論文 - 内田　裕之

Relationship between polydipsia and antipsychotics: A systematic review of clinical studies and case reports

Kirino S., Sakuma M., Misawa F., Fujii Y., Uchida H., Mimura M., Takeuchi H.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  96   109756 2020年01月

ISSN  02785846

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© 2019 Elsevier Inc. Objective: This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics. Methods: We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics. Results: We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n = 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n = 14, 35.0%). Conclusions: Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.

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Antipsychotic treatment in the maintenance phase of schizophrenia: An updated systematic review of the guidelines and algorithms

Shimomura Y., Kikuchi Y., Suzuki T., Uchida H., Mimura M., Takeuchi H.

Schizophrenia Research （Schizophrenia Research）  215   8 - 16 2020年01月

ISSN  09209964

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© 2019 Elsevier B.V. Background: We updated our previous systematic review regarding clinical guidelines and algorithms on antipsychotic treatment in the maintenance phase of schizophrenia (doi: 10.1016/j.schres.2011.11.021) to incorporate and synthesize more recent findings to guide clinical practice. Methods: We conducted a systematic literature search to identify clinical guidelines and algorithms describing antipsychotic treatment in the maintenance phase of schizophrenia using MEDLINE and Embase. We assessed overall quality of the guidelines/algorithms according to the AGREE II instrument and extracted information on treatment recommendations. Results: We identified 20 guidelines/algorithms from various regions, including 11 updated or newly launched ones after the previous systematic review in 2012. All of the guidelines/algorithms satisfied a certain level of quality. Where mentioned, endorsements were sorted into “recommended”, “partially recommended”, or “not recommended”. As for antipsychotic discontinuation strategy, a majority of guidelines/algorithms that mentioned this strategy did not recommend it for multiple-episode schizophrenia (N = 5/6). On the other hand, the guidelines/algorithms tended to shift from “not recommended” to “partially recommended” both for schizophrenia in general (N = 7/13, N = 7/8 for those published after 2013) and first-episode schizophrenia (N = 10/11, N = 7/7 for those published after 2013) regarding this strategy. All guidelines/algorithms (N = 9/9) converged to discourage antipsychotic intermittent/targeted strategy. Similar to antipsychotic discontinuation strategy, all of the updated or new guidelines/algorithms (N = 6/6) endorsed antipsychotic dose reduction/lower dose strategy. Conclusion: Recent clinical guidelines and algorithms on antipsychotic maintenance treatment in schizophrenia shifted more toward a possibility of antipsychotic discontinuation and dose reduction/lower dose strategies. Nonetheless, clinicians need to contemplate on the risk-benefit balance of these strategies for individual patients.

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Lower Proportion of Fatal Arrhythmia in Sudden Cardiac Arrest Among Patients With Severe Mental Illness Than Nonpsychiatric Patients

Ishida T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychosomatics （Psychosomatics）  61 （ 1 ） 24 - 30 2020年01月

ISSN  00333182

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© 2019 Academy of Consultation-Liaison Psychiatry Background: Sudden unexpected deaths occur more frequently among patients with severe mental illness (SMI), but direct evidence on the causes is still scarce. Objective: The objective of this study is to investigate initial rhythms and characteristics of out-of-hospital cardiac arrest among patients with SMI. Methods: We conducted a systematic chart review of adult patients who suffered from out-of-hospital cardiac arrest and transferred to Tokyo Metropolitan Bokutoh Hospital in Japan between January 2011 and December 2017. The initial rhythms, clinical characteristics, and outcomes were compared between patients with schizophrenia or mood disorders (i.e., SMI) and nonpsychiatric control patients. Values of interest were compared using Fisher's exact test or Mann-Whitney U-test, as appropriate. Multiple regression analysis was also conducted to investigate the effect of SMI on the initial rhythms. Results: A total of 2631 patients were included in this study. Of these, 157 patients had SMI. Fatal arrhythmias (i.e., ventricular fibrillation and ventricular tachycardia) were less frequently noted as the initial rhythms among patients with SMI than among controls (5.7% vs. 18.8%, adjusted odds ratio = 0.27, 95% confidence interval = 0.13–0.55, P < 0.001). Patients with SMI were significantly younger (median [range], 58 years [22–85] vs. 72 years [18–108], P < 0.001) and less frequently had comorbid physical illnesses than controls (the proportion of patients without comorbidities; 58.6% vs. 37.1%, P < 0.001). Survival and neurological function at discharge were not different between the 2 groups. Conclusion: Fatal arrhythmia may account for a relatively small portion in excess of sudden death among patients with SMI. Furthermore, appropriate medical checkups for the patients with SMI at earlier ages would be important to prevent sudden cardiac death.

