Published papers

© 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.

© Copyright 2017 Physicians Postgraduate Press, Inc. Objective: The aim of this post hoc analysis was to evaluate which specific depressive items could predict subsequent durable recovery in patients with bipolar depression. Methods: The study population was at least 18 years old and met DSM-IV criteria for a major depressive episode associated with either bipolar I or II disorder. The data were derived from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment for acute depression with a mood stabilizer plus an adjunctive antidepressant drug or placebo. The primary and secondary outcomes were durable recovery (ie, 8 consecutive weeks of euthymia) and treatment-emergent affective switch (ie, transition to mania or hypomania), respectively. Binary logistic regression analysis was performed to identify specific symptoms whose improvement during the first 2 weeks predicted those outcomes; the score change of each individual symptom in the continuous symptom subscales for depression (SUM-D) from week 0 to week 2 was used as an independent variable. Results: In the evaluable 188 participants who took placebo and active drugs, the improvement in loss of self-esteem (P =.037) or loss of energy (P =.040) at week 2 was significantly associated with higher chances of subsequent durable recovery. For participants taking active drugs (n = 91), solely the improvement in loss of energy at week 2 was significantly associated with subsequent durable recovery (P =.027). There was a significant association between the improvement of psychomotor retardation at week 2 and subsequent affective switch (P =.008). Conclusions: These findings imply that focusing on individual symptoms is important in bipolar depression, rather than relying solely on a summed score in rating scales. Trial Registration: The original STEP-BD dataset is registered on ClinicalTrials.gov (identifier: NCT00012558).

© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology Aim: It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods: This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6-week double-blind, placebo-controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results: Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2:.51,.42 and.55,.54, respectively). Conclusion: Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.

Objective: To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner. Methods: In this open-label study, 17 patients with treatment-refractory schizophrenia, who failed to respond to a sequential monotherapy with olanzapine, quetiapine and risperidone, were subsequently treated with a combination therapy with olanzapine plus risperidone for at least 8 weeks. Results: Seven responded according to the primary endpoint defined as the post-treatment Brief Psychiatric Rating Scale being less than 70% of the pretreatment values, and they were classified as such an average of 10 weeks after the initiation of polypharmacy. Two of them were successful in a later conversion to monotherapy. None dropped out prematurely. Four (out of 13 inpatients) got better enough to be discharged from the hospital, while six patients did not show any response. The Global Assessment of Functioning score improved from 37.1 to 53.0 in responders (mean maximum dose: olanzapine 12.9 mg; risperidone 3.14 mg), while it showed non-significant changes among others (mean maximum dose: olanzapine 14.5 mg; risperidone 5.50 mg). Body weight, prolactin, and total cholesterol increased significantly. Conclusions: Antipsychotic polypharmacy might be sometimes helpful for difficult populations but at the cost of adverse effects. More studies of antipsychotic combination therapy versus clozapine, augmentation strategies or tenacious longer-term monotherapy are warranted for refractory schizophrenia. Copyright © 2008 John Wiley & Sons, Ltd.

The relationship between age and prescribed antipsychotic dose in patients with schizophrenia has been examined by assuming only a linear correlation in two age subgroups at most. The age of illness onset has also not been under adequate consideration in past prescription surveys. The objective of this study was to better evaluate these age effects on antipsychotic dose prescribed in these patients across a broad age range. Methods: Review of prescriptions for antipsychotic medications in patients with schizophrenia spectrum disorders was conducted across 30 sites in Tokyo. A total of 1,418patients (655 inpatients, 763 males, age range: 16.6-90.2 years) were studied. Results: Age had significant effects on prescribed antipsychotic dose; the dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The age of illness onset also had significant effects on the dose; late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychoses (VLOS) patients received lower doses than early onset schizophrenia (EOS) patients. LOS and VLOS patients who did not experience any hospitalization for the previous year were treated with 1/2 and 1/3, respectively, of the dose for EOS of comparable current age. Conclusion: Our results suggested biphasic effects of age on antipsychotic dose prescribed in patients with schizophrenia spectrum disorders. The natural history of schizophrenia and physiological aging may contribute to this inverted U-shaped relationship. In addition, our results may add another evidence of dis-ttnction among EOS, LOS, and VLOS from a clinical psychopharmacological perspective. © 2008 American Association for Geriatric Psychiatry.

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT 2AR) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods We derived 5-HT 2AR nondisplaceable binding potentials (BP ND) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results The 5-HT 2AR BP NDs decreased with age, a relationship best described by an exponential-decay regression. The BP NDs were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. Copyright © 2011 John Wiley & Sons, Ltd.

© 2017 Elsevier Ltd Introduction Since falls may lead to fractures and have serious, potentially fatal outcomes, prevention of falls is an urgent public health issue. We examined the effects of chair yoga therapy on physical fitness among psychiatric patients in order to reduce the risk of falls, which has not been previously reported in the literature. Methods In this 12-week single-blind randomized controlled trial with a 6-week follow-up, inpatients with mixed psychiatric diagnoses were randomly assigned to either chair yoga therapy in addition to ongoing treatment, or treatment-as-usual. Chair yoga therapy was conducted as twice-weekly 20-min sessions over 12 weeks. Assessments included anteflexion in sitting, degree of muscle strength, and Modified Falls Efficacy Scale (MFES) as well as QOL, psychopathology and functioning. Results Fifty-six inpatients participated in this study (36 men; mean ± SD age, 55.3 ± 13.7 years; schizophrenia 87.5%). In the chair yoga group, significant improvements were observed in flexibility, hand-grip, lower limb muscle endurance, and MFES at week 12 (mean ± SD: 55.1 ± 16.6 to 67.2 ± 14.0 cm, 23.6 ± 10.6 to 26.8 ± 9.7 kg, 4.9 ± 4.0 to 7.0 ± 3.9 kg, and 114.9 ± 29.2 to 134.1 ± 11.6, respectively). Additionally, these improvements were observable six weeks after the intervention was over. The QOL-VAS improved in the intervention group while no differences were noted in psychopathology and functioning between the groups. The intervention appeared to be highly tolerable without any notable adverse effects. Conclusions The results indicated sustainable effects of 20-min, 12-week, 24-session chair yoga therapy on physical fitness. Chair yoga therapy may contribute to reduce the risk of falls and their unwanted consequences in psychiatric patients.

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

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. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

© 2014, Mary Ann Liebert, Inc. 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.

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. © 2013 Elsevier Ltd.

Once developed, tardive dyskinesia (TD) is a challenging condition to treat. The recent evidence has indicated that zonisamide, an antiepileptic drug indicated for partial-onset seizures, may also have beneficial effects for ameliorating dyskinesia in Parkinson's disease. However, this finding has not systematically been tested in psychiatric patients with TD associated with antipsychotic treatment. The objective of this study was to examine the efficacy, tolerability, and safety of zonisamide against TD in these patients. In this 4-week open-label study, subjects who suffered TD were given 50-100 mg/day of add-on zonisamide. Severity of TD was evaluated at the baseline and endpoint, using the Abnormal Involuntary Movement Scale (AIMS). Eleven subjects (6 females; mean ± SD age, 75.5 ± 4.7 years; schizophrenia [N = 6], bipolar affective disorder [N = 2], schizoaffective disorder [N = 1], mental retardation [N = 1], mental retardation with epilepsy [N = 1]; 6 were antipsychotic free at baseline) participated in this study. The AIMS total score (mean ± SD) was significantly decreased from 24.1 ± 5.5 to 19.5 ± 5.9, with 36.4% of the subjects (N = 4) demonstrating 20% or more decrease in the AIMS total score. Treatment with zonisamide was well-tolerated and no participants dropped out prematurely. In conclusion, zonisamide may be safe and effective for the treatment of TD associated with antipsychotic treatment. These preliminary findings need to be further explored by larger well-designed trials. © 2012 Elsevier B.V. All rights reserved.