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Challenging the need for sustained blockade of dopamine D2 receptor estimated from antipsychotic plasma levels in the maintenance treatment of schizophrenia: A single-blind, randomized, controlled study

Schizophrenia Research, Volume 164, Issue 1-3, May 2015, Pages 149 - 154

Editorial Comment:
Traditionally antipsychotic response has been linked to achieving at least 65% blockade of dopamine D2 receptors. Recent studies, albeit with methodological weaknesses, suggest that lower levels of blockade may be effective for maintenance treatment. In this single-blind RCT two clinically stable groups of patients were randomized to receive different antipsychotic doses that, based on plasma levels and a predictive model, were estimated to correspond to two different degrees of striatal D2 blockade; continuous D2 blockade (i.e. estimated trough D2 blockade of >65%) and non-continuous blockade (i.e. estimated peak level of >65% with an estimated trough level of <65%). After 1 year of follow-up no significant differences were seen between the two groups on the PANSS or a series of other outcome measures. The results support the view that maintenance treatment can be achieved with D2 blockade that is lower than 65%. However, as the authors highlight, this is a pilot study and that the results are preliminary. Further work is needed with larger samples, a longer follow up and direct measurement of D2 receptor occupancy.

Prof. Peter Haddad, University of Manchester, UK

Abstract

Objective

Blockade of dopamine D2 receptors with antipsychotics above 65% is associated with optimal chance of clinical response although recent data suggest a lower threshold for the maintenance treatment of schizophrenia. The objective of this study was to prospectively examine whether such continuous high blockade would be necessary for maintenance treatment.

Method

In this single-blind, 52-week, randomized controlled trial, clinically stable patients with schizophrenia receiving risperidone or olanzapine were randomly assigned to the continuous D2 blockade (i.e. an estimated trough D2 blockade of > 65%) or non-continuous blockade group (i.e. an estimated peak level of > 65% with an estimated trough level of < 65%). Oral doses corresponding to the assigned blockade levels were estimated from random plasma drug concentrations, using the models we developed; antipsychotic doses were then adjusted accordingly. Psychopathology and side effects were assessed at baseline and one year with the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS).

Results

Sixty-eight subjects (34 in each group) were enrolled. Twenty-six (76.5%) and thirty-one (91.2%) subjects completed the study in the continuous and non-continuous blockade groups, respectively, without any significant group difference. No significant differences were found on any of the assessment scales between the two groups. The degree of dosage change was small in both groups.

Conclusion

These results offer support that the threshold for D2 receptor blockade in the maintenance treatment can be lower than 65%. However, these preliminary findings have to be confirmed through double-blind, larger scale trials with longer follow-up periods.

Keywords: Antipsychotics, Dopamine D2 receptor, Maintenance treatment, Schizophrenia.

1. Introduction

For the maintenance treatment of schizophrenia, regular dosing of antipsychotic drugs is considered essential since antipsychotics not only improve psychotic symptoms but also prevent relapse (Davis, 1975 and Uchida et al, 2011a). Antipsychotic drugs are presumed to exert their antipsychotic effect by blocking dopamine D2 receptors; evidence obtained from brain imaging studies has demonstrated that dopamine D2 receptor blockade over 65% with antipsychotic drugs optimizes chance of clinical response, while risk of extrapyramidal side effects increases with 80% blockade or more (Farde et al, 1992, Kapur et al, 2000, and Uchida et al, 2011b).

This said, it is not clear as to whether it is necessary to maintain this threshold of dopamine D2 receptor blockade in order to sustain clinical response. In fact, recent clinical data have challenged the conventional threshold of continuous dopamine D2 receptor blockade over 65% in the maintenance treatment (Uchida et al, 2008, Remington et al, 2011, Ikai et al, 2012, Mizuno et al, 2012, Moriguchi et al, 2013, and Takeuchi et al, 2013). However, it should be noted that these observations are derived from cross-sectional data (Ikai et al, 2012 and Mizuno et al, 2012), post-hoc analyses of prospective clinical trials (Uchida et al, 2008, Moriguchi et al, 2013, and Takeuchi et al, 2013), and a prospective clinical trial without any measurement or estimation of dopamine D2 receptor blockade (Remington et al., 2011). To date, this has not yet been tested in a prospective manner, taking into account dopamine D2 receptor occupancy.

