Published papers

Objective: While the Kraepelinian dichotomy explicitly distinguishes between schizophrenia and bipolar disorder, it remains unclear as to whether a deficit form of bipolar disorder exists. Method: We conducted a study to investigate the prevalence rate of the deficit form of bipolar disorder; the criteria of which were basically adopted by the original proposal for schizophrenia that described the predominance of negative symptoms for over a year. Moreover, we presented a series of cases with deficit bipolar disorder to characterize its clinical pictures in detail. Results: Consecutive outpatients who visited one psychiatric hospital in Tokyo, Japan in March 2007 were evaluated cross-sectionally. Additionally, medical charts of inpatients who were hospitalized in the same hospital between April 2006 and March 2007 were also thoroughly reviewed. Of 494 patients, 7 patients (1.4%; 10.9% of 64 bipolar cases) fulfilled the criteria for bipolar disorder with deficit syndrome. Seven deficit cases had a mean±SD age of 61±5 year-old with the age at onset being 25±8 year-old. In addition to pervasive negative symptoms, they exhibited evidence of cognitive impairments close to the magnitude of what is usually noted in schizophrenia (i.e. a mean±SD total IQ score of 80±9 in the Wechsler Adult Intelligence Scale and 0.4±0.5 in the Wisconsin Card Sorting Test, categories achieved). Conclusion: Although preliminary, the evidence on deficit status in patients with bipolar disorder that we found in this study appears more consistent with recent evidence and challenges the Kraepelinian dichotomy that reserves deficit status solely to schizophrenia patients. © 2012 Elsevier B.V.

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥. 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥. 600. mg/day for ≥. 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥. 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤. 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤. 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤. 2, a ≥. 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥. 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials. © 2012 Elsevier Ltd.

Background: Clinical relevance of dental caries is often underestimated in patients with schizophrenia. The objective of this study was to examine dental caries and to identify clinical and demographic variables associated with poor dental condition in patients with schizophrenia.Methods: Inpatients with schizophrenia received a visual oral examination of their dental caries, using the decayed-missing-filled teeth (DMFT) index. This study was conducted in multiple sites in Japan, between October and December, 2010. A univariate general linear model was used to examine the effects of the following variables on the DMFT score: age, sex, smoking status, daily intake of sweets, dry mouth, frequency of daily tooth brushing, tremor, the Clinical Global Impression-Schizophrenia Overall severity score, and the Cumulative Illness Rating Scale for Geriatrics score.Results: 523 patients were included in this study (mean ± SD age = 55.6 ± 13.4 years; 297 men). A univariate general linear model showed significant effects of age group, smoking, frequency of daily tooth brushing, and tremor (all p's < 0.001) on the DMFT score (Corrected Model: F (23, 483) = 3.55, p < 0.001, R 2 = 0.42) . In other words, older age, smoking, tremor burden, and less frequent tooth brushing were associated with a greater DMFT score.Conclusions: Given that poor dental condition has been related with an increased risk of physical co-morbidities, physicians should be aware of patients' dental status, especially for aged smoking patients with schizophrenia. Furthermore, for schizophrenia patients who do not regularly brush their teeth or who exhibit tremor, it may be advisable for caregivers to encourage and help them to perform tooth brushing more frequently. © 2012 Tani et al.; licensee BioMed Central Ltd.

© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology. Aims The aim of this cross-sectional study was to examine the prevalence of psychological dependence on benzodiazepines in outpatients with panic disorder and elucidate demographic and clinical characteristics associated with this condition. Methods Subjects were eligible if they were outpatients in four clinics in Tokyo, Japan, aged 18 years or older and met the diagnostic criteria for panic disorder according to the ICD-10. The subjects received the following assessments: the Severity of Dependence Scale, Japanese Version (SDS), the Self-Report Version of Panic Disorder Severity Scale, Japanese Version (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version. The following information was also collected: age, sex, ethnicity, duration of illness, physical and psychiatric comorbidities, and details of prescribed psychotropic medications. Results The data from 51 outpatients showed that 31 patients (60.8%) showed psychological dependence (i.e. a total score of ≥5 in the SDS). The proportion of patients with dependence was significantly lower in remitted patients (i.e. a total score of ≤4 in the PDSS) (44.1%, n-=-15/34) than those who were not (94.1%, n-=-16/17) (Pearson χ2-=-11.9, P-<-0.001). A multiple regression analysis showed that the PDSS scores showed a positive correlation with the SDS total scores (β-=-0.60, 95% confidence interval-=-0.30-0.90, P-=-0.0001). Conclusion These findings emphasize the need for enhanced awareness about benzodiazepine dependence in patients and psychiatrists, as well as especially close attention to patients with panic disorder who present severe symptomatology.

© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. DATA SOURCES: MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). STUDY SELECTION: The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. DATA EXTRACTION: The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. RESULTS: Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. CONCLUSIONS: The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean ± SD age, 48.8 ± 13.8. years; male [N = 14]; Asians [N = 23], Caucasians [N = 12]; risperidone [N = 20] at 3.2 ± 2.3. mg/day, and olanzapine [N = 15] at 9.2 ± 4.9. mg/day) between September and December 2010. 48.6% (N = 17) did not achieve a continuous blockade of ≥ 65%. Moreover, 11.4% (N = 4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥ 65%. The results suggest that sustained D2 receptor occupancy levels of ≥ 65% may not always be necessary for the maintenance treatment of schizophrenia. © 2011 Elsevier Inc.

Rationale: Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives: The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods: Positron emission tomography (PET) scans with [11C]- raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [11C]- raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results: Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. Conclusions: The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %). Clinical Trials Registration: 24-Hour Time Course of Striatal Dopamine D 2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298, NCT00818298 © 2013 Springer-Verlag Berlin Heidelberg.

© 2015 Elsevier B.V. Background: No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia. Methods: We included patients with schizophrenia 50years or older who were antipsychotic-free for at least 3months. We compared non-displaceable binding potential (BPND) of [11C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Results: Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=42, p=52). Conclusion: The preliminary results suggest no differences in D2/3R availability between antipsychotic-free older patients with schizophrenia and controls.

© 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com. Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [11C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.