Published papers

症例は妊娠28週の36歳女性で、5日前より発熱があり、インフルエンザA型と診断された。葛根湯で治療したが、解熱しなかった。発熱は持続し、四肢優位、顔面、体幹に紫斑が出現した。オセルタミビルが処方して自宅療養を継続したが、状態は悪化した。発熱、意識障害、全身に紫斑、子宮収縮による腹痛、性器出血を認め、救急搬送された。第2病日に分娩した。血液培養からメチシリン感受性黄色ブドウ球菌(MSSA)を検出し、経食道心エコーで僧帽弁に10.2×6.9mmの可動性のある疣贅が指摘され、感染性心内膜炎と診断した。敗血症、DICの状態で、多発脳梗塞、感染性脳動脈瘤、脳出血、及び両側肺、脾臓、眼底など全身性に敗血症性塞栓症を合併した。第2病日からセフトリアキソン(CTRX)を開始した。第51病日に腹痛を訴え、血液検査では肝胆道系酵素の上昇を認めた。CTを再検査し、総胆管結石、胆管拡張を認め、経過からCTRXによる胆泥形成、胆管炎と診断した。抗菌薬治療はセフォタキシムへ変更し、慎重に経過観察した。77病日に軽快退院した。

アジスロマイシン点滴静注用(AZM)は、静脈炎予防の観点から1mg/mLに希釈して投与しなければならない。しかし体液貯留状態の患者に対して1回500mLの輸液負荷は過剰輸液になるおそれがあり、適応が難しい現状がある。米国では2mg/mLでの投与が承認されており、希釈用輸液を制限して投与を行える可能性が考えられることから、本邦での忍容性を評価することとした。疼痛評価可能な肺炎症例を対象に、AZM500mgを250mLの希釈用輸液(5%ブドウ糖液:10例、生理食塩液:2例)を用いて2mg/mLに調製し末梢静脈から2時間かけて点滴静注した際の忍容性について評価した。AZMを12症例21回投与した。19回は忍容性良好であった。1例で投与4日目に静脈炎所見が認められたが、抜針経過観察で改善した。点滴漏れが発生した投与が1回あり、評価対象から除外した。患者危険因子および希釈用輸液の種類と忍容性に関連を認めなかった。本検討は症例数が少なく、本邦での忍容性について十分検討できていないことから2mg/mLでの画一的な投与は避け輸液負荷が問題となる症例に限り選択肢の一つとすべきと考える。(著者抄録)

発達障害児者の支援に携わる全国の2,790の医療機関および福祉機関を対象に,アセスメントツールの利用の実態と利用を規定する要因を検討することを目的に調査を行った。一般的ツールの利用率は,医療機関や児童相談所では9割,発達障害者支援センターや保健センターでは7〜8割であったが,福祉施設・事業所ではわずかに2割以下であった。全般的に知能検査・発達検査が比較的よく利用されている一方で,生活能力,問題行動,発達障害特性に関するツールは利用する機関が少なかった。特に,18歳未満の利用者がいない福祉施設・事業所では,アセスメントツールの普及が遅れていた。アセスメントツールの利用には,実施者や購入資金,実施時間といった資源の不足のみならず,アセスメントに対する理解の不足,ツールの利便性の問題なども影響することが推測された。(著者抄録)

Overdosing often occurs among patients with borderline personality disorder (BPD) and confronts physicians with the dilemma of whether to prescribe psychotropic agents for them or not. Prescribing psychotropic agents is often unavoidable in the real world, because psychotherapy alone is sometimes insufficient to control their labile emotions. We report two cases of BPD in which overdosing was successfully prevented by changing the dosage form from tablets to a powder and adding a bitter taste to make it difficult to swallow a large dose at one time. Prevention of overdosing by BPD patients definitely requires a comprehensive treatment approach in terms of its social, biological, psychological, and psychopathological aspects. Although no perfect method of preventing overdosing is currently available, our method provides an option when psychotropic agents are prescribed for BPD patients in clinical practice.