Given that brain imaging techniques are not widely available, we have established models to estimate striatal dopamine D2 receptor blockade levels with risperidone and olanzapine from plasma antipsychotic concentrations (Uchida et al., 2011c). Moreover, doses that result in any given target plasma levels at any point in time (e.g. trough and peak) can be estimated, using plasma levels of those drugs with two sparsely collected plasma samples with population pharmacokinetic (PPK) techniques (Ikai et al., 2012). By combining these two models, doses that correspond to any given dopamine D2 receptor occupancy (e.g. 65% at trough) can be estimated for each individual.

In this one-year, single-blind, randomized controlled pilot study, we compared effectiveness in terms of relapse prevention between continuous blockade of dopamine D2 receptors above 65% and non-continuous blockade in clinically stable patients with schizophrenia, where dopamine D2 receptor occupancy was estimated using the PPK techniques and our D2 prediction model.

2. Experimental/materials and methods

2.1. Subjects and settings

Patients were included in the study if they met the following criteria: (1) International Classification of Diseases, 10th edition (ICD-10) diagnosis of schizophrenia, schizophreniform disorder, or delusional disorder, (2) a stable dose of either risperidone or olanzapine as antipsychotic monotherapy for the previous six months, (3) 18 years of age or older, and (4) capable of providing informed consent. Patients who had a history of treatment with long-acting risperidone within the previous six months were excluded. This study was conducted at Keio University Hospital, Minami-Hannou Hospital, Ohizumi Hospital, Ohizumi Mental Clinic, Asakadai Mental Clinic, Inokashira Hospital, and Toyoko-Keiai Hospital in Japan. The study was approved by the institutional review board at each participating site, and prior to study entry subjects provided written informed consent after receiving detailed information about the protocol. The protocol was strictly followed in this study. The study was registered at the University Medical Information Network Clinical Trial Registry (Identifier: UMIN000006011) and carried out in compliance with the guidelines for Good Clinical Practice.

2.2. Study description

The study flow is shown in Fig. 1. Subjects were randomly assigned to one of two groups: continuous D2 blockade group (i.e. a trough D2 blockade of > 65%) or non-continuous D2 blockade group (i.e. a peak D2 blockade > 65% with trough level < 65%) in a 1:1 ratio. This randomization was conducted using the envelope method as follows. The person who was independent of this study prepared a piece of paper on which one of the assigned group was designated according to a computer generated randomization list, inserted it into an envelope with a subject ID number written, and sealed it. Upon registration of each subject, one of the investigators opened the envelope that corresponded to their ID, and the person who prepared the envelopes confirmed that the envelopes were appropriately opened. Following the baseline assessments of psychopathology and side effects (see below), plasma samples were taken for all the subjects to measure plasma concentrations of risperidone plus 9-hydroxyrisperidone (active moiety) or olanzapine at any two given points in time. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and olanzapine were assayed in heparinized plasma using LC/MS/MS (liquid chromatography with tandem mass spectrometry detection) at the Centre for Addiction and Mental Health (Toronto, Canada) with a limit of quantitation of 2 nmol/L (0.82 ng/mL), 5 nmol/L (2.13 ng/mL), and 7.5 nmol/L (2.3 ng/mL), respectively. Using the two plasma drug concentrations, antipsychotic doses that resulted in target dopamine D2 receptor occupancy levels at peak and trough were estimated as described below. Antipsychotic doses were individually titrated (i.e. increased or decreased) to achieve the target doses for 2 to 6 weeks; doses of risperidone and olanzapine were gradually titrated by 0.5 mg or 2.5 mg, respectively. Subjects were then treated with the target doses and observed for 52 weeks.

gr1

Fig. 1 Overview of the study design.

The following assessments were carried out at baseline and week 52: the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), the Calgary Depression Scale for Schizophrenics (CDSS) (Addington et al., 1990), and the Subjective Well-being under Neuroleptic treatment (SWN) (Naber, 1995). In addition, they received assessments with the Simpson-Angus Scale (SAS) (Simpson and Angus, 1970), the Barnes Akathisia Rating Scale (BARS) (Barnes, 1989), the Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976), the Clinical Global Impression-Schizophrenia (CGI-SCH) scale (Haro et al., 2003), and the Global Assessment of Functioning (GAF) (Endicott et al., 1976) every four weeks. This study represents a single-blind trial, with all assessments conducted by one of the trained investigators who were not aware of group assignment. The following information was also collected: concomitant medications, time of last dose, medication side effects, medication compliance, as well as anonymous demographic information including age, weight, diagnoses, sex, race, height, duration of illness, and smoking habit.

