Published papers

Background: The dominant diagnostic model of the classification of depression today is unitarian; however, since Kurt Schneider (1920) introduced the concept of endogenous depression and reactive depression, the binary model has still often been used on a clinical basis. Notwithstanding this, to our knowledge, there have been no collective data on how psychiatrists differentiate these two conditions. We therefore conducted a survey to examine how psychiatrists in Japan differentiate patients with major depressive disorder who present mainly with melancholic features and those with reactive features.Methods: Three case scenarios of melancholic and reactive depression, and one-in-between were prepared. These cases were designed to present with at least 5 symptoms listed in the DSM-IV-TR with severity being mild. We have sent the questionnaires regarding treatment options and diagnosis for those three cases on a 7-point Likert scale (1 = "not appropriate", 4 = "cannot tell", and 7 = "appropriate"). Five hundred and two psychiatrists from over one hundred hospitals and community clinics throughout Japan have participated in this survey.Results: The melancholic case resulted significantly higher than the reactive case on either antidepressants (mean ± SD: 5.9 ± 1.2 vs. 3.6 ± 1.7, p < 0.001), hypnotics (mean ± SD: 5.5 ± 1.1 vs. 5.0 ± 1.3, p < 0.001), and electroconvulsive therapy (mean ± SD: 1.5 ± 0.9 vs. 1.2 ± 0.6, p < 0.001). On the other hand, the reactive case resulted in significantly higher scores compared to the melancholic case and the one- in-between cases in regards to psychotherapy (mean ± SD: 4.9 ± 1.4 vs. 4.3 ± 1.4 vs. 4.7 ± 1.5, p < 0.001, respectively). Scores for informing patients that they suffered from "depression" were significantly higher in the melancholic case, compared to the reactive case (mean ± SD: 4.7 ± 1.7 vs. 2.2 ± 1.4, p < 0.001).Conclusions: Japanese psychiatrists distinguish between major depressive disorder with melancholic and reactive features, and thus choose different treatment strategies regarding pharmacological treatment and psychotherapy. © 2013 Mizushima et al.; licensee BioMed Central Ltd.

Objective: To report the usefulness of antipsychotic dose-reduction for avoiding paralytic ileus in a patient with chronic schizophrenia and comorbid dementia. Case summary: A 65-year-old in-patient developed severe paralytic ileus warranting a transfer to the general hospital. Constipation was very troublesome and he often needed enema to prevent intestinal obstruction. He had originally been treated with 24 mg of bromperidol, which was reduced to 4 mg, and other psychotropic treatments were simultaneously simplified. As a result, bowel habits improved and enema is now only rarely necessary. Constipation is a frequent adverse effect of antipsychotics and adjunctive psychotropics, which can be severe and may lead to life-threatening paralytic ileus. Dose-reduction obviated a necessity of enema against persistent constipation, while the patient's mental status remained under control. Assessment using the Naranjo probability scale revealed a definite causal relationship. Discussion: With an increasing number of elderly patients with schizophrenia, more cases of severe gastrointestinal motility problems from antipsychotic medication are to be expected. In this patient population dose-reduction of antipsychotics and simplification of concomitant psychotropics should be seriously considered. © 2007 The Authors.

Objective: Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D2 binding of long-acting risperidone administered intramuscularly once a month. Method: Following at least 3 maintenance monthly injections of 50 mg long-acting risperidone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder underwent PET using [11C]raclopride to measure D2 binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. Results: The mean ± SD D2 receptor occupancy was 56% ± 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D2 occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean ± SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 ± 12.3 ng/mL (range, 5.7-40.8). Conclusion: As with plasma levels, there was considerable variability in D2 occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D2 occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. Trial Registration: clinicaltrials.gov Identifier: NCT00236353 © Copyright 2008 Physicians Postgraduate Press, Inc.

© 2018 Elsevier Ltd Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

© 2019 Royal Society of Chemistry. All rights reserved. Introduction Kampo is a Japanese traditional medicinal system and is represented by unity of mind and body. It is originally based upon Chinese traditional medicine but has uniquely developed in Japan. Methods A narrative review on the use of Kampo for psychiatric conditions is provided. Results Kampo formula is a combination of several crude ingredients; most derive from natural plants and some from animals and minerals. These Kampo formulae are widely prescribed in almost all medical disciplines, including psychiatry, in Japan; they have been used for various psychiatric disorders such as dementia, schizophrenia spectrum disorders, mood disorders, anxiety disorders, and personality disorders. Kampo is a versatile traditional medicine with a variety of positive effects on mental states with relatively benign side effect profiles. Kampo formulae can be adjunctively combined with or substituted for the Western psychotropic drugs, which will provide more treatment options to patients with psychiatric conditions. Discussion This review summarizes the current knowledge on Kampo for psychiatric conditions, highlighting a paucity of data and a need for further good-quality evidence on these medications.

