Published papers

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.

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. © 2013 Elsevier B.V.

Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS. OBJECTIVE To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS. DESIGN, SETTING, AND PARTICIPANTS An open-label, single-arm prospective study with a 3- To 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015. INTERVENTIONS Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction. MAIN OUTCOMES AND MEASURES Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels). RESULTS Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stabilitywas 50%. Extrapyramidal symptoms (EPSs)were more likely to occur with D2/3R occupancies higher than 60%: 90.5%(19 of 21) of the participants with baseline EPSs and 76.9%(10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancieswere lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58%[15%] vs 72%[10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased. CONCLUSIONS AND RELEVANCE Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

Although serotonin reuptake inhibitors are recommended as first-line agents for major depressive disorder, delayed onset of action is problematic, and faster effective treatment is needed. Sulpiride, a dopamine-mediated agent, has been reported to show faster antidepressant efficacy, and we examined the efficacy of adjunctive sulpiride in combination with paroxetine (PAX), compared with PAX alone, to clarify whether the combined treatment exerts faster effect. Forty-one major depressive disorder patients were enrolled in this 12-week open-label trial and were randomly assigned to a PAX (10-40 mg/d) or a PAX (10-40 mg/d) plus sulpiride (100 mg/d) group. Assessments included the Montgomery-Asberg Depression Rating Scale, the 17-item Hamilton Rating Scale for Depression, and the Zung Self-rating Depression Scale on an intent-to-treat basis, and safety was also monitored. Thirty-three patients completed the study. Both PAX + sulpiride and PAX treatments showed a mean reduction in the total Montgomery-Asberg Depression Rating Scale score of 34.4 to 5.6 and 32.2 to 10.4, respectively (P < 0.001). The combined treatment group had a significantly superior outcome in terms of the change in the total Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Zung Self-rating Depression Scale scores between week 1 and the study end point (P < 0.05). Median times to response among responders alone for the combined treatment and monotherapy were 2 and 6 weeks, respectively. Both treatments were well tolerated, with no clinically significant differences in safety measures except for an elevation of prolactin in the combined treatment group. The combination treatment may be a safe and effective strategy for accelerating antidepressant response.

Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens.

Objective: Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite-N- desmethylclozapine (NDMC)-could explain these discrepancies. Methods: Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC. Results: Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model. Conclusions: After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition.

The negative impact of antipsychotic drugs on attention is expected to be greater in late-life schizophrenia because of the age-related changes in the dopamine receptor reserve. The objective of this study was to examine the relationship between dopamine D2 receptor blockade by risperidone and the cognitive function in late-life schizophrenia. Subjects with schizophrenia or schizoaffective disorder aged 50 or older who were receiving risperidone completed a [C]raclopride positron emission tomography scan to measure D2-binding potential in the striatum. The D2 receptor blockade by risperidone was calculated using age-corrected measures from healthy individuals and region of interest analysis of dynamic positron emission tomography data coregistered to the subjects' magnetic resonance imaging scans. Cognitive function was assessed using a battery of neuropsychological tests that included the Dementia Rating Scale-2 (DRS). Eleven subjects (mean ± SD age, 64 ± 8 years) participated in this study. The mean ± SD D2 receptor blockade was 69% ± 14% (range, 34%-80%). The age-corrected score on the attention subscale in the DRS was negatively correlated with the D2 receptor blockade. The DRS attention subscale score was lower in the subjects who experienced 74.9% or higher D2 blockade (median value, corresponding to a daily risperidone dose of >3.0 mg) than in those who did not. Although a causal attribution cannot be made in light of the cross-sectional nature of this study, the results suggest the critical importance of identifying the lowest effective dose of antipsychotic drugs in older patients with schizophrenia.

