Published papers

Objective: Physical restraint sometimes causes deep vein thrombosis (DVT) and pulmonary embolism. Although unfractionated heparin (UFH) is used for the prophylaxis of DVT, its effectiveness remained unknown for restrained patients. Method: We conducted a chart review of restrained inpatients at Sakuragaoka Memorial Hospital in Japan. Restrained patients received subcutaneous injection of UFH 5000 IU bid from December 2008 to September 2010 [heparin (+) period] while UFH was not used from December 2010 to September 2012 [heparin (-) period]. A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared between the two periods by chi-square test. A multiple logistic regression model was used to examine effects of demographic and clinical characteristics on the incidence of DVT. Results: No significant difference was found in the incidence of DVT between the heparin (+) and (-) periods [11.8% (11/93) vs. 11.1% (13/117)]. Sedation [odds ratio (OR)=3.78], physical comorbidities (OR=6.29) and a longer duration of restraint (OR=1.22) were associated with the incidence of DVT. Conclusion: The use of UFH was not associated with any reduction in the incidence of DVT in restrained psychiatric patients.

Background: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. Objective: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Data Sources: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Study Selection: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Data Extraction: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Data Synthesis: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. Conclusion: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

Objective: To examine the effects of Hatha yoga therapy on resilience, brain-derived neurotrophic factor (BDNF) levels, and salivary alpha amylase (SAA) activity in patients with schizophrenia-spectrum disorders. Design and participants: Single-blinded, randomized controlled study in which outpatients with schizophrenia or related psychotic disorders (according to International Classification of Diseases, 10th Revision) were randomly assigned to a yoga or a control group. Setting: November 2012-April 2013 at Yamanashi Prefectural Kita Hospital, Japan. Interventions: In the yoga group, patients received weekly 1-hour Hatha yoga sessions, in addition to regular treatment, for 8 weeks. Those in the control group underwent regular treatment, which included a daycare rehabilitation program. Outcome measures: Assessments included the 25-item Resilience Scale (RS), Positive and Negative Syndrome Scale (PANSS), plasma and salivary BDNF level, and SAA activity. Results: Fifty patients participated (25 in each group; mean age±standard deviation, 50.9±11.3 years; mean duration of illness, 25.0±10.3 years; mean total PANSS score, 78.2±17.3). No significant differences in changes in any variable from baseline to week 8 were found between the two groups (changes in the yoga group versus the control group: RS score, -1.6±19.9 versus 0.3±17.2; PANSS score, 0.5±12.0 versus 5.0±15.6; plasma BDNF, 41.6±377.0âpg/dl versus 73.4±346.0 pg/dl; SAA, -26.2±72.6 kU/l versus -13.8±68.0 kU/l, respectively). Conclusions: Adjunct yoga therapy showed no positive changes in resilience level or stress markers. Duration and intensity of yoga sessions and the focus on patients with chronic illness may explain the negative observations in light of past positive evidence regarding yoga therapy.

Background: While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D2 receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. Method: In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D2 occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness. Results: Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D2 occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D2 receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study. Conclusions: The results suggest that the therapeutic threshold regarding dopamine D2 occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings.

Introduction: The objective of this study was to examine the evolution of antidepressant switch and adjunctive therapy. Methods: This chart review was conducted at 6 primary psychiatric clinics or hospitals, in Tokyo, Japan. A chart review of longitudinal prescriptions was conducted regarding 633 outpatients with major depressive disorder for up to 2 years after their first visit. Patients who had already received antidepressants prior to the visit were excluded. Results: 22.6% (N=143) of the patients completed or continued the outpatient treatment over the 2 years while 27 (4.3%), 23 (3.6%), and 439 (69.4%) patients discontinued it due to hospitalization, referral to another clinic, and loss to follow-up, respectively. A total of 597 episodes of antidepressant treatment were identified. Among them, 482 episodes (80.7%) were associated with the suggested dose ranges while antidepressant drugs were under-dosed in 19.3% (N=115) of the episodes. 50 patients (7.9%) received adjunctive therapy; it was employed after a median of only one antidepressant had been tried. Conclusion: Psychiatrists may be hasty in prescribing an adjunctive therapy in the treatment of depression.

Objective In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. Design Open-label intervention. Setting Centre for Addiction and Mental Health, Toronto. Participants Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. Intervention A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. Measurements Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [11C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. Results Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D2/3 RRO. Conclusion EPS diminished less than 70% D2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan.