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Predicting relapse with residual symptoms in schizophrenia: A secondary analysis of the PROACTIVE trial

Saito Y., Sakurai H., Kane J.M., Schooler N.R., Suzuki T., Mimura M., Uchida H.

Schizophrenia Research （Schizophrenia Research）  215   173 - 180 2020年01月

ISSN  09209964

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© 2019 Elsevier B.V. Introduction: Little attention has been paid to the contribution of individual residual symptom to predict relapse in patients with schizophrenia receiving oral or long-acting injectable (LAI) antipsychotics. Method: We used the data from the Preventing Relapse on Oral Antipsychotics Compared to Injectables - Evaluating Efficacy (PROACTIVE) study, in which 305 outpatients with schizophrenia were randomly allocated to either biweekly LAI-risperidone (LAI-R) or daily oral second-generation antipsychotics (SGA) and assessed for up to 30 months. Baseline individual symptoms that could predict subsequent relapse were identified, using a Cox proportional hazards model. Moreover, among those who relapsed during the study (n = 73), individual symptoms were compared between baseline and biweekly ratings 8 to 2 weeks before relapse, using the linear mixed model. Results: A greater score in grandiosity at baseline was significantly associated with subsequent relapse (adjusted HR = 1.24, p = 0.006). When the two treatment groups were separately analyzed, more severe grandiosity (adjusted HR = 1.43, p = 0.003) and less severe hallucinatory behavior (adjusted HR = 0.70, p = 0.013) at baseline were significantly associated with relapse in the oral SGA group, but none was identified in the LAI-R group. Emotional withdrawal was significantly worse 8 and 2 weeks before relapse compared to the baseline (p = 0.032 and p = 0.043, respectively). Discussion: More severe grandiosity and less hallucination may have led to more frequent relapses in patients with schizophrenia receiving oral antipsychotics, which was not a case in those receiving LAI-R. The exploratory analysis indicates an increase in emotional withdrawal before relapse may be a useful marker for earlier interventions to possibly avert relapse.

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Study protocol for a pilot randomized controlled trial on a smartphone application-based intervention for subthreshold depression: Study protocol clinical trial (SPIRIT Compliant).

Kato Y, Kageyama K, Mesaki T, Uchida H, Sejima Y, Marume R, Takahashi K, Hirao K

Medicine 99 （ 4 ） e18934 2020年01月

ISSN  0025-7974

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Drug attitude, insight, and patient’s knowledge about prescribed antipsychotics in schizophrenia: A cross-sectional survey

Nagai N., Tani H., Yoshida K., Gerretsen P., Suzuki T., Ikai-Tani S., Mimura M., Uchida H.

Neuropsychiatric Disease and Treatment （Neuropsychiatric Disease and Treatment）  16   781 - 787 2020年