Introduction While the current nomenclature of psychotropic drugs is disease-based, their approved indications do not always match their classifications. Methods Information on approved indications of “second-generation antipsychotics” and “newer antidepressants” that are available in the United States (US), the United Kingdom (UK), France, Germany, and Japan were extracted from their packet inserts. Results A significant proportion of “atypical antipsychotics” were approved for psychiatric conditions other than psychotic disorders (i. e., bipolar disorder, major depressive disorder, and autistic disorder) as follows: 76.9% in the US, 66.7% in the UK, 66.7% in France, 60.0% in Germany, and 44.4% in Japan. Likewise, more than half of “newer antidepressants” had approved indications for psychiatric conditions other than depression (e. g., panic disorder, obsessive compulsive disorder, social anxiety disorder, general anxiety disorder, and post-traumatic stress disorder): 56.3% in the US, 69.2% in the UK, 69.2% in France, 50.0% in Germany, and 62.5% in Japan. Conclusions Our results raise concerns regarding generic terminologies of “antipsychotics” and “antidepressants” since the conventional indication-based nomenclature does not fit well with the official indication.

Background. Mutual understanding between recipients and donors is indispensable when living donor liver transplantation (LDLT) is performed, which, however, has gained little attention and remains unaddressed in the literature. Methods. Fiftyseven pairs, a recipient (mean ± SD age at the operation, 48.3 ± 10.6 years; mean ± SD years after the operation, 6.2 ± 4.7 years) and his or her donor, who underwent LDLT completed a 13-item questionnaire on a 7-point Likert scale (1: strongly agree to 7: strongly disagree) that was designed to assess for their psychological attitudes toward transplantation. They were also asked to estimate their donor's or recipient's response to the questionnaire, respectively. Values of interest were compared between groups, using paired t tests. Following Bonferroni correction, a P value less than 0.0038 (0.05/13) was considered statistically significant. Results. Significant differences were observed between actually answered and estimated responses in 7 of the 13 items in the questionnaire for donors. For example, donors did not feel pressure to become a donor to the same degree as their recipients estimated (4.6 ± 1.9 vs 3.4 ± 1.8). In contrast, only 1 item showed a significant difference between actually answered and estimated responses in the questionnaire for recipients; recipients did not worry about the transplanted liver compared to their donors' estimation (3.1 ± 1.9 vs 2.1 ± 0.8). Conclusions. Recipients did not fully understand the donors' feelings toward LDLT, whereas donors almost correctly understood their recipients' attitudes. Our findings clearly revealed the gap in their mutual understanding and emphasize the need of psychological education to bridge the gap.

© Wolters Kluwer Health, Inc. All rights reserved. Purpose/Background Although discontinuing antipsychotics clearly increases the risk of relapse in schizophrenia, some patients remain clinically well without continuous antipsychotic treatment. However, data on the characteristics of such patients are still scarce. Methods/Procedures A systematic literature review was conducted to identify predictive factors for successful antipsychotic discontinuation in schizophrenia using PubMed (last search; June 2018) with the following search terms: (antipsychotic∗ or neuroleptic) AND (withdraw∗ or cessat∗ or terminat∗ or discontinu∗) AND (schizophreni∗ or psychosis). The search was filtered with humans and English. Factors associated with a lower risk of relapse, when replicated in 2 or more studies with a follow-up period of 3 months or longer, were considered successful. Findings/Results Systematic literature search identified 37 relevant articles. Mean relapse rate after antipsychotic discontinuation was 38.3% (95% confidence interval = 16.0%-60.6%) per year. Factors associated with a lower risk of relapse were being maintained on a lower antipsychotic dose before discontinuation, older age, shorter duration of untreated psychosis, older age at the onset of illness, a lower severity of positive symptoms at baseline, better social functioning, and a lower number of previous relapses. Implications/Conclusions Although this literature review suggests some predictors for successful antipsychotic withdrawal in patients with schizophrenia, the very limited evidence base and unequivocally high relapse rates after discontinuation must remain a matter of serious debate for risk/benefit considerations.

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. Methods: We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors’ faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. Results: Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. Conclusion: Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.

