研究者詳細 - 内田　裕之

論文 - 内田　裕之

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Relapse of ileus in patients with psychiatric disorders

Kitahata Ryosuke, Nakajima Shinichiro, Suzuki Takefumi, Plitman Eric, Mimura Masaru, Uchida Hiroyuki

General Hospital Psychiatry 38 31 - 36 2016年01月

ISSN 0163-8343

Objective: To explore risk factors for relapse of paralytic ileus in a psychiatric population. Method: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. Results: Sixty-three subjects (38 women; age, 66.0±11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P = .03, odds ratio=4.34, 95% CI=1.15-16.42) and duration of psychiatric disorders (P = .02, odds ratio=1.00, 95% CI=1.00-1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P = .01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P = .02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. Conclusions: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus.

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Dopamine D_2/3 Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations

Nakajima Shinichiro, Uchida Hiroyuki, Bies Robert R., Caravaggio Fernando, Suzuki Takefumi, Plitman Eric, Mar Wanna, Gerretsen Philip, Pollock Bruce G., Mulsant Benoit H., Mamo David C., Graff-Guerrero Ariel

Schizophrenia Bulletin 42 （ 1 ） 212 - 219 2016年01月

ISSN 0586-7614

Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D_2/3 receptors (D_2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [¹¹C]-raclopride positron emission tomography scan to measure D_2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D_2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D_2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D_2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D_2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D_2/3R occupancy on an individual basis.

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Dopamine D<inf>2/3</inf> Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial

Nakajima S., Uchida H., Bies R., Caravaggio F., Suzuki T., Plitman E., Mar W., Gerretsen P., Pollock B., Mulsant B., Mamo D., Graff-Guerrero A.

Schizophrenia Bulletin （Schizophrenia Bulletin） 42 （ 1 ） 212 - 219 2016年01月

ISSN 05867614

© 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com. Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [11C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.

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Relapse of ileus in patients with psychiatric disorders: A 2-year chart review

Kitahata R., Nakajima S., Suzuki T., Plitman E., Mimura M., Uchida H.

General Hospital Psychiatry （General Hospital Psychiatry） 38 31 - 36 2016年01月

ISSN 01638343

© 2016 Elsevier Inc.. Objective: To explore risk factors for relapse of paralytic ileus in a psychiatric population. Method: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. Results: Sixty-three subjects (38 women; age, 66.0±11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P = .03, odds ratio=4.34, 95% CI=1.15-16.42) and duration of psychiatric disorders (P = .02, odds ratio=1.00, 95% CI=1.00-1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P = .01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P = .02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. Conclusions: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus.

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Early Improvements in Individual Symptoms to Predict Later Remission in Major Depressive Disorder Treated With Mirtazapine

Funaki K., Nakajima S., Suzuki T., Mimura M., Uchida H.

Journal of Clinical Pharmacology （Journal of Clinical Pharmacology） 56 （ 9 ） 1111 - 1119 2016年

ISSN 0091-2700

© 2016, The American College of Clinical Pharmacology Few studies, to our knowledge, have examined whether early improvements in individual, instead of overall, depressive symptoms predict remission in major depressive disorder (MDD). This post hoc analysis used data from 194 patients with MDD enrolled in a 6-week double-blind, placebo-controlled, randomized trial of mirtazapine, to identify improvements in specific individual depressive symptoms in the early phase that are associated with subsequent remission. Trajectories of individual depressive symptoms over 6 weeks were compared between remitters and nonremitters. Early improvement was defined as a ≥20% decrease in the Hamilton Rating Scale for Depression 17 items (HAM-D17) total score in weeks 1 and 2, and remission was defined as a HAM-D17 final score of ≤7. Reliability parameters were calculated for early improvements in predicting later remission. Whether improvement in each of the HAM-D17 symptoms in weeks 1 or 2 predicted remission was examined, using binary logistic regression analyses. As a result, improvements in weeks 1 and 2 were associated with sensitivity of 0.82 and 0.99 and specificity of 0.54 and 0.44, respectively, in predicting remission in week 6. Improvements in insomnia late (P =.04) and insight (P =.007) in week 1 and somatic symptoms general (P =.002) and insight (P =.04) in week 2 were associated with remission in week 6. In conclusion, early improvements in insight, insomnia late, and somatic symptoms general, as well as overall depressive symptoms, may serve as specific clinical indicators of subsequent remission in patients with MDD receiving mirtazapine.