2.3. Calculation of target dose

By incorporating the two plasma drug concentrations collected from each individual subject into the PPK model (see below), peak and trough antipsychotic concentrations corresponding to consecutive doses from 0.0 mg/day to the upper limit of the dose ranges indicated in the packet inserts (i.e. 6.0 mg/day for risperidone and 20.0 mg/day for olanzapine) in increments of 0.5 mg/day for risperidone or 2.5 mg/day for olanzapine were estimated. Subsequently, peak and trough dopamine D2 receptor occupancy levels that correspond to those consecutive doses were estimated using the D2 prediction model (Uchida et al., 2011c). The D2 prediction model is based on the one-site binding model for the relationship between plasma antipsychotic concentrations and D2 receptor occupancy levels, using the pooled data from published articles identified through a systematic literature search. D2 receptor occupancy levels can be estimated with a high degree of accuracy for risperidone and olanzapine as mean prediction errors for risperidone and olanzapine are 0.0 ng/mL and − 0.1 ng/mL, respectively (Uchida et al., 2011c). The dose that achieved target dopamine D2 receptor blockade in accordance with the assigned group was then chosen. If one or more antipsychotic doses were expected to result in the target blockade, choice of dose was at the discretion of the subject's physician-of-record.

2.4. PPK analysis

Plasma antipsychotic concentrations at peak and trough were estimated using the two plasma samples and the nonlinear mixed-effect PPK approach with NONMEM VII (Sheiner et al., 1977). The mixed-effect models for risperidone and olanzapine have been previously established using data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) studies (Bigos et al, 2008 and Feng et al, 2008). All compounds were adequately described using a one-compartment linear model with first order absorption. The previously established models utilized exponentiated or log-normal interindividual variability on each pharmacokinetic parameter, a mixture distribution to assign the tri-modal distribution of risperidone of clearance as CYP 2D6 genotype was not available for that drug, an age effect on clearance of the 9-hydroxyrisperidone moiety, and sex, race, and age effects on olanzapine disposition. Empirical Bayes Estimates generated for each individual PK parameter and these parameters utilized to calculate the peak and trough concentrations.

2.5. Statistical analysis

Statistical analyses were carried out using IBM SPSS Version 21.0 (IBM, New York, USA). The primary outcome was completion rate, while the secondary outcomes were score changes in the assessment scales for psychopathology and side effects. Baseline demographic and clinical characteristics were compared between the two groups of interest by the Fisher's exact test for categorical variables and by the Student's t test for continuous variables. Completion rates were compared between the two groups by the Student's t test and the generalized Wilcoxon test for survival analysis. The between-group differences in changes at last visit from baseline in all the assessments were tested by variance analysis whose covariates were baseline values, using a last observation carried forward (LOCF) method as a primary analysis and observed case analysis as a secondary analysis. Moreover, drop-out rates and changes from baseline to endpoint in the PANSS total scores were compared among participants whose doses increased, remained the same, and decreased by the Fisher's exact test and the analysis of variance, respectively. A two-tailed P value of < 0.05 was considered statistically significant for all tests.

3. Results

3.1. Characteristics of the sample

Recruitment took place between December, 2011 and October, 2012. 150 subjects were screened; of these, 71 were excluded due to the criteria and 11 did not wish to participate in this study. Thus, 68 subjects were enrolled and randomly assigned to the continuous D2 blockade group (n = 34) or the non-continuous D2 blockade group (n = 34). Baseline demographic and clinical characteristics of the subjects are shown in Table 1, Table 2, and Table 3. Sixty-six subjects were diagnosed with schizophrenia, one with schizoaffective disorder and another with delusional disorder. No statistical differences were found in any of the baseline values other than the baseline dose of olanzapine (Table 1).

Table 1 Demographic and clinical characteristics of the subjects.

