Published papers

Objective: The pharmacokinetic and pharmacodynamic profile of the immediate-release (IR) formulation of quetiapine is characterized by a rapid peak in plasma level and striatal dopamine D2 receptor occupancy, followed by a rapid decrease to baseline levels, necessitating the use of twice-daily dosing. An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D2 receptor binding between the IR and XR formulations. Method: In this open-label, crossover positron emission tomography study using [11C]-raclopride, we compared the central D2 receptor binding potential at expected peak and trough plasma levels using equivalent daily doses of the IR and XR formulations (300, 600, and 800 mg/day) in 12 subjects. Data were collected from April 2002 to May 2003. Results: The mean plasma level of quetiapine at trough was significantly lower than that at peak for all dose groups of both formulations except for IR 300 and 800 mg (all p values < .05), while the mean plasma level did not differ significantly between formulations at trough and peak. The mean occupancy at peak was significantly higher than that at trough for all dose groups other than IR 800 mg/day (all p values < .05) and did not differ significantly between formulations at trough and peak. Conclusion: Once-daily dosing of the XR formulation gives peak and trough plasma levels and central D2 receptor occupancy comparable to twice-daily dosing of the IR formulation. These data should be considered while determining equivalent doses, as well as switching strategies. © Copyright 2008 Physicians Postgraduate Press, Inc.

There are sporadic reports of antipsychotic-induced visual hypersensitivity attack (VHA). VHA is characterized by hypersensitivity of perception mainly in the visual modality and sometimes accompanied by an oculogyric crisis. However, some researchers regard VHA as a schizophrenia symptom. To determine whether VHA is an adverse effect of antipsychotic agents, we examined the effect of dose reduction on VHA. This was an open-label 36-week study. We randomized 34 patients with VHA to a reduced-dose group and a fixed-dose group. Primary outcome measures were the frequency and duration of VHA, assessed with patients' self-reports, and the Clinical Global Impressions (CGI). Assessment also included the Drug-induced Extrapyramidal Symptoms Scale for extrapyramidal symptoms, the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, and the CGI for other diagnoses. Data were collected from August 2000 to April 2005 at 4 psychiatric hospitals in Tokyo. VHA diminished in 16 patients (94.1%) in the reduced-dose group in the CGI score, the frequency (number of episodes per week), and the duration of the episodes (from 4.06 to 1.77, P < 0.001; from 2.59 to 0.82, P = 0.001; and from 1.92 to 0.66 hours, P = 0.007, respectively), but there were no changes in the fixed-dose group. There were no changes in the underlying illness as measured by the PANSS in both groups. Reducing the dose of antipsychotic agents ameliorates VHA and represents the ideal treatment option for patients with VHA. Copyright © 2006 by Lippincott Williams & Wilkins.

Antipsychotic medications are often used at higher than the recommended dose and sometimes in a combination regimen to treat schizophrenia. However, in general, high-dose therapies have been abandoned in recent clinical studies. In this study, dose reduction of antipsychotic medication was implemented for patients with chronic schizophrenia, most of whom (81%) had been treated with an antipsychotic high-dose polypharmacy regimen consisting of more than 1000 mg/day in total amount. The results show that merely reducing the amount of antipsychotic led to favourable outcome in 23 out of 41 cases (56%), with another 13 cases (32%) showing no change. Dose reduction ended in failure in only five subjects (12%). Overall, the amount as well as the number of antipsychotic medications was significantly reduced from 1984 mg to 812 mg per day (reductions of 59% and from 3.6 to 2.2, respectively; both P<0.0001). The Global Assessment of Functioning scale improved from 30.6 to 37.2, which reached significance (P<0.001). Accordingly, the Severity of Illness improved from 4.7 to 4.2, and was also significant (P<0.01). Dose reduction is an encouraging strategy to consider for those patients with schizophrenia who have chronically been treated with high-dose antipsychotic polypharmacy, even if judged unavoidable in the past. © 2003 Lippincott Williams & Wilkins.

© 2016 Elsevier Inc.. Objective: To explore risk factors for relapse of paralytic ileus in a psychiatric population. Method: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. Results: Sixty-three subjects (38 women; age, 66.0±11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P = .03, odds ratio=4.34, 95% CI=1.15-16.42) and duration of psychiatric disorders (P = .02, odds ratio=1.00, 95% CI=1.00-1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P = .01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P = .02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. Conclusions: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus.

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

Copyright: © 2020 Kitagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.