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Development of a Transnasal Delivery System for Recombinant Human Growth Hormone (rhGH): Effects of the Concentration and Molecular Weight of Poly-L-arginine on the Nasal Absorption of rhGH in Rats.

Kawashima R, Uchida M, Yamaki T, Ohtake K, Hatanaka T, Uchida H, Ueda H, Kobayashi J, Morimoto Y, Natsume H

Biological & pharmaceutical bulletin 39 （ 3 ） 329 - 35 2016年

ISSN 0918-6158

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A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature

Zohar J., Stahl S., Moller H.J., Blier P., Kupfer D., Yamawaki S., Uchida H., Spedding M., Goodwin G.M., Nutt D.

European Neuropsychopharmacology （European Neuropsychopharmacology） 25 （ 12 ） 2318 - 2325 2015年12月

ISSN 0924-977X

© 2015. Neuroscience based Nomenclature (NbN) is a new system of classifying psychotropic drugs by their pharmacological profile. The NbN was developed to replace the current indication-based nomenclature and to provide an up-to-date and more useful framework to better inform pharmacological decisions. NbN provides updated relevant and specific scientific, regulatory and clinical information, aiming to support rational and lucid prescribing. This pharmacologically driven nomenclature, which highlights pharmacological domains and modes of action, may also increase drug adherence as it clarifies the rationale for selecting a specific psychotropic agent.

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Effects of glutamate positive modulators on cognitive deficits in schizophrenia

Iwata Y., Nakajima S., Suzuki T., Keefe R. S E, Plitman E., Chung J. K., Caravaggio F., Mimura M., Graff-Guerrero A., Uchida H.

Molecular Psychiatry 20 （ 10 ） 1151 - 1160 2015年10月

ISSN 1359-4184

Hypofunction of N-methyl-d-Aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-Analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

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Effects of glutamate positive modulators on cognitive deficits in schizophrenia: A systematic review and meta-Analysis of double-blind randomized controlled trials

Iwata Y., Nakajima S., Suzuki T., Keefe R., Plitman E., Chung J., Caravaggio F., Mimura M., Graff-Guerrero A., Uchida H.

Molecular Psychiatry （Molecular Psychiatry） 20 （ 10 ） 1151 - 1160 2015年10月

ISSN 13594184

© 2015 Macmillan Publishers Limited All rights reserved. Hypofunction of N-methyl-d-Aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-Analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

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Predicting Plasma Olanzapine Concentration Following a Change in Dosage

Tsuboi T., Bies R. R., Suzuki T., Takeuchi H., Nakajima S., Graff-Guerrero A., Mamo D. C., Caravaggio F., Plitman E., Mimura M., Pollock B. G., Uchida H.

Pharmacopsychiatry 48 （ 7 ） 286 - 291 2015年10月

ISSN 0176-3679

Introduction: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. Methods: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM^®, using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. Results: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p

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Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study

Tsuboi T., Bies R., Suzuki T., Takeuchi H., Nakajima S., Graff-Guerrero A., Mamo D., Caravaggio F., Plitman E., Mimura M., Pollock B., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 48 （ 7 ） 286 - 291 2015年10月

ISSN 01763679

© Georg Thieme Verlag KG Stuttgart New York. Introduction: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. Methods: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM®, using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. Results: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001). Discussion: Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty.