Background: The aim of the study was to develop the Japanese versions of Executive Interview (J-EXIT25) and Executive Clock Drawing Task (J-CLOX) and to evaluate the aspects of executive function that these two tests will be examining. Methods: The concurrent validity and reliability of J-EXIT25 and J-CLOX were first examined in all participants (n = 201). Next, the relationship between the two tests was examined using receiver operating characteristic (ROC), correlation, and regression analyses in healthy participants (n = 45) and participants with mild cognitive impairment (n = 36) and dementia (n = 95). Results: Satisfactory concurrent validity and reliability of J-EXIT25 and J-CLOX were shown. ROC analysis indicated that J-EXIT25 and J-CLOX1 were superior to the Frontal Assessment Battery, but inferior to the Mini-Mental State Examination (MMSE), in discriminating between non-dementia and dementia. J-EXIT25, J-CLOX1, and J-CLOX2 scores were significantly correlated with age, scores on the MMSE, Instrumental Activities of Daily Living (IADL) and Physical Self-Maintenance Scale (PSMS), and care level. In stepwise regression analyses of IADL scores, MMSE and J-EXIT25 were significantly independent predictors in men, and MMSE, age, and J-CLOX1 were significantly independent predictors in women. J-EXIT25, MMSE, and J-CLOX1 were significantly independent predictors in stepwise regression analysis of PSMS scores, and J-EXIT25 was the only significantly independent predictor in stepwise regression analysis of care level. Conclusions: J-EXIT25 and J-CLOX are valid and reliable instruments for assessment of executive function in older people. The present results suggest that these tests have common and distinct psychometric properties in the assessment of executive function.

Background: Although physical restraint is still used in psychiatric inpatient settings, it sometimes causes serious side effects, including deep vein thrombosis (DVT) and resulting pulmonary embolism. Objective: The aim of this study was to investigate the incidence of the DVT in restrained patients who were receiving routine prophylaxis and to identify the risk factors of this condition. Methods: This study was conducted at Sakuragaoka Memorial Hospital, Japan from December 2008 to September 2010. Inpatients who were restrained during the study period were included. All restrained patients wore graduated compression stockings and were recommended to receive subcutaneous injection of unfractionated heparin during the period of restraint unless it was contraindicated. When plasma d-dimer level at the time of removal of restraint was ≥ 0.50. μg/dL, the patients underwent a Doppler ultrasound scanning of their lower extremities to examine the presence of DVT. A multiple logistic regression model was used to examine the effects of demographic and clinical characteristics on the incidence of DVT. Results: A total of 181 patients (98 men; mean ± standard deviation age, 47.8 ± 17.0. y) were included; DVT was detected in 21 patients (11.6%). A longer duration of restraint (odds ratio = 9.77, 95% confidence interval = 1.56-61.03, p = 0.015), excessive sedation (odds ratio = 4.90, 95% confidence interval = 1.33-18.02, p = 0.017), lower antipsychotic dosage (odds ratio = 0.05, 95% confidence interval = 0.005-0.57, p = 0.016), and recent medical hospitalization (odds ratio = 11.44, 95% confidence interval = 2.13-61.47, p = 0.004) were significantly associated with the incidence of DVT. Conclusion: The incidence of DVT in restrained psychiatric patients was not low in spite of prophylaxis. These findings emphasize the importance of regular screening of and thorough assessments of DVT, especially in restrained psychiatric patients.

Alzheimer's disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an 'anticholinergic burden', and also that medicine with anticholinergic properties would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning the relationship between anticholinergic burden and clinical AD symptoms. Therefore, we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA-) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation, hallucinations and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances.