Continuous group (n = 34) Non-continuous group (n = 34)
Male, N (%) 22 (64.7%) 19 (55.9%)
Outpatient, N (%) 16 (47.1%) 23 (67.6%)
Age, years, mean (SD) 58.4 (14.3) 52.4 (15.1)
Smokers, N (%) 12 (35.3%) 10 (29.4%)
Duration of illness, years, mean (SD) 27.3 (16.7) 22.6 (16.2)
Duration of treatment, years, mean (SD) 22.2 (15.1) 18.7 (14.9)
Number of previous admissions, mean (SD) 2.9 (2.3) 1.9 (2.1)
Antipsychotics used
 Risperidone, N (%) 16 (47.1%) 17 (50.0%)
 Olanzapine, N (%) 18 (52.9%) 17 (50.0%)

Table 2 Changes in dosage and estimated dopamine D2 receptor occupancy.

Continuous group (n = 34) Non-continuous group (n = 34)
Antipsychotics used
 Risperidone, N (%) 16 (47.1%) 17 (50.0%)
 Baseline dose, mg/day, mean (SD) 3.8 (2.0) 2.7 (1.1)
 Target dose, mg/day, mean (SD)a 3.4 (1.6) 1.9 (0.7)
 Olanzapine, N (%) 18 (52.9%) 17 (50.0%)
 Baseline dose, mg/day, mean (SD)b 11.9 (5.7) 8.1 (4.1)
 Target dose, mg/day, mean (SD)c 10.4 (4.4) 7.1 (2.7)
Estimated dopamine D2 receptor occupancy
 Peak at baseline, mean (SD)a 75.3 (6.4) 70.0 (7.3)
 Trough at baseline, mean (SD)d 71.9 (6.8) 66.3 (8.4)
 Peak after titration, mean (SD)e 73.8 (3.6) 66.9 (1.7)
 Trough after titration, mean (SD)e 70.6 (4.0) 62.6 (2.0)

Significant p-values are labeled as follows: aP = 0.002, bP = 0.027, cP = 0.01, dP = 0.004, eP < 0.001.

Table 3 Clinical psychopathology, extrapyramidal symptoms, and body weight.

Continuous group (n = 34) Non-continuous group (n = 34) Difference in change between 2 groups, P-value
Baseline Change from baseline to endpoint Baseline Change from baseline to endpoint
PANSS
 Total score 61.7 (15.6) − 0.6 (3.3) 54.1 (15.3) − 1.5 (5.6) .464
 Positive symptoms 12.2 (4.4) − 0.2 (0.9) 10.6 (3.5) − 0.8 (2.0) .012
 Negative symptoms 18.8 (6.5) 0.0 (1.9) 16.3 (6.6) − 0.2 (2.8) .720
 General psychopathology 31.0 (7.6) − 0.7 (2.4) 27.4 (7.4) − 0.8 (2.7) .918
GAF 52.6 (11.6) 0.1 (4.2) 57.6 (12.7) 0.5 (3.9) .692
CDSS total 2.5 (2.9) − 0.2 (1.4) 3.0 (3.3) − 0.1 (1.3) .820
SWN 82.4 (12.5) − 0.6 (5.6) 81.6 (16.3) 2.1 (7.7) .115
SAS total score 3.0 (3.6) − 0.2 (1.2) 1.2 (2.0) − 0.1 (0.8) .475
BARS global clinical assessment 0.2 (0.6) 0.0 (0.6) 0.1 (0.3) 0.0 (0.4) .705
AIMS total (1–7 items) 1.0 (2.0) 0.0 (0.3) 0.6 (1.6) − 0.1 (0.5) .152
Body weight, kg 62.1 (15.5) 0.0 (3.4) 58.7 (10.8) 0.1 (4.4) .873

Values are shown as mean (SD).

Significant P-values of < 0.05 are labeled with an asterisk.

Abbreviations: PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning; CDSS, Calgary Depression Scale for Schizophrenics; SWN, Subjective Well-being under Neuroleptic treatment; SAS, Simpson-Angus Scale; BARS, Barnes Akathisia Rating Scale; AIMS, Abnormal Involuntary Movement Scale.