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Clinical and biological correlates of resilience in patients with schizophrenia and bipolar disorder

Mizuno Yuya, Hofer Alex, Suzuki Takefumi, Frajo-Apor Beatrice, Wartelsteiner Fabienne, Kemmler Georg, Saruta Juri, Tsukinoki Keiichi, Mimura Masaru, Fleischhacker W. Wolfgang, Uchida Hiroyuki

Schizophrenia Research 2015年09月

ISSN 0920-9964

Objective: The concept of resilience is relevant in understanding the heterogeneous outcomes noted in schizophrenia and bipolar disorder. However, clinical and biological correlates of resilience in these populations have rarely been investigated. We aimed to identify key correlates of subjective resilience in such patients using comprehensive assessments and to explore associations between resilience levels and peripheral biomarkers. Method: 180 subjects with DSM-IV schizophrenia, bipolar disorder, and healthy controls (60 per group) were included. Demographic and clinical variables were assessed by means of interview and various psychometric scales. Furthermore, blood and saliva samples were obtained for the assessment of brain-derived neurotrophic factor, adrenocorticotropic hormone, cortisol, high sensitivity C-reactive protein, and alpha-amylase levels. Cross-sectional associations with resilience, as assessed by the 25-item Resilience Scale were sought. Results: Resilience Scale total scores were significantly higher in healthy individuals (130.1, 95% confidence intervals (CI): 124.8-135.4) compared to subjects with schizophrenia (109.9, 95% CI: 104.6-115.2, p.

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Evaluation of antipsychotic dose reduction in late-life schizophrenia

Graff-Guerrero Ariel, Rajji Tarek K., Mulsant Benoit H., Nakajima Shinichiro, Caravaggio Fernando, Suzuki Takefumi, Uchida Hiroyuki, Gerretsen Philip, Mar Wanna, Pollock Bruce G., Mamo David C.

JAMA Psychiatry 72 （ 9 ） 927 - 934 2015年09月

ISSN 2168-622X

IMPORTANCE Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D<inf>2/3</inf> receptor (D<inf>2/3</inf>R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D<inf>2/3</inf>R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS An open-label, single-arm prospective study with a 3- To 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. INTERVENTIONS Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. MAIN OUTCOMES AND MEASURES Striatal dopamine D<inf>2/3</inf>R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). RESULTS Dopamine D<inf>2/3</inf>R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D<inf>2/3</inf>R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D<inf>2/3</inf>R occupancies higher than 60%: 90.5%(19 of 21) of the participants with baseline EPSs and 76.9%(10 of 13) of the participants with postreduction EPSs had striatal D<inf>2/3</inf>R occupancies higher than 60%. The baseline D<inf>2/3</inf>R occupancieswere lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58%[15%] vs 72%[10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased. CONCLUSIONS AND RELEVANCE Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D<inf>2/3</inf>R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

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Antidepressant dose and treatment response in bipolar depression

Tada Mitsuhiro, Uchida Hiroyuki, Mizushima Jin, Suzuki Takefumi, Mimura Masaru, Nio Shintaro

Journal of Psychiatric Research 68 151 - 156 2015年09月

ISSN 0022-3956

The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with </=2 symptoms) and treatment-emergent affective switch (i.e. transition to mania or hypomania), respectively. In the evaluable 333 subjects, subjects in both the high-dose (n=102) and placebo groups (n=169) more significantly achieved durable recovery than the low-dose group (n=62) (odds ratio=3.013 [p=0.009], 2.899 [p=0.008], respectively). No significant association was found between the dose status and treatment-emergent affective switch (p=0.614). The allocation to either high- and low-dose antidepressants was not randomized and the dose was guided by a case-by-case decision, which hampers to draw a firm conclusion on dose-response issues and renders the findings as preliminary. Nevertheless, higher doses of adjunctive antidepressant drugs seem to have potential for yielding greater clinical improvement without increasing any risk of manic switch compared to lower doses, at least in carefully selected patients.

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Antidepressant dose and treatment response in bipolar depression: Reanalysis of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) data

Tada M., Uchida H., Mizushima J., Suzuki T., Mimura M., Nio S.