ISSN  11766328

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© 2020 Nagai et al. Introduction: While patients’ perspectives toward pharmacotherapy are expected to be directly influenced by their motivation and understanding of the treatment that they are currently receiving, no study has comprehensively investigated the impact of insight into illness and knowledge for the ongoing pharmacotherapy on the attitude towards drug treatment among patients with schizophrenia. Materials and Methods: One hundred forty-eight Japanese outpatients diagnosed with schizophrenia, according to the International Classification of Diseases 10th edition, were included (mean±SD age, 47.3±12.4 years; 90 men (60.8%)). Attitudes toward antipsychotic treatment and insight into illness were assessed with the Drug Attitude Inventory-10 (DAI-10) and the VAGUS, respectively. In addition, a multiple-choice questionnaire that was designed to examine patients’ knowledge about therapeutic effects, types, and implicated neurotransmitters of antipsychotic drugs they were receiving was utilized. Results: The mean±SD of DAI-10 score was 4.7±4.2. The multiple regression analysis found that lower Positive and Negative Syndrome Scale (PANSS) scores, higher VAGUS scores, and longer illness duration were significantly associated with higher DAI-10 scores (β=−0.226, P=0.009; β=0.250, P=0.008; β=0.203, P=0.034, respectively). There was a significant difference in the DAI-10 scores between the subjects who gave more accurate answers regarding the effects of their primary antipsychotic and those who did not (mean ±SD, 5.57±4.38 vs 4.13±4.04, P=0.043); however, this finding failed to survive the multiple regression analysis. Conclusion: Better insight into illness and treatment, lower illness severity, longer illness duration, and possibly greater knowledge about the therapeutic effects of medications may lead to better attitudes towards pharmacotherapy among patients with schizophrenia, which has an important implication for this typically chronic mental condition requiring long-term antipsychotic treatment to sustain stability.

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Pharmacological management of bipolar disorder: Japanese expert consensus

Sakurai H., Kato M., Yasui-Furukori N., Suzuki T., Baba H., Watanabe K., Inada K., Kishida I., Sugawara Kikuchi Y., Kikuchi T., Katsuki A., Uchida H.

Bipolar Disorders （Bipolar Disorders）  2020年

ISSN  13985647

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© 2020 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd Objectives: The aim of this study was to develop a consensus guideline by certified experts of the Japanese Society of Clinical Neuropsychopharmacology on the psychopharmacological treatment for bipolar disorders I and II (BP-I and BP-II), in order to fill the gap in the literature and provide more concrete guidance for challenging and controversial real-world situations. Methods: Experts were asked to assess treatment options regarding 19 clinical situations of bipolar disorder with a nine-point Likert scale (one = “disagree” and nine = “agree”). According to the responses from 119 experts, the options were categorized into the first-, second-, and third-line treatments. Results: For the treatment of BP-I, lithium monotherapy was categorized as a first-line treatment for manic episodes (mean ± standard deviation score, 7.0 ± 2.2), depressive episodes (7.1 ± 2.0), and the maintenance phase (7.8 ± 1.8). Combination therapy of lithium and an atypical antipsychotic was endorsed for manic episodes (7.7 ± 1.7), depressive episodes with (7.1 ± 2.0) and without mixed features (6.9 ± 2.2), and the maintenance phase (6.9 ± 2.1). Similarly, in BP-II, lithium monotherapy was categorized as a first-line treatment for hypomanic episodes (7.3 ± 2.2), depressive episodes (7.0 ± 2.2), and the maintenance phase (7.3 ± 2.3), while combination therapy of lithium and an atypical antipsychotic was recommended for hypomanic episodes (6.9 ± 2.4).No antipsychotic monotherapy or antidepressant treatment was categorized as a first-line treatment for any type of episode. Conclusions: These recommendations reflect the current evidence and represent the experts' consensus on using lithium for the treatment of bipolar disorder. Clinicians should consider the effectiveness and adverse effects of antipsychotic and antidepressant medications for the treatment of bipolar disorder.

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Factors Associated with Delirium following Electroconvulsive Therapy: A Systematic Review

Tsujii T., Uchida T., Suzuki T., Mimura M., Hirano J., Uchida H.