© 2017 Elsevier Ltd While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D2 receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D2 receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.

© 2017 Elsevier Inc. Objective The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. Methods This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). Results One hundred outpatients with depression (mean ± SD age, 50.8 ± 14.5 years; 44 men; MADRS total score 9.8 ± 9.0) and 36 healthy family members (mean ± SD age, 56.5 ± 15.0 years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean ± SD, 112.3 ± 17.1 vs. 84.8 ± 27.7, p < 0.001). No correlation was found in RS total scores between patients and their family members (p = 0.265), regardless of patients' remission status. Conclusions Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.

© 2016 Elsevier B.V. The resilience levels between patients with schizophrenia residing in a rural island and a metropolitan area in Tokyo, Japan, was compared and the factors associated with resilience were explored. The Resilience Scale (RS) and EuroQol were assessed, together with biological markers and multiple demographic variables. No significant difference was found in the RS scores between the two groups (40 subjects each). However, longer duration of illness and higher EuroQol score were significantly associated with a greater RS score, which indicates that potentially successful adaptation and subjective perspectives appear more pertinent than the degree of urbanicity in determining resilience levels.

© 2016 Elsevier B.V. Resilience is becoming an important topic in people with schizophrenia since there is evidence that it increases the probability for long-term recovery. The current study investigated transcultural differences in resilience across schizophrenia patients from two different geographical regions, Austria and Japan. Another objective was to examine transcultural differences in internalized stigma, self-esteem, and hopelessness, which can be expected to be relevant in this context, as well as the interrelations between these subjective elements of recovery and symptom severity. To this end, patients from outpatient mental health services in Innsbruck, Austria (= 52) and Tokyo, Japan (= 60) as well as 137 healthy comparison subjects from both countries were included into this cross-sectional study. Notably, we detected a significant country effect with markedly lower resilience (= 74.4, p < 0.001) and self-esteem scores (= 226.0, p < 0.001) as well as higher hopelessness scores (= 37.4, p < 0.001) among Japanese subjects in general. In addition, both Austrian and Japanese patients indicated significantly lower degrees of resilience (= 57.5, p < 0.001), self-esteem (= 51.8, p < 0.001), and hope (= 29.5, p < 0.001) compared to healthy control subjects. The inter-correlations between subjective elements of recovery were comparable in size in the two patient samples, but the inter-correlations between these issues and residual symptoms of schizophrenia as objective domains of recovery were markedly higher in Austrian subjects. This suggests that schizophrenia patients from Western European and Japanese cultures may have different needs to achieve recovery. In conclusion, it will be critical to develop culture-specific psychosocial programs and to examine their feasibility and effectiveness among these patients.

Antipsychotic medications are the standard of care for both acute and maintenance treatment of schizophrenia, the latter requiring an indefinite treatment across a patients life span. However, dosing and tolerability of antipsychotics have been studied primarily in younger patients, and very limited data are available for age- and phase-specific dosing. This leaves the clinician with no guidance on dose adjustment as patients grow olderan issue of critical importance, especially in light of recent concerns about increased morbidity and mortality associated with antipsychotics.

Objective: Many rating scales have been in use to evaluate various symptomatic domains, and eventually there are too many scales to be selected and widely utilized in busy real-world settings. Relevant, quick, and user-friendly assessment scales are needed to facilitate measurement-based treatment of schizophrenia. Methods: The authors created unique convenient assessment scales: Targeted Inventory on Problems in Schizophrenia (TIP-Sz), and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). The TIP-Sz consists of 10 items (behavioral dyscontrol/disorganization, hostility/agitation/violence, indifference/affective withdrawal/motor retardation, symptoms on mood/anxiety/obsession/compulsion, insight/reality testing, social competence/independence, adherence to treatment, therapeutic alliance/comfort of therapists on the situation, overall prognostic impression, and subjective well-being/satisfaction with therapy). They are all common and frequently problematic, and each item is rated from 0-10. The FACT-Sz evaluates psychosocial functioning of patients with a score of 0-100, and is judged entirely on an objective basis. Their correlations with the frequently utilized Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), and Clinical Global Impression-Severity subscale were determined. Results: Data on 36 patients, assessed separately by four experienced psychiatrists, were analyzed. Under an excellent interrater reliability among raters (Intraclass correlation coefficients: 0.822-0.966), correlations among the scales were very high (Spearman's ρ: 0.825-0.909), and other indicators of the scale were generally good. Specifically, the TIP-Sz and FACT-Sz could be rated at 1/3-1/4 of time to complete the PANSS and GAF. Conclusion: The TIP-Sz and FACT-Sz proved to be reliable and valid, which would be of value in daily clinical practice as a minimum standardized assessment set.