Objective: Constipation is often overlooked in patients with schizophrenia. We examined their awareness of constipation and whether they reported it to their psychiatrists. Method: Five hundred three inpatients with schizophrenia (International Classification of Diseases, 10th Revision) were interviewed about their recent bowel movements and evaluated for the diagnostic criteria for functional constipation. If constipation was present, patients were asked if they were aware of it and had reported it to their psychiatrists in charge. Additionally, their global psychopathology and functioning were assessed using the Clinical Global Impression-Schizophrenia (CGI-SCH) and the Global Assessment of Functioning (GAF), respectively. Results: The criteria for constipation were met by 184 patients (36.6%); of these patients, only 56.0% (103/184) were aware of it. Moreover, only 34 of the constipated patients (18.5%) reported its presence to their psychiatrists. No significant differences were found in the CGI-SCH overall severity or subscale scores or in the GAF scores between those patients who reported and those who failed to report constipation. Conclusions: The present study demonstrated that constipation was neither recognized nor reported to psychiatrists by a significant percentage of the patients. These findings underscore the importance of greater vigilance and active evaluation of constipation in patients with schizophrenia for appropriate clinical management.

Objective: The objective of this analysis was to evaluate both cross-sectional and longitudinal relationships between estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in patients with schizophrenia. Method: The data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used in this analysis. The cross-sectional data included 371 patients receiving risperidone, olanzapine, or ziprasidone, who had completed the Drug Attitude Inventory (DAI-10) at six months and provided plasma antipsychotic concentrations. Samples were analyzed to examine the relationship between DAI-10 total scores and estimated D2 occupancy using Spearman's rank correlations, followed by multiple regression analysis. In addition, to elucidate the relationship between changes in DAI-10 scores and estimated D2 occupancy, the longitudinal data from 45 patients who experienced an increase in antipsychotic dosage between six and 12. months were analyzed. Mean peak and trough D2 occupancy levels were estimated from plasma antipsychotic concentrations using a population pharmacokinetic approach. Results: A positive association was found between estimated D2 occupancy and DAI-10 total scores in patients receiving ziprasidone in the cross-sectional dataset (rs= 0.395, P= 0.001). In contrast, a negative association was found in changes in estimated D2 occupancy and DAI-10 scores among patients receiving olanzapine in the longitudinal dataset (rs= -0.534, P= 0.010). No significant associations were found in patients receiving risperidone, or in the whole sample regarding both cross-sectional and longitudinal datasets. Conclusion: Dopamine D2 receptor occupancy may mediate subjective experience/drug attitude in patients with schizophrenia. The directionality may however differ between antipsychotics, which warrants further investigation.

Introduction: Postural instability is a serious concern in patients with schizophrenia-spectrum disorders since it is expected to increase the risk of falls that may lead to fractures. The impact of yoga therapy on postural stability has not been investigated. Methods: In this eight-week single-blind randomized controlled study with an eight-week follow-up, outpatients with schizophrenia or related psychotic disorder (ICD-10) were randomly assigned to either yoga therapy or a control group. In the yoga therapy group, the subjects received weekly sessions of 60-minyoga therapy for eight weeks in addition to their ongoing treatment. In the control group, the subjects received a weekly regular day-care program. The assessments that were performed at the baseline and endpoint included the Clinical Stabilometric Platform (CSP), anteflexion in standing. Results: Forty-nine patients participated in this study (32 men; mean±SD age, 53.1±12.3 years): yoga therapy group (n=25) and control group (n=24). In the yoga group, significant improvements were observed in a total length of trunk motion, the Romberg ratio, and anteflexion in standing at week 8 (mean±SD: 63.9±40.7-53.4±26.2cm, 1.6±0.9-1.1±0.6, and-8.7±9.5 to-3.8±12.4cm, respectively) while there were no significant changes in the control group. However, those clinical gains returned to the baseline level at week 16. Conclusions: The results confirmed the beneficial effects of the yoga therapy on postural stability in patients with schizophrenia. However, the therapeutic effects seemed transient, which warrants further investigations on strategies to sustain the improvements.

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.

In treating schizophrenia, 65% to 80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D2 receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D2 prediction model. Estimated mean ± SD peak and trough D2 receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D2 occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D2 receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D2 receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.

While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r2=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP.

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

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