Journal of ECT （Journal of ECT）  35 （ 4 ） 279 - 287 2019年12月

ISSN  10950680

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© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives Delirium following electroconvulsive therapy (ECT) has been a clinical challenge, which, however, has not been investigated through a systematic literature review. The objective of this study was to systematically synthesize available evidence regarding factors associated with post-ECT delirium. Methods We conducted a systematic literature search for any type of original investigations that reported risk factors of post-ECT delirium, using PubMed. Results The literature search identified 43 relevant articles. One study found an association between catatonic feature and increased risk of postictal delirium. Five studies reported that the presence of cerebrovascular disease, Parkinson disease, or dementia was related to higher incidence of post-ECT delirium. Incidence of post-ECT course delirium was increased with bitemporal stimulation (3 studies). One study showed that ultrabrief pulse ECT reduced reorientation time following seizure compared with brief pulse ECT. High stimulus intensity resulted in more prolonged reorientation time after ECT than lower stimulus intensity (2 studies). Longer seizure length was significantly associated with post-ECT delirium in 1 study. Eight studies that examined postictal delirium in association with medications used, including lithium, did not show any consistent finding in their relationships. Four studies showed decreased incidence of postictal delirium in those receiving dexmedetomidine. Conclusions Limited evidence suggests that catatonic feature, cerebrovascular disease, Parkinson disease, dementia, bitemporal electrode placement, high stimulus intensity, or longer seizure length are associated with an increased risk of post-ECT delirium. Moreover, dexmedetomidine and ultrabrief pulse ECT seem to have preventive effects of post-ECT delirium.

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Concomitant use of alcohol and benzodiazepine hypnotics in psychiatric outpatients: A cross-sectional survey

Uchida T., Hirano J., Sakurai H., Suzuki T., Mimura M., Uchida H.

International Clinical Psychopharmacology （International Clinical Psychopharmacology）  34 （ 6 ） 291 - 297 2019年11月

ISSN  02681315

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© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. Concomitant use of benzodiazepines and alcohol appears prevalent in a clinical setting. The objectives of this study were as follows: (1) to investigate the prevalence of concomitant use of benzodiazepine hypnotics and alcohol in psychiatric outpatients, (2) to examine the clinical characteristics and factors associated with the concomitant use, and (3) to investigate the awareness of the psychiatrists-in-charge about the concomitant use. Outpatients with schizophrenia, depression, and insomnia who were receiving benzodiazepine hypnotics were asked to fill in a sleeping diary for seven consecutive days in which use of hypnotics and alcohol was also recorded. Clinical characteristics were assessed, and logistic analysis was performed to examine factors associated with the concomitant use. In addition, psychiatrists-in-charge were asked as to whether they thought their patients were concomitantly using them. The prevalence rate of the concomitant use was 39.8% (37/93). The CAGE score showed significant positive association with the concomitant use (odds ratio = 2.40, 95% confidence interval = 1.39-4.16, P = 0.002). Only in 32.4% of the concomitant users were suspected by their psychiatrists. The results suggest that concomitantly used benzodiazepine hypnotics and alcohol appears prevalent, and has been frequently overlooked by treating psychiatrists. The CAGE questionnaire may be helpful to screen such potentially hazardous users.

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Circadian patterns of hallucinatory experiences in patients with schizophrenia: Potentials for chrono-pharmacology

Koizumi T., Suzuki T., Pillai N., Bies R., Takeuchi H., Yoshimura K., Mimura M., Uchida H.

Journal of Psychiatric Research （Journal of Psychiatric Research）  117   1 - 6 2019年10月