Background It remains unclear regarding the contribution of each individual symptom in predicting the outcome in major depressive disorder (MDD). The objective of this analysis was to evaluate trajectories of individual symptoms over time to identify which specific depressive item(s) could predict subsequent clinical response. Methods The data of 2874 outpatients with nonpsychotic MDD who received citalopram for up to 14 weeks in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. Average trajectories of individual symptoms over time were estimated for remitters and non-remitters. Moreover, specific symptoms whose improvement at week 2 predicted remission were identified, using binary logistic regression analysis. Results Trajectories were significantly different between remitters and non-remitters in all depressive symptoms. All depressive symptoms in the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR16) in the two groups, except for hypersomnia and weight change in non-remitters, substantially improved within 2 weeks and gradually continued to improve thereafter throughout the 14 weeks. Early improvements in the following five symptoms, in order of magnitude, in the QIDS-SR16 were significantly associated with remission: sad mood, negative self-view, feeling slowed down, low energy, and restlessness (P<0.001, P<0.001, P=0.001, P=0.004, P=0.021). Limitations The participants were limited to the nonpsychotic MDD outpatients who received citalopram. Further, symptomatology was not evaluated at the very beginning of treatment. Conclusions While the data pertain to citalopram and replication is necessary for other antidepressants, early improvements in certain core depressive symptoms may serve as a predictor of subsequent remission.

Antipsychotics are increasingly being prescribed to older patients for the management of a variety of neuropsychiatric conditions. Available evidence supports the use of second-generation antipsychotics (SGAs) when treating these conditions. However, given their modest clinical effect for certain conditions (e.g., behavioural and psychological symptoms of dementia), their adverse effects, and their safety profile, a careful analysis of their risks and benefits is needed before initiating treatment with an SGA for an older patient. Among SGAs, choice of medication should be guided by their respective clinical indications and adverse effect profile, with use of lower initial and target doses (compared to younger adults) and periodic reviews of whether or not their continued use is warranted.

Impaired insight into illness (IMP-INS) is common among individuals with schizophrenia spectrum disorders (SSD), contributing to medication nonadherence and poor clinical outcomes. Caloric vestibular simulation (CVS) is typically used to assess peripheral vestibular system function. Left cold CVS is also a transiently effective treatment for IMP-INS and hemineglect secondary to right brain hemisphere stroke, and possibly for IMP-INS and mood stabilization in patients with SSD. Participants with SSD and moderate-to-severe IMP-INS participated in an exploratory double blind, crossover, randomized controlled study of the effects of CVS on IMP-INS. Participants sequentially received all experimental conditions—left cold (4 °C), right cold, and body temperature/sham CVS—in a random order. Repeated measures ANOVA were performed to compare changes in IMP-INS, mood and positive symptom severity pre and 30 min post CVS. A significant interaction was found between CVS condition, time, and body temperature nystagmus peak slow phase velocity (PSPV) for IMP-INS, indicating that single session left cold CVS transiently improved IMP-INS while right cold CVS may have worsened IMP-INS, particularly in participants with greater vestibular reactivity (i.e. higher PSPV) to body temperature CVS. The procedure's effectiveness is attributed to stimulation of underactive right hemisphere circuits via vestibular nuclei projections to the contralateral hemisphere.

Objective: To compare outcomes between increasing versus maintaining the dose of mirtazapine in patients with depression without initial improvement. Method: Data from a 6-week double-blind randomized placebo-controlled trial of mirtazapine in major depressive disorder (DSM-IV) conducted from November 2004 to December 2005 were used. Percentages of remitters (ie, a score of ≤ 7 in the 17-item Hamilton Depression Rating Scale [HDRS-17]) and HDRS-17 score changes from baseline to week 6 were compared in the following 2 pairs, using Fisher exact test or mixed-effects model for repeated measures: (1) subjects who failed to show a ≥ 20% decrease in the HDRS-17 total scores at week 1 but were assigned to continue 15 mg/d (stay15 group) versus those who were assigned to increase the dose to 30 mg/d (increase30 group) and (2) subjects who failed to show a ≥ 20% decrease in the HDRS-17 total scores with 30 mg/d at week 2 but were assigned to continue 30 mg/d (stay30 group) versus those who were assigned to increase the dose to 45 mg/d (increase45 group). Results: The increase30 group showed a numerically but not significantly higher remission rate and a significantly greater decrease in the HDRS-17 total score at week 6 than the stay15 group (34.7% [8 of 23 patients] vs 14.3% [3 of 21 patients], P = .2; least squares mean, -15.8 vs -10.9, P = .003). No significant differences were found between the increase45 and stay30 groups. Conclusions: Dose increase of mirtazapine from 15 mg/d to 30 mg/d may be effective for patients with depression without initial improvement. However, effectiveness may not be the case beyond 30 mg/d.