Introduction Therapeutic drug monitoring is necessary for lithium, but clinical application of several prediction strategies is still limited because of insufficient predictive accuracy. We herein proposed a suitable model, using creatinine clearance (CLcr)-based lithium clearance (Li-CL). Methods Patients receiving lithium provided the following information: serum lithium and creatinine concentrations, time of blood draw, dosing regimen, concomitant medications, and demographics. Li-CL was calculated as a daily dose per trough concentration for each subject, and the mean of Li-CL/CLcr was used to estimate Li-CL for another 30 subjects. Serum lithium concentrations at the time of sampling were estimated by 1-compartment model with Li-CL, fixed distribution volume (0.79 L/kg), and absorption rate (1.5/hour) in the 30 subjects. Results One hundred thirty-one samples from 82 subjects (44 men; mean±standard deviation age: 51.4±16.0 years; body weight: 64.6±13.8 kg; serum creatinine: 0.78±0.20 mg/dL; dose of lithium: 680.2±289.1 mg/day) were used to develop the pharmacokinetic model. The mean±standard deviation (95% confidence interval) of absolute error was 0.13±0.09 (0.10–0.16) mEq/L. Discussion Serum concentrations of lithium can be predicted from oral dosage with high precision, using our prediction model.

The current nomenclature is based on clinical indications; for example, drugs used for mania and psychosis are classified as "mood stabilizers" and "antipsychotic drugs", respectively. This discrepancy between their names and indications often confuses patients and their caregivers and sometimes leads to a misunderstanding of the effects of prescribed medications. In addition, up-to-date scientific knowledge on these drugs has not been reflected in the current nomenclature. To overcome these limitations of the current nomenclature, following an initiative of the European Congress of Neuropsychopharmacology (ECNP), a taskforce for psychotropic nomenclature was established with representatives from 5 international organizations, including the Asian College of Neuropsychopharmacology (AsCNP). The mission of this taskforce is to provide a pharmacologically-driven (rather than indication-based) nomenclature, which is now referred to as Neuroscience-based Nomenclature (NbN). The NbN project has just started. Since it always takes time to change the culture, we understand the transition will likely involve some expected and unexpected responses from the field. However, we believe that such responses and feedback will surely improve the quality of the NbN, which in turn will be beneficial for clinicians, researchers, and patients as well as their caregivers.

We describe real-world psychopharmacological treatment in a Japanese, male, closed psychiatric unit where clozapie was still unavailable. Fifty-five persistently-ill patients with schizophrenia (ICD-10), mean±S.D. age: 57.5±13.0 y.o., duration of illness and admissions: 30.9±15.2 years and 20.7±14.5 years, respectively) treated longitudinally were evaluated. The rule was to treat with a simplest possible psychotropic regimen without polypharmacy. Compared to the baseline, the number and dose of antipsychotics were reduced from 1.9 to 1.1 and 1012 mg/day to 607 mg/day, respectively. The number of total psychotropics was minimized from 4.7 to 2.1, with a simplified once or twice daily dosing. Overall, the CGI-Severity and FACT-Sz (global functioning) improved slightly from 5.8 to 5.5 and 28.7 to 32.6, respectively. Of note, no patients got worse in comparison with the baseline clinical presentation. Forty-four patients were successfully treated with a single antipsychotic; only seven needed two antipsychotics simultaneously while 36 had been treated with antipsychotic polypharmacy at baseline. Benzodiazepines (mostly lorazepam) and antiparkinsonian drugs were prescribed in 28 and only two, respectively. Nineteen needed adjunctive valproate (average blood levels: 99.3±21.8 μg/mL) and nine used lithium (0.61±0.26. mEq/L). Optimization of psychopharmacotherapy is still possible for difficult-to-treat patients and, while augmentation of an antipsychotic with mood stabilizers is frequently needed, antipsychotic polypharmacy should be exceptional.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. Method: Data of 672 patients with schizophrenia randomized to placebo in nine double-blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5-Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. Results: Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per-protocol analysis or a 15% reduction in last-observation-carried-forward analysis in the PANSS total score at week 1 showed the highest predictive power. Conclusion: These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia.