ?. 2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean. ±. SD age: 58.5. ±. 11.0. years; duration of treatment: 26.7. ± 13.8. years). Patients were divided into a prolactin-raising antipsychotic (n = 141) or prolactin-sparing (n = 23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4. ± 1.6. years, a significant antipsychotic-class vs. time interaction was found (p = 0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings.

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Dopamine D_2/3 occupancy of ziprasidone across a day

Suzuki Takefumi, Graff-Guerrero Ariel, Uchida Hiroyuki, Remington Gary, Caravaggio Fernando, Borlido Carol, Pollock Bruce, Mulsant Benoit, Deluca Vincenzo, Ismail Zahinoor, Mamo David

Psychopharmacology 228 （ 1 ） 43 - 51 2013年07月

ISSN 0033-3158

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D_2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods: Positron emission tomography (PET) scans with [¹¹C]- raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [¹¹C]- raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D_2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D_2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. Conclusions: The absence of ziprasidone striatal D_2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D_2/3 receptor occupancy (i.e. 60 %). Clinical Trials Registration: 24-Hour Time Course of Striatal Dopamine D ₂ Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298, NCT00818298

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Reintroduction of clozapine after perforation of the large intestine-A case report and review of the literature

Ikai S., Suzuki T., Uchida H., Mimura M., Fujii Y.

Annals of Pharmacotherapy （Annals of Pharmacotherapy） 47 （ 7-8 ） e31 2013年07月

ISSN 1060-0280

OBJECTIVE: To report on a patient who was successfully rechallenged with cloza - pine after perforation of the large intestine and pulmonary embolism post opera - tively, and provide a literature review on clozapine rechallenge. CASE SUMMARY: A 46-year-old Japanese man with treatment-resistant schizo - phrenia developed constipation and slight abdominal discomfort while taking clozapine 275 mg/day. He developed appendicitis, leading to perforation of the large intestine. During the postsurgery period, a partial embolism of the pulmonary artery was revealed. The patient's constipation was relieved when clozapine was discontinued, but other antipsychotics failed to control his delusions well. After thorough discussion, it was decided to rechallenge with clozapine. The low dose of clozapine 200 mg/day was tolerable for his delusion, and his constipation was managed with laxatives and exercises until 8 months after the accident. DISCUSSION: Clozapine is a gold standard medication in treatment-resistant schizophrenia but is associated with various adverse effects, some of which are life-threatening. Reintroduction of clozapine after severe adverse drug effects when other medications are not effective almost always poses a clinical dilemma for mental health professionals. A PubMed search (to January 25, 2013) using the key words clozapine and rechallenge found 50 articles. There were only sporadic positive case reports regarding the rechallenge after clozapine-related serious gastrointestinal problems. CONCLUSIONS: From the currently available evidence, most psychiatrists appear to avoid reintroduction of clozapine. However, the evidence is too weak to draw a definitive conclusion about reintroduction of this drug. Reintroduction of clozapine after initial adverse effects in patients with treatment-resistant schizophrenia may warrant case-by-case judgment, but needs to be further investigated. © 1967-2013 Harvey Whitney Books Co. All rights reserved.

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Dopamine D<inf>2/3</inf> occupancy of ziprasidone across a day: A within-subject PET study

Suzuki T., Graff-Guerrero A., Uchida H., Remington G., Caravaggio F., Borlido C., Pollock B., Mulsant B., Deluca V., Ismail Z., Mamo D.

Psychopharmacology （Psychopharmacology） 228 （ 1 ） 43 - 51 2013年07月

ISSN 00333158

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods: Positron emission tomography (PET) scans with [11C]- raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [11C]- raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. Conclusions: The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %). Clinical Trials Registration: 24-Hour Time Course of Striatal Dopamine D 2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298, NCT00818298 © 2013 Springer-Verlag Berlin Heidelberg.

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Single cell visualization of yeast gene expression shows correlation of epigenetic switching between multiple heterochromatic regions through multiple generations.

Mano Y, Kobayashi TJ, Nakayama J, Uchida H, Oki M

PLoS biology 11 （ 7 ） e1001601 2013年07月

ISSN 1544-9173

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日本版Vineland-II適応行動尺度の開発　適応行動尺度の測定精度の検討

行廣隆次, 伊藤大幸, 谷伊織, 平島太郎, 安永和央, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 萩原拓, 原幸一, 岩永竜一郎, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 田中恭子, 辻井正次

精神医学（(株)医学書院） 55 （ 7 ） 627 - 635 2013年07月

ISSN 0488-1281

本研究は,全年齢に適用可能であり国際的に広く利用されるVineland Adaptive Behavior Scales,Second Editionの日本版の標準化に関する研究の一環として,適応行動尺度の測定精度を検討した。内的整合性の観点から各下位領域の信頼性を検討したところ,ほぼ十分な値が得られた。情報量による検討の結果からも,対象者の適応状況を正確に評価できる特性範囲が示され,それがどのような年齢段階の標準的レベルに相当するかが明らかになった。以上より,Vineland-IIの適応行動下位尺度は,それぞれ十分な信頼性を持つことが示された。また,一般群の場合,下位尺度ごとに,対象とする適応行動を敏感にとらえる年齢帯が存在することが明らかとなった。(著者抄録)

The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: Findings from a longitudinal observational cohort

Takahashi T., Uchida H., John M., Hirano J., Watanabe K., Mimura M., Correll C., Kishimoto T.

Schizophrenia Research （Schizophrenia Research） 147 （ 2-3 ） 383 - 386 2013年07月

ISSN 09209964

To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received ?. 2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean. ±. SD age: 58.5. ±. 11.0. years; duration of treatment: 26.7. ± 13.8. years). Patients were divided into a prolactin-raising antipsychotic (n = 141) or prolactin-sparing (n = 23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4. ± 1.6. years, a significant antipsychotic-class vs. time interaction was found (p = 0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings. © 2013 Elsevier B.V.

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[The effects of age, period, and birth cohorts on the rates of overweight and underweight students in 1977-2006 and a prediction of the rates in 2007-2016].

Odagiri Y, Uchida H, Koyama K

[Nihon koshu eisei zasshi] Japanese journal of public health 60 （ 6 ） 356 - 69 2013年06月

ISSN 0546-1766

日本版感覚プロフィールの標準化--信頼性および標準値の検討

伊藤大幸, 平島太郎, 萩原拓, 岩永竜一郎, 谷伊織, 行廣隆次, 内山登紀夫, 小笠原恵, 黒田美保, 稲田尚子, 原幸一, 井上雅彦, 村上隆, 染木史緒, 中村和彦, 杉山登志郎, 内田裕之, 市川宏伸, 辻井正次

精神医学（(株)医学書院） 55 （ 6 ） 537 - 548 2013年06月

ISSN 0488-1281

本研究では発達障害,精神疾患などにより生じる感覚処理の問題を包括的に評価する尺度として国際的に広く利用されている感覚プロフィールの日本版(SP-J)を開発し,1,441名のコミュニティサンプルのデータに基づき,その信頼性と標準値を検討した。大部分の項目で十分な修正済み項目-合計相関が示され,内的整合性の指標であるα係数もフロア効果が著しい一部の下位尺度を除いておおむね十分な値が得られた。原版の適用範囲である3〜10歳と11歳以上では,修正済み項目-合計相関もα係数も同等の結果が得られ,11歳以上にも同等の信頼性で測定を行えることが示唆された。7年齢帯ごとの標準値が得られ,SP-Jによる感覚異常の評価が可能になった。(著者抄録)

Dopamine D₂ receptor occupancy and cognition in schizophrenia

Sakurai Hitoshi, Bies Robert R., Stroup Scott T., Keefe Richard S E, Rajji Tarek K., Suzuki Takefumi, Mamo David C., Pollock Bruce G., Watanabe Koichiro, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Bulletin 39 （ 3 ） 564 - 574 2013年05月

ISSN 0586-7614

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D₂ receptors in the treatment of schizophrenia. However, effects of D₂ receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D₂ receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D₂ receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D₂ occupancy levels, on neurocognitive functions. Results: D₂ occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D₂ receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D₂ occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.

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