Background: There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. Method: A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. Results: Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000. mg/day for ≥ 6. weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. Conclusion: Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response. © 2011 Elsevier B.V.

Patients with schizophrenia have many problems as well as symptoms, and various rating scales have been in use to address them. The authors review past representative rating scales and some pivotal studies to focus on treatment target in schizophrenia. Traditionally, positive symptoms have been the main target of treatment. However, other crucial domains such as negative and cognitive symptoms, and subjective perspectives are drawing due attention because of their clinical relevance. Given many domains to be addressed, there have eventually been too many assessment scales to be selected and widely utilized in real-world clinical settings, and there has been still no concrete consensus on which scales to utilize in a given situation, which is currently decided at the discretion of the investigators. Measurement is frequently difficult even with the existing assessments, especially as what constitutes an acceptable clinical status is hard to define, considering highly hetero generous nature of the illness. Many rating scales are met with limitations especially in time and in pragmatic comprehensiveness, which often hinder their routine application in time-limited busy settings. Still, problems and functioning of patients are the reasonable target to evaluate for measurement-based treatment. The authors suggest assessment of problems resulting from symptoms together with objective functioning, which clinical psychiatrists are actually doing in everyday practice, would serve as a minimum set of standardized assessment in schizophrenia, and the newly developed TIP-Sz and FACT-Sz would serve for that purpose. Other crucial viewpoints could be supplemented with (subjective) assessment scales as appropriate.

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

© 2020 Elsevier Inc. Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p <.05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

Rationale: Taking psychotropic medications is frequently problematic from both consumers' and caregivers' perspective. Occasionally missed doses may lead to pervasive non-adherence with relapse a likely outcome. Objective: To evaluate the simple medication regimen, all psychotropics were given at night for patients with chronic schizophrenia, who had been taking them at least twice a day for more than 12 weeks before the entry. Methods: Switching of agents took place in two ways: converting only antipsychotic medications followed by other psychotropics, and changing all psychotropics simultaneously. Any psychotropics of little clinical significance were then cautiously minimized. Final evaluation was made 12 weeks after the competed dose consolidation. Patients finally rated their subjective impression on this intervention. Results: Twenty-five patients were recruited in each treatment arm (50 in total). After switching, 11 got better, 29 remained stable whereas seven got worse, according to the Global Improvement. Three were not assessable. Overall, there were no relevant changes in clinical ratings including adverse effects. However, the chlorpromazine equivalent dose of antipsychotics and the number of total psychotropics were significantly reduced from 957 to 722 mg/day (p<0.0001) and from 4.0 to 3.2 (p<0.0001), respectively. Dose deflation of psychotropics was feasible in 35 subjects (74.5%). Twenty-six (of 40 successful) patients indicated that they favored the night-time regimen mainly because it was less complicated. Sedation in the morning was identified as an important adverse event, which should be addressed by reducing the dose. Conclusions: The procedure may be of value to counteract a recent trend of psychotropic polypharmacy in schizophrenia.

We describe four elderly male inpatients with chronic schizophrenia successfully withdrawn from long-lasting antipsychotic treatment. Then we review studies in which antipsychotics were discontinued in patients 65 y.o. (or at least 50 on the average) or older using PubMed (last search; August 2014). The average (±S.D.) age, duration of illness and total duration of hospitalization of the patients were 77.0±8.6 y.o., 46.0±26.9 years, and 41.0±27.3 years, respectively. Illness severity as assessed with the Clinical Global Impression (CGI)-Severity was five for three patients and six for the other. After withdrawal from antipsychotic treatment for 28.3±11.4 weeks, none showed appreciable changes in psychopathology, functioning as well as adverse effects and the resultant CGI-Improvement was four for all patients. Compared with those who needed continuous antipsychotic treatment in the same unit (n=51; mean±S.D. age: 56.0±12.1 y.o.), they were significantly older and treated with a fewer number of total psychotropics at baseline (1.50±1.00 versus 4.94±1.93 agents). A literature search failed to find any studies in which antipsychotics were discontinued exclusively in patients with schizophrenia 65 years or older and underscored a clear paucity of data on this important topic. Cessation of chronic antipsychotic treatment could be a viable option at least in some patients with geriatric schizophrenia although more systematic studies are necessary.