Journal of Psychiatric Research （Journal of Psychiatric Research） 68 151 - 156 2015年09月

ISSN 00223956

© 2015 Elsevier Ltd. The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with </=2 symptoms) and treatment-emergent affective switch (i.e. transition to mania or hypomania), respectively. In the evaluable 333 subjects, subjects in both the high-dose (n=102) and placebo groups (n=169) more significantly achieved durable recovery than the low-dose group (n=62) (odds ratio=3.013 [p=0.009], 2.899 [p=0.008], respectively). No significant association was found between the dose status and treatment-emergent affective switch (p=0.614). The allocation to either high- and low-dose antidepressants was not randomized and the dose was guided by a case-by-case decision, which hampers to draw a firm conclusion on dose-response issues and renders the findings as preliminary. Nevertheless, higher doses of adjunctive antidepressant drugs seem to have potential for yielding greater clinical improvement without increasing any risk of manic switch compared to lower doses, at least in carefully selected patients.

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Evaluation of antipsychotic dose reduction in late-life schizophrenia: A prospective dopamine D<inf>2/3</inf> receptor occupancy study

Graff-Guerrero A., Rajji T., Mulsant B., Nakajima S., Caravaggio F., Suzuki T., Uchida H., Gerretsen P., Mar W., Pollock B., Mamo D.

JAMA Psychiatry （JAMA Psychiatry） 72 （ 9 ） 927 - 934 2015年09月

ISSN 2168622X

Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS An open-label, single-arm prospective study with a 3- To 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. INTERVENTIONS Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. MAIN OUTCOMES AND MEASURES Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). RESULTS Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D2/3R occupancies higher than 60%: 90.5%(19 of 21) of the participants with baseline EPSs and 76.9%(10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancieswere lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58%[15%] vs 72%[10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased. CONCLUSIONS AND RELEVANCE Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

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Language barriers and access to psychiatric care

Ohtani Ai, Suzuki Takefumi, Takeuchi Hiroyoshi, Uchida Hiroyuki

Psychiatric Services 66 （ 8 ） 798 - 805 2015年08月

ISSN 1075-2730

Objective: The objective of this study was to synthesize the available evidence regarding the impact of patients' language proficiency on access to psychiatric care. Methods: A systematic literature search of PubMed, EMBASE, Medline, and PsycINFO was performed to identify studies published between January 1950 and July 2014 that examined the impact of language proficiency on access to and utilization of psychiatric services in the general population or among patients with psychiatric disorders. The keywords were psychiatry, language, utilization, access, and mental health care. Only articles in English were included. Cross-referencing of the identified articles was also performed. Results: Eighteen articles from four countries were identified, including 13 from the United States, two from Australia, two from Canada, and one from the Netherlands. These reports were generally consistent in showing a clear association between insufficient language proficiency and underutilization of psychiatric services; 15 studies reported that limited language proficiency was significantly associated with less frequent mental health care visits.Only one article showed an inverse relationship between limited language proficiency and use of mental health services, and two articles reported no association. No published data were found on the effects of linguistic interventions on access to mental health care among people with limited language proficiency. Conclusions: It is plausible that limited language proficiency is closely associated with underutilization of psychiatric services. Still, the lack of prospective interventional data clearly highlights the need for further investigations of the impact of language barriers on access to psychiatric care.

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Language barriers and access to psychiatric care: A systematic review

Ohtani A., Suzuki T., Takeuchi H., Uchida H.

Psychiatric Services （Psychiatric Services） 66 （ 8 ） 798 - 805 2015年08月

ISSN 10752730

Objective: The objective of this study was to synthesize the available evidence regarding the impact of patients' language proficiency on access to psychiatric care. Methods: A systematic literature search of PubMed, EMBASE, Medline, and PsycINFO was performed to identify studies published between January 1950 and July 2014 that examined the impact of language proficiency on access to and utilization of psychiatric services in the general population or among patients with psychiatric disorders. The keywords were psychiatry, language, utilization, access, and mental health care. Only articles in English were included. Cross-referencing of the identified articles was also performed. Results: Eighteen articles from four countries were identified, including 13 from the United States, two from Australia, two from Canada, and one from the Netherlands. These reports were generally consistent in showing a clear association between insufficient language proficiency and underutilization of psychiatric services; 15 studies reported that limited language proficiency was significantly associated with less frequent mental health care visits.Only one article showed an inverse relationship between limited language proficiency and use of mental health services, and two articles reported no association. No published data were found on the effects of linguistic interventions on access to mental health care among people with limited language proficiency. Conclusions: It is plausible that limited language proficiency is closely associated with underutilization of psychiatric services. Still, the lack of prospective interventional data clearly highlights the need for further investigations of the impact of language barriers on access to psychiatric care.