The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean ± SD age, 38 ± 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg.The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine, smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form.The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring. Copyright © 2009 by Lippincott Williams & Wilkins.

© 2017 American Association for Geriatric Psychiatry Objectives To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D2 receptor availability in the whole striatum, and identify their relationship in patients with schizophrenia aged 50 years or older. Design Open-label prospective PET [11C]-raclopride study. Setting A tertiary care center outpatient setting. Participants Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months. Intervention Gradual reduction in their olanzapine or risperidone daily dose of up to 40%. Measurements Clinical and cognitive assessments, and [11C]-raclopride PET to determine D2 receptor availability at baseline and after the dose reduction. Main outcome measures were overall cognition and D2 receptor availability in whole striatum. Results Reducing the antipsychotic dose resulted in an increase in D2 receptor availability in the whole striatum and an association between D2 receptor availability and overall cognition despite lack of change in the latter. There was also an association between change in D2 receptor availability and change in overall cognition. Conclusions Our findings suggest that optimizing D2 receptor availability by reducing antipsychotic dose allows this system to contribute more significantly to cognitive function in patients with schizophrenia. This uncovered association could be harnessed by cognitive-enhancing interventions.

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. Concomitant use of benzodiazepines and alcohol appears prevalent in a clinical setting. The objectives of this study were as follows: (1) to investigate the prevalence of concomitant use of benzodiazepine hypnotics and alcohol in psychiatric outpatients, (2) to examine the clinical characteristics and factors associated with the concomitant use, and (3) to investigate the awareness of the psychiatrists-in-charge about the concomitant use. Outpatients with schizophrenia, depression, and insomnia who were receiving benzodiazepine hypnotics were asked to fill in a sleeping diary for seven consecutive days in which use of hypnotics and alcohol was also recorded. Clinical characteristics were assessed, and logistic analysis was performed to examine factors associated with the concomitant use. In addition, psychiatrists-in-charge were asked as to whether they thought their patients were concomitantly using them. The prevalence rate of the concomitant use was 39.8% (37/93). The CAGE score showed significant positive association with the concomitant use (odds ratio = 2.40, 95% confidence interval = 1.39-4.16, P = 0.002). Only in 32.4% of the concomitant users were suspected by their psychiatrists. The results suggest that concomitantly used benzodiazepine hypnotics and alcohol appears prevalent, and has been frequently overlooked by treating psychiatrists. The CAGE questionnaire may be helpful to screen such potentially hazardous users.

Background: Patients coping methods to palliate side effects of antidepressants have not been reported in the literature. Methods: Through an Internet survey, 856 participants who were diagnosed with depression and receiving antidepressants were recruited to report on the methods of coping with side effects. They were asked which side effect(s) they experienced and to write freely about the way they tried to counteract these effects. We classified active coping methods into the following sub-types: adjustment of prescriptions, additional medication, complementary therapy, consultation with physicians, and daily relief. Results: The prevalence of active coping differed across side effects (from 26.7%, sexual dysfunction, to 89.5%, dry mouth). Events with a lower percentage of active coping were more likely to be managed with adjustment of prescriptions: (sexual dysfunction, 41.9%; fatigue, 36.8%; sweating, 20.0%; tremor, 42.5%; and somnolence, 31.8%). Further, a strong negative correlation was found between the percentage of participants reporting an adjustment of prescription and that reporting an active coping (r=-0.907, p<0.001). The daily relief sub-type contained a variety of strategies, including negative methods such as vomiting for nausea and weight gain and drinking alcohol for insomnia. Limitations: Sampling of subjects were biased due to an Internet survey and diagnosis of depression and experience of side effects were self-reported. Conclusion: Patients with depression use various ways in alleviating antidepressants side effects. Some effects such as sexual dysfunction and fatigue may not be amenable to subjective coping efforts and others are sometimes managed inappropriately, which warrants a prudent attention. © 2012 Elsevier B.V.