ISSN  00223956

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© 2019 Elsevier Ltd The objective of this study was to investigate possible circadian pattern of psychotic symptoms in patients with schizophrenia, which could be reflected on the dosing schedule/regimen, i.e. chrono-pharmacology. Patients with schizophrenia (ICD-10) who reported having auditory hallucination, receiving monotherapy with risperidone, olanzapine or paliperidone for at least two weeks were included. The subjects were provided a diary and asked to record the time and duration of auditory hallucinations during the eight time periods (i.e. 00:00–03:00, 03:00–06:00, 06:00–09:00, 09:00–12:00, 12:00–15:00, 15:00–18:00, 18:00–21:00, and 21:00–24:00). In the diary, times of medication doses and sleep were also recorded. Time and degree of peak and trough dopamine D2 receptor blockade with antipsychotics were estimated from 2 sparsely collected plasma drug concentrations. The prevalence and duration of auditory hallucinations were statistically examined among the eight time periods, respectively. Forty-nine patients participated in this study (mean ± SD age, 50.7 ± 14.8 years; 36 men (73.5%); 34 inpatients (69.4%)). Auditory hallucinations occurred most frequently and lasted for the longest duration in the period of 18:00–21:00 (75.5% (37/49) and 1.37 ± 1.67 h). This happened despite the fact that the difference in D2 receptor occupancy between the peak and trough was less than 2%, indicating a stable drug delivery. Since the dopamine D2 receptor blockade by antipsychotics was stable, the nocturnal circadian pattern found in this study may reflect intrinsic dopaminergic fluctuation or generally quieter environments at night. These circadian patterns may be considered to devise individualized treatment approach in the context of “chrono-pharmacology” for patients with schizophrenia.

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山梨県の肝がん死亡率低下と医療行政施策の関連の検討　Joinpoint回帰

横道 洋司, 岩佐 景一郎, 内田 裕之, 小野 千恵, 米山 晶子, 高倉 江利花, 山縣 然太朗

厚生の指標 （(一財)厚生労働統計協会）  66 （ 12 ） 21 - 28 2019年10月

ISSN  0452-6104

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目的 日本の肝がん有病率は,世界の中で大きい。国と県は,1970年代より肝がん対策を行ってきた。全国と同様に,山梨県の肝がんによる死亡率は低下を続けている。これには多くの肝炎,肝がん対策が奏効していると考えられるが一方で,どの施策がその死亡率低下にどれだけ影響しているかは明らかではない。治療の向上や施策の導入の効果を推定した資料は,今後,感染症に起因する疾病に対抗する施策を考える上で必要となる。本研究は,国と山梨県が行ってきた肝炎,肝がん対策の歴史と県内の肝がんによる死亡率の変曲点との関係を,生態学的に検討することを目的とした。方法 国と県の肝炎,肝がん対策を年次推移にまとめた。次に2000年から2015年までの10万人あたりの山梨県における肝がん死亡率の分岐点をJoinpoint回帰により探索し,統計学的に変曲点を探索した。肝がん死亡率は昭和60年の日本人モデル人口により直接法で調整した。肝炎,肝がん対策の変遷と肝がん死亡率の推移を比較し,死亡率の変曲点の意味づけを試みた。結果 肝がん死亡率は2000年から2016年にかけて大きく低下し,全年齢では3つの変曲点が検出された。年齢階級別の解析では死亡率に単調な低下傾向はあるものの,変曲点は見いだされなかった。結論 B型肝炎ウイルス(HBV)ワクチン投与は1982年から段階的に拡大され,現在では乳児の定期接種ワクチンとなっている。このワクチンが肝がん死亡率低下に効果を現すのは2020年代後半以降だろうと考えられた。B型肝炎ウイルスの持続感染に対し,1985年にインターフェロン(IFN)療法が,2000年代に相次いで核酸アナログ製剤の投与が導入された。2005年からの急峻な肝がん死亡率低下にこの治療成績が寄与している可能性が示唆された。C型肝炎ウイルス持続感染に対して1992年にIFN療法が開始されている。2002年に老人保健法による「節目検診」として肝炎ウイルス検査も行われるようになった。2005年からの肝がん死亡率低下にこれらの施策も同様に貢献している可能性がある。2011年からの急峻な低下には,2001年のHCV持続感染に対するIFNとリバビリンの併用療法導入が貢献している可能性がある。山梨県がん登録データから,B型・C型肝炎の治療の発展が肝がん死亡率の低下に貢献している可能性が示された。(著者抄録)

Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis

Shinfuku M., Kishimoto T., Uchida H., Suzuki T., Mimura M., Kikuchi T.