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Optimization of psychopharmacotherapy for schizophrenia in a male, locked, non-acute unit serving for persistently ill patients over one year

Suzuki T., Uchida H., Takeuchi H., Tsunoda K., Ishizuki T., Mimura M.

Psychiatry Research （Psychiatry Research） 228 （ 1 ） 26 - 30 2015年07月

ISSN 0165-1781

© 2015 Elsevier Ireland Ltd. We describe real-world psychopharmacological treatment in a Japanese, male, closed psychiatric unit where clozapie was still unavailable. Fifty-five persistently-ill patients with schizophrenia (ICD-10), mean±S.D. age: 57.5±13.0 y.o., duration of illness and admissions: 30.9±15.2 years and 20.7±14.5 years, respectively) treated longitudinally were evaluated. The rule was to treat with a simplest possible psychotropic regimen without polypharmacy. Compared to the baseline, the number and dose of antipsychotics were reduced from 1.9 to 1.1 and 1012 mg/day to 607 mg/day, respectively. The number of total psychotropics was minimized from 4.7 to 2.1, with a simplified once or twice daily dosing. Overall, the CGI-Severity and FACT-Sz (global functioning) improved slightly from 5.8 to 5.5 and 28.7 to 32.6, respectively. Of note, no patients got worse in comparison with the baseline clinical presentation. Forty-four patients were successfully treated with a single antipsychotic; only seven needed two antipsychotics simultaneously while 36 had been treated with antipsychotic polypharmacy at baseline. Benzodiazepines (mostly lorazepam) and antiparkinsonian drugs were prescribed in 28 and only two, respectively. Nineteen needed adjunctive valproate (average blood levels: 99.3±21.8 μg/mL) and nine used lithium (0.61±0.26. mEq/L). Optimization of psychopharmacotherapy is still possible for difficult-to-treat patients and, while augmentation of an antipsychotic with mood stabilizers is frequently needed, antipsychotic polypharmacy should be exceptional.

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Relationships between global assessment of functioning and other rating scales in clinical trials for schizophrenia

Suzuki T., Uchida H., Sakurai H., Ishizuki T., Tsunoda K., Takeuchi H., Mimura M.

Psychiatry Research （Psychiatry Research） 227 （ 2-3 ） 265 - 269 2015年06月

ISSN 0165-1781

© 2015 Elsevier Ireland Ltd. The relationship between the Global Assessment of Functioning (GAF) with other scales in schizophrenia has rarely been investigated. A systematic literature search was conducted to identify articles that reported the GAF score together with scores in the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) or Brief Psychiatric Rating Scale (BPRS), using MEDLINE, EMBASE and PsycINFO, with keywords of schizophrenia, clinical trial and global assessment of functioning (last search 30 June 2013). Correlational analyses with weighting by the study participant numbers across these rating scales were performed. In 40 clinical trials (. n=8000) that reported cross-sectional data on the GAF and PANSS, a significant but modest correlation was noted (Pearson[U+05F3]s r=-0.401, p<0.0001). Furthermore, a correlation between the GAF and CGI-severity (CGI-S) at study baseline in 38 studies ( n=11,315) was robust ( r=-0.893, p<0.0001). In longitudinal studies, changes in the GAF scores were negatively correlated with those in the PANSS as well as CGI-S scores ( p<0.0001 for both). Data on the BPRS were all statistically significant although relatively scarce. While optimal degree of concordance is undetermined among psychiatric scales that are presumed to be measuring different but overlapping constructs, this study found significant correlations in the GAF and CGI-S or PANSS, both cross-sectionally and longitudinally. The GAF-CGI-S relationship was especially tighter, making it a reliable clinical indicator.

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