3.2. Outcomes

Following dose titration and clinical follow-up for one year, a total of 57 patients completed all study procedures; 26 subjects (76.5%) in the continuous D2 blockade group and 31 subjects (91.2%) the non-continuous D2 blockade group successfully completed the study (Table 2). This difference was not statistically significant. Moreover, a survival analysis also failed to show any significant difference in the completion rates between the two groups. Reasons for dropping out were as follows: relapse (n = 5), side effects (hyperglycemia) (n = 1), and loss to follow-up (n = 2) in the continuous group, and relapse (n = 1), side effects (sedation) (n = 1), and withdrawal of consent (n = 1) in the non-continuous group. There were no significant differences in any of the baseline demographic characteristics between the completers and the dropouts.

No significant differences between the two groups were found in changes from baseline to endpoint in the PANSS Total, Negative, or General Psychopathology subscale score as well as the GAF, CDSS, or SWN total scores (Table 3). On the other hand, the PANSS positive subscale score was significantly, albeit only modestly, decreased in the non-continuous D2 blockade group when compared with the continuous counterpart (Table 3). With regard to extrapyramidal symptoms and body weight, there were no significant differences in pre–post changes between the two groups (Table 3). Results were generally similar when observed cases were analyzed (Table 4). There were no significant differences in drop-out rates or changes from baseline to endpoint in the PANSS total scores among participants whose doses increased (n = 12), remained the same (n = 26), and decreased (n = 30).

Table 4 Clinical psychopathology, extrapyramidal symptoms, and body weight in the completers.

Continuous group (n = 26) Non-continuous group (n = 31) Difference in change between 2 groups, P-value
Baseline Change from baseline to endpoint Baseline Change from baseline to endpoint
PANSS
 Total score 59.0 (14.9) − 0.7 (3.8) 54.7 (15.4) − 1.6 (5.8) .536
 Positive symptoms 11.4 (4.3) − 0.2 (1.1) 10.7 (3.6) − 0.9 (2.0) .040*
 Negative symptoms 17.8 (5.4) 0.0 (2.1) 16.7 (6.6) − 0.2 (2.9) .776
 General psychopathology 29.8 (7.4) − 0.9 (2.8) 27.6 (7.4) − 0.8 (2.9) .831
GAF 53.4 (12.2) 0.3 (3.1) 56.4 (12.4) 0.7 (3.5) .609
CDSS total 2.1 (2.2) − 0.2 (1.6) 2.7 (3.1) − 0.1 (1.4) .692
SWN 84.2 (11.9) − 0.7 (6.4) 82.0 (15.7) 2.3 (8.0) .150
SAS total score 2.5 (3.5) 0.0 (0.8) 1.3 (2.0) − 0.1 (0.8) .457
BARS global clinical assessment 0.2 (0.6) 0.0 (0.4) 0.1 (0.3) 0.0 (0.4) .847
AIMS total (1–7 items) 1.2 (2.2) 0.1 (0.3) 0.7 (1.6) − 0.1 (0.5) .083
Body weight, kg 62.8 (15.8) 0.1 (3.9) 57.6 (10.4) 0.1 (4.8) .783

Values are shown as mean (SD).

A significant P-value of < 0.05 is labeled with an asterisk.

Abbreviations: PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning; CDSS, Calgary Depression Scale for Schizophrenics; SWN, Subjective Well-being under Neuroleptic treatment; SAS, Simpson-Angus Scale; BARS, Barnes Akathisia Rating Scale; AIMS, Abnormal Involuntary Movement Scale.

4. Discussion

To the best of our knowledge, this is the first prospective trial to examine the relationship between estimated dopamine D2 receptor occupancy and clinical outcomes in the maintenance treatment of schizophrenia. Our results indicate that non-continuous blockade of dopamine D2 receptors with antipsychotics is comparable to continuous blockade exceeding 65% in terms of relapse prevention as well as side effects.

These findings corroborate previous findings from small positron emission tomography (PET) studies indicating that dopamine D2 receptor blockade with antipsychotics may not need to be continuously above 65% for relapse prevention (Nyberg et al, 1995 and Uchida and Suzuki, 2014). However, interpretation of those two PET studies is limited by the small sample sizes and lack of randomization. Although dopamine D2 receptor blockade was not measured directly but, instead, estimated in the present study, findings from this one-year single-blind randomized controlled trial with a larger sample size provide further support to the position that continuous D2 receptor blockade above 65% is not necessary, at least for some patients, in the maintenance treatment of schizophrenia.