Objective: The primary objective of this article is to review the literature regarding clinical effects, pharmacokinetics, and pharmacodynamics of antipsychotics in older people and to examine potential mechanisms underlying the age-related antipsychotic sensitivity. Data Sources: Data for this review were identified by searches of PubMed (1950-2007) and references from relevant articles and books. Search terms included antipsychotic, neuroleptic, elderly, aging, pharmacokinetics, pharmacodynamics, and dopamine, and only articles written in English or Japanese were consulted. Data Selection: Studies, reviews, and books pertaining to the clinical effects, pharmacokinetics, and pharmacodynamics with regard to the use of antipsychotics in older patients were selected. Data Synthesis: The prevailing practices and clinical guidelines suggest that elderly patients can obtain therapeutic benefits at a lower dose and experience adverse effects from antipsychotics more often than younger patients, although there are still few trials that have directly compared elderly patients with the young. The literature suggests an age-related increase in brain access of drugs and demonstrates a decrease with age in the principal components in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Conclusions: While clinicians conclusively hold that patients become more sensitive to antipsychotics as they become older, this proposition has only modest empirical support and warrants further investigation. Age-related functional decline in the dopaminergic system predicts lower antipsychotic doses for older patients. We propose a hierarchical series of testable hypotheses to address the relative contribution of age-related pharmacokinetic and pharmacodynamic changes to antipsychotic drug sensitivity. © Copyright 2009 Physicians Postgraduate Press, Inc.

© Copyright 2016 Physicians Postgraduate Press, Inc. Objective: While doctors often increase the dose of an antipsychotic when there is insufficient response, there is limited evidence that this intervention is any better than waiting longer on the lower dose. We put the proposition to test. Method: In this 4-week, double-blind, randomized controlled trial conducted in psychiatric care from September 2012 to March 2015, 103 patients with schizophrenia (ICD-10) who did not respond to olanzapine 10 mg/d or risperidone 3 mg/d were randomly allocated to a dose-increment or -continuation group. In the increment group, antipsychotic doses were doubled for 4 weeks, whereas in the continuation group, doses were not changed. Completion rate (primary outcome measure); changes in psychopathology, function, and extrapyramidal symptoms; and response rate were compared between the groups. The relationship between baseline plasma antipsychotic concentrations and changes in psychopathology was examined. Results: The completion rate was significantly lower in the increment group than in the continuation group (69.2% [36/52] vs 86.3% [44/51], P = .038). No significant superiority was observed in any of the outcome measures in the increment group compared to the continuation group, except the Positive and Negative Syndrome Scale (PANSS) positive subscale score change in intentionto- treat analysis. Those with lower plasma concentrations of olanzapine on their initial treatment showed a greater improvement on the PANSS positive subscale when their dose was increased (P = .042). Conclusions: As a general strategy, patients with schizophrenia failing to respond to moderate antipsychotic doses may not benefit from an increase in dose. The possibility of benefit in those whose plasma antipsychotic concentrations at baseline are still low cannot be ruled out. Trial Registration: UMIN.ac.jp/ctr/index.htm identifier: UMIN000008667.

© 2017 Elsevier Ireland Ltd Little is known about the influence of D2 receptor occupancy on impaired insight into illness (III)—a core feature of schizophrenia. III is associated with illness severity and cognitive dysfunction. Comparably, supratherapeutic D2 receptor occupancy can impair cognition. However, it is unclear how illness severity, cognition, and D2 receptor occupancy interact to influence III in schizophrenia. The aim of this study was to explore the influence of antipsychotic dose reduction on the relationships of illness severity and cognition to III. III was assessed at baseline and 28 weeks post-antipsychotic dose reduction in 16 participants with schizophrenia and plasma antipsychotic concentrations. III was assessed primarily with the Schedule for the Assessment of Insight–Japanese version, and secondarily with the Positive and Negative Syndrome Scale item G12. Correlation and regression analyses were performed to explore III's relationship to illness severity, cognition, and estimated D2 receptor occupancy (Est.D2). Cognition and Est.D2 predicted III at baseline. At 28 weeks post-reduction, illness severity and Est.D2 predicted III. Our findings suggest a complex relationship may exist among III, illness severity, cognition and Est.D2. At higher D2 receptor occupancies, III is influenced by cognitive dysfunction, whereas, at lower occupancies, illness severity has a stronger effect on III.