International clinical psychopharmacology （International clinical psychopharmacology）  34 （ 5 ） 211 - 221 2019年09月

ISSN  02681315

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Long-term benzodiazepines (BZDs) use is not endorsed in the treatment guidelines for anxiety disorders, but is prevalent in the real-world clinical settings. A systematic literature review was performed by using PubMed (last search: May 2019) to identify randomized controlled trials (RCTs) or maintenance studies following RCT that examined the effectiveness of BZDs in patients with anxiety disorders for a duration of 13 weeks or more. Meta-analyses were then conducted regarding changes in the Hamilton Anxiety Rating Scale (HAM-A) scores from baseline through endpoint, all-cause discontinuation, side effects, and the numbers of panic attacks at endpoint. Eight studies were identified (N = 1228). There were no significant differences in all outcomes between BZDs and antidepressants after the initial 8-week treatment. While no significant difference was noted in the HAM-A score changes between BZDs and placebo, BZDs resulted in a lower discontinuation rate and more frequent constipation and dry mouth than placebo. Our study indicates that for those who respond to an initial 8-week treatment, continuing BZDs is equivalent to antidepressants in efficacy and safety. However, the limited number of studies warranted further investigations of the long-term effectiveness and safety of BZDs.

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Alteration in AMPA receptor subunit expression and receptor binding among patients with addictive disorders: A systematic review of human postmortem studies

Ueno F., Suzuki T., Nakajima S., Matsushita S., Mimura M., Miyazaki T., Takahashi T., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports）  39 （ 3 ） 148 - 155 2019年09月

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© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd. Background and Objectives: Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. Methods: A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. Results: Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. Conclusions and Scientific Significance: The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.

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Model-guided antipsychotic dose reduction in schizophrenia: A pilot, single-blind randomized controlled trial

Ozawa C., Bies R., Pillai N., Suzuki T., Mimura M., Uchida H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology）  39 （ 4 ） 329 - 335 2019年07月

ISSN  02710749

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© 2019 Wolters Kluwer Health, Inc. All rights reserved. Purpose/Background Patients with schizophrenia as well as their psychiatrists are hesitant to reduce the antipsychotic dose in fear of relapse. To overcome such dilemmas, we developed models to individually calculate an oral dose that corresponds to a given target dopamine D2 receptor occupancy. Methods/Procedures In this pilot, 52-week single-blind randomized controlled trial, 35 clinically stable patients with schizophrenia receiving either risperidone or olanzapine monotherapy were randomly assigned to dose reduction (n = 17) or dose maintenance group (n = 18). In the former group, baseline doses were reduced to the doses corresponding to 65% D2 occupancy (the lower end of therapeutic window) at trough that were calculated from randomly collected plasma concentrations using our models. Findings/Results In the dose reduction group, doses of risperidone and olanzapine were decreased from 4.2 ± 1.9 to 1.4 ± 0.4 and 12.8 ± 3.9 to 6.7 ± 1.8 mg/d, whereas the doses in the dose maintenance group were 4.3 ± 1.9 and 15.8 ± 4.6 mg/d, respectively. Twelve subjects (70.5%) and 13 subjects (72.2%) in the dose reduction and dose maintenance groups completed the study (P = 0.604), whereas 3 subjects (18.8%) and none dropped out because of clinical worsening in the dose reduction and dose maintenance groups, respectively. There were not significant differences in score changes in Positive and Negative Syndrome Scale between the 2 groups but in Positive subscale scores in the Clinical Global Impression-Schizophrenia (0.4 ± 0.7 in the dose reduction group vs -0.1 ± 0.7 in the dose maintenance group, P = 0.029). Implications/Conclusions Although our model-guided dose reduction strategy was found to be comparable with no-dose change in terms of dropout rates, safety issues have to be further examined.

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The microenvironment surrounding FAD mediates its conversion to 8-formyl-FAD in Aspergillus oryzae RIB40 formate oxidase.