Japanese researchers often find it difficult to write up academic reports in English, which may be associated with a perceived "language barrier." However, in fact, it is "emotional barrier" that discourages "potential" researchers from publishing their data. The plain English that we have learnt at school is sufficient to write academic articles in English. What is important is your guts, determination, and perseverance. In this article, tips on how to practically publish your data in English are presented.

Background: Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia. Aims: To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia. Method: Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of metaregression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment. Results: Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0-76%). The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression - Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356). Conclusions: Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early. More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

Objective: Most patients with schizophrenia first start with a single antipsychotic, and yet most finally end up 'switching' or using 'polypharmacy'. The objective of this study was to examine the evolution of antipsychotic switch and polypharmacy in the real-world from a longitudinal perspective. Methods: A systematic review of longitudinal antipsychotic prescriptions in 300 patients with schizophrenia (ICD-10) for up to 2. years after their first visit to one of the 4 participating psychiatric clinics in Tokyo, Japan between January, 2007 and June, 2008, was conducted. Reasons for prescription change were also examined. The evolution of switching and polypharmacy was studied, and prescribed doses were compared to suggested dose ranges by the Texas Medication Algorithm Project (TMAP). Results: 208 patients started their antipsychotic treatment with monotherapy. 34.1% of the patients gave up monotherapy with an initial antipsychotic to move to antipsychotic switch (27.4%) and/or polypharmacy (17.8%) within 2. years. The main reason for antipsychotic switch was 'ineffectiveness'; interestingly, this happened despite the fact that the monotherapy dose was below the recommended range in 47.4% of the antipsychotic switch. In a subgroup of 100 patients who started as antipsychotic-free, 2-year prevalence rates of switching and antipsychotic polypharmacy were 27.0% and 18.0%, respectively, and polypharmacy was resorted to after a median of 1 antipsychotic had been tried for 84. days (median). Conclusions: These findings raise a concern that physicians may perform an antipsychotic switch without exploring the entire dose range and resort to antipsychotic polypharmacy without trying an adequate number of antipsychotics.

Antipsychotic medications are widely used to manage psychotic and behavioral disorders in older adults, including primary psychotic disorders such as schizophrenia, and psychosis and behavioral disturbances associated with dementia. These two broad diagnostic indications are associated with contrasting recommended treatment durations, with the former requiring indefinite treatment across the life span. Antipsychotic drug dosing for schizophrenia is based primarily on studies of younger patients and thus may not apply to older adults. It is critically important to address the effects of aging on antipsychotic dosing given the recent emergence of data that suggest a critical role for age-related sensitivity to these drugs. Antipsychotic drugs are not only associated with somatic and neurological adverse effects but also increased all-cause mortality and sudden cardiac death in this vulnerable population. This review focuses on the sensitivity of older adults to adverse effects from antipsychotic medications and the current pharmacokinetic and pharmacodynamic explanatory models of susceptibility. Implications of recent research findings for individualized pharmacotherapy are discussed.

Data on benzodiazepine use in mood disorders are still limited, especially among seniors. A cross-sectional review of psychotropic prescriptions in 948 outpatients with mood disorders (405 male; mean ± SD age, 52 ± 17 years; age range, 16- 91 years) was conducted in Japan. The use of benzodiazepine-derivative anxiolytics was approximately 60% in all decades, including older patients, without a group difference. The frequent use of benzodiazepines is a cause for concern because they are not preferred treatment, given their well-known adverse effects especially in the elderly.

Concerns have been raised that treatment with antipsychotic medication might adversely affect long-term outcomes for people with schizophrenia. The evidence cited for these concerns includes the association of antipsychotic treatment with brain volume reduction and with dopamine receptor sensitization, which might make patients vulnerable to relapse and illness progression. An international group of experts was convened to examine findings from clinical and basic research relevant to these concerns. Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment. Randomized controlled trials strongly support the efficacy of antipsychotics for the acute treatment of psychosis and prevention of relapse; correlational evidence suggests that early intervention and reduced duration of untreated psychosis might improve longer-term outcomes. Strategies for treatment discontinuation or alternative non-pharmacologic treatment approaches maybenefit a subgroup of patients but may be associated with incremental risk of relapse and require further study, including the development of biomarkers that will enable a precision medicine approach to individualized treatment.