Background: It still remains unclear as to how to counteract antipsychotic polypharmacy that remains controversial but common. The objective of this study was to synthesize the clinical evidence to reduce antipsychotic polypharmacy (i.e. use of multiple antipsychotics) in schizophrenia. Methods: A literature search was performed to identify clinical trials that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia by any form of systematic intervention using PubMed as well as MEDLINE, EMBASE, and PsycINFO (last search: June 2012). The search terms included "antipsychotics" and "polypharmacy". Cross-referencing was also performed. Results: The literature search identified 17 studies. Only 3 studies (1 randomized controlled trial and 2 open-label trials) were found that systematically switched antipsychotic polypharmacy to monotherapy. In two of them, more than two thirds of the subjects successfully completed the switch (40/58, 69.0%; 34/44, and 77.3%, respectively) while less than half the subjects tolerated it in the other study (6/14 and 42.9%) although the sample size was very small. On the other hand, 14 studies that examined impacts of interventions have physicians refrain from antipsychotic polypharmacy. While a modest intervention with educational approach alone was effective in three of the five articles, a more assertive intervention that directly cautioned physicians on the use of polypharmacy was effective in 10 of 12 articles. Conclusion: The literature search revealed the paucity of the data. Careful switching from polypharmacy to monotherapy seems feasible in a majority of patients with schizophrenia. Assertive interventions, rather than passive educational approaches alone, appear more effective in reducing antipsychotic polypharmacy. © 2012 Elsevier B.V.

Rationale: Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2. weeks and early treatment nonresponse is a predictor of subsequent nonresponse. Objectives: We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy. Method: Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50. mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100. mg, whereas sertraline was switched to paroxetine 20-40. mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8. Results: Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001). Conclusions: Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression. © 2011 Elsevier Inc.

The aim of this study was to explore the factor structure of a novel, 10-item rating scale, the Targeted Inventory on Problems in Schizophrenia (TIP-Sz). Determining the factor structure will be useful in the brief evaluation of medication and non-medication treatment of the disease. Methods: An exploratory factor analysis was performed on TIP-Sz scores obtained from 100 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia. Results: The factor analysis extracted four factors that were deemed clinically pertinent, which we labeled: disorganization, social cooperativeness, functional capacity, and emotional state. The items exhibited cross-loadings on the first three factors (i.e., some items loaded on more than one factor). In particular, the 'behavioral dyscontrol and disorganization,' 'insight and reality testing,' and 'overall prognostic impression' items had comparable cross-loadings on all of the first three factors. The emotional state factor was distinct from the other factors in that the items loading on it did not cross-load on other factors. Conclusion: The TIP-Sz scale comprises factors that are associated with the psychosocial functioning and emotional state of patients, which are important outcome parameters for successful treatment of the disease.

Objective: How honestly patients report their symptoms and medication adherence to their physicians has not been adequately addressed in patients with depression. We therefore conducted a large-scale Internet survey in an effort to discover how successful physicians are in eliciting the truth from their patients and also to examine reasons for patients' truth-concealing behaviors. Method: 2,354 participants who had received treatment for depression within the past year and had been diagnosed with depression by Patient Health Questionaire were identified from 323,226 registrants at the Macromill database through screening procedures. Participants were asked to complete a questionnaire regarding their treatment for depression with a special focus on patientphysician relationship. This study was conducted from December 7 to 13, 2010, in Japan. Results: 2,020 participants successfully completed the questionnaire. Overall, 70.2% of responders reported that they had withheld the truth from their physicians. A logistic regression model found significant associations of such a behavior with female sex (95% CI, 1.15-1.74; P = .001), younger age (95% CI, 0.49-0.97; P = .030), and a lower degree of satisfaction in mutual communication (95% CI, 3.17-6.58; P < .001). 69.2% and 52.6% of the participants refrained from telling about their "daily activities" and "symptoms," respectively. Female participants were more likely to hide the facts concerning "adherence to prescribed medication" and "figures such as body temperature and weight." 31.9% of participants had discontinued the treatment without consulting their physician, which was again more frequent in females, younger persons, and those who were not satisfied with communication with their physician. Conclusions: While the findings obtained herein need to be replicated in other patient populations, a majority of patients with depression were reluctant to uncover the truth, which emphasizes the need for more finetuned suspicion among physicians about symptoms and medication adherence.

The objective was to examine effects of active interventions on physician's prescribing of antipsychotic polypharmacy. Prescriptions for patients with schizophrenia at the Centre for Addiction and Mental Health, Canada were collected in 2006 (n = 648) and 2008 (n = 778). During the intervening period, a pharmacist monitored prescriptions with antipsychotic polypharmacy and contacted corresponding prescribers to provide education on risks of polypharmacy. Moreover, educational sessions on polypharmacy were presented to inpatient and outpatient teams. A three-fold decrease in the prevalence of antipsychotic polypharmacy was observed between 2006 (18.3%) and 2008 (6.6%). Thus, active monitoring of prescriptions with educational interventions could reduce antipsychotic polypharmacy.