Doubayashi D, Oki M, Mikami B, Uchida H

Journal of biochemistry 166 （ 1 ） 67 - 75 2019年07月

ISSN  0021-924X

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Long-term proton pump inhibitor use after <i>Helicobacter pylori</i> eradication may create a gastric environment for <i>N</i>-nitrosamine formation and gastric cancer development.

Kobayashi J, Uchida H, Ito J

Gut 68 （ 6 ） 1131 2019年06月

ISSN  0017-5749

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Molecular regulation of skeletal muscle mass and the contribution of nitric oxide: A review.

Kobayashi J, Uchida H, Kofuji A, Ito J, Shimizu M, Kim H, Sekiguchi Y, Kushibe S

FASEB bioAdvances 1 （ 6 ） 364 - 374 2019年06月

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Etiology of out-of-hospital cardiac arrest in psychiatric patients: Chart review

Ishida T., Miyazaki K., Yukawa T., Yamagishi T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences）  73 （ 5 ） 243 - 247 2019年05月

ISSN  13231316

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© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: Although sudden cardiac deaths are more common in psychiatric patients than the general population, data on their causes are very limited. The aim of this study was to investigate initial rhythms and causes of out-of-hospital cardiac arrest (OHCA) in patients with psychiatric disorders. Methods: We conducted a systematic chart review of patients resuscitated after OHCA and hospitalized in the Tertiary Emergency Medical Center of Tokyo Metropolitan Bokutoh Hospital in Japan between January 2010 and December 2017. The initial rhythms and causes of OHCA were compared between psychiatric patients and non-psychiatric patients. Parameters of interest were compared using chi-squared test, Fisher's exact test, or the Mann–Whitney U-test, as appropriate. Results: A total of 49 psychiatric and 600 non-psychiatric patients were eligible for this study. Fatal but shockable arrhythmias (i.e. ventricular fibrillation and ventricular tachycardia) were less frequently observed as initial rhythms in patients with psychiatric disorders than the others (22.4% vs 49.7%, P < 0.001). Cardiac origin was less common as the cause of OHCA (26.5% vs 58.5%, P < 0.01), while airway obstruction and pulmonary embolism were more frequent in psychiatric versus non-psychiatric patients (24.5% vs 6.5%, P < 0.01; and 12.2% vs 1.5%, P < 0.01, respectively). The results were similar when psychiatric patients were compared with sex- and age-matched controls selected from the non-psychiatric patient group. Conclusion: Although fatal arrhythmias may be less common, non-cardiac causes such as pulmonary embolism and airway obstruction need to be treated with high clinical suspicion in an event of sudden cardiac arrest in psychiatric patients.

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The effects of illness severity, cognition, and estimated antipsychotic dopamine receptor occupancy on insight into the illness in schizophrenia: An analysis of clinical antipsychotic trials of intervention effectiveness (CATIE) data

Ozzoude M., Nakajima S., Plitman E., Chung J., Kim J., Iwata Y., Caravaggio F., Takeuchi H., Uchida H., Graff-Guerrero A., Gerretsen P.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  89   207 - 213 2019年03月

ISSN  02785846

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© 2018 Background: The relationship between dopamine D 2 receptor (D 2 R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses. Aim and methods: We investigated the influence of estimated D 2 R (Est.D 2 R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18−62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D 2 R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D 2 R. Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D 2 R did not predict IIA, and Est.D 2 R did not serve either a moderating or mediating role in both regression and path analyses. Conclusions: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D 2 R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity.

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Impact of subjective vs. objective remission status on subjective cognitive impairments in depression

Sawada K., Yoshida K., Ozawa C., Mizuno Y., Rubinstein E., Suzuki T., Mimura M., Uchida H.

Journal of Affective Disorders （Journal of Affective Disorders）  246   99 - 104 2019年03月

ISSN  01650327

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© 2018 Elsevier B.V. Objective: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. Methods: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery–Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. Results: 102 participants were included (45 men; mean ± SD age, 50.5 ± 14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0–12.0] vs. 3.0 [range: 2.0–4.0], p < 0.001). Conclusions: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.

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