Of note, we did not observe any advantages for non-continuous blockade in terms of side effects. This may reflect a ceiling effect since estimated dopamine D2 receptor blockade levels following dose titration were not high in both groups. Further, the relationship between dopamine D2 receptor blockade with antipsychotic drugs and side effects such as cognitive impairment, motor side effects, and prolactin elevation is not necessarily linear; evidence suggests that these side effects are likely to occur once the D2 blockade exceeds certain thresholds (Uchida et al, 2011b, Sakurai et al, 2013, and Tsuboi et al, 2013a). The issue of side effects warrants further attention, calling for discrete measures that also distinguish between short and longer-term comparisons.

The results support the use of lower antipsychotic doses for the maintenance treatment of schizophrenia although the degree of estimated dopamine D2 receptor blockade, rather than the dose, was the focus in the present study. Given that the risk for various antipsychotic side effects including motor and cardiovascular side effects is often dose-related (Jeste et al, 1995, Lemmens et al, 1999, and Ray et al, 2009), the use of the lowest possible effective antipsychotic dose for relapse prevention is critically important. Our previous meta-analysis revealed that the efficacy of moderately low and standard doses is comparable in preventing relapse in schizophrenia while less than half the standard dose may increase the risk of relapse (Uchida et al., 2011a). We acknowledge individual differences in patient's response to antipsychotics on various pharmacokinetic and pharmacodynamic levels (Rasmussen et al, 2006, Uchida et al, 2009a, and Uchida et al, 2009b), precluding our ability to propose a uniformed treatment approach for relapse prevention (Uchida et al., 2009c). Still, those findings have important implications for the dosing of antipsychotics for the maintenance treatment of schizophrenia and emphasize the need of further investigations to address this controversial dosing issue.

There are several limitations to be noted in the present study. First, dopamine D2 receptor occupancy levels used were not directly measured but only estimated. Moreover, our estimation of D2 occupancy is based on results from a pooled-analysis study; individual studies used different radioligands and studied different regions of interest (Uchida et al., 2011c). Second, the single-blind design in which subjects were aware of the group allocation could have resulted in a certain degree of expectation bias. Third, while the 65% threshold of dopamine D2 receptor occupancy was adopted in this study, there has been no robust scientific evidence for this choice for the maintenance treatment. Although recent cross-sectional data and results of post-hoc analyses have demonstrated that continuous blockade of dopamine D2 receptors above 65% may not be always necessary for relapse prevention (Mizuno et al, 2012 and Moriguchi et al, 2013), the use of 65% threshold should be considered preliminary. Fourth, changes in the antipsychotic doses and estimated D2 occupancy levels were small, which should be acknowledged when the data are interpreted. Fifth, the follow-up period of one year may still be too short to thoroughly assess long-term consequences in the maintenance treatment of schizophrenia although the follow-up period in previous pivotal randomized controlled trials for maintenance treatment of schizophrenia has been one year or shorter (Leucht et al., 2012). Sixth, the sample size, although larger than previous PET studies addressing this question, was small. Moreover, no sample size calculation was performed since this trial was conducted as a pilot study. Seventh, LOCF or a completer analysis was used to analyze the differences between the two groups in the present study. Mixed-effect models for repeated measures would have been ideal; however, it was not employed in this study since assessments of the PANSS were conducted only at the baseline and endpoint. In addition, there were a number of potential intervening variables such as age and duration of current psychotropic regimen. Eighth, the accuracy of predicted plasma concentrations using the PPK techniques was not confirmed in this study while the high prediction performance was confirmed for risperidone and olanzapine elsewhere (Uchida et al, 2012 and Tsuboi et al, 2013b). Moreover, the two-step prediction model that was used to determine the dose provided estimated dopamine D2 blockade levels based on plasma antipsychotic concentrations at peak and trough estimated, using PPK models; the use of two estimates has to be noted although the prediction error of this model was reported to be small elsewhere (Uchida et al., 2013). Ninth, 42.6% of the subjects (n = 29) were inpatients, which may reflect a reality in Japan where many clinically stable psychiatric patients have been long hospitalized due to insufficient social resources. Finally, since only risperidone and olanzapine were included in this study and all patients were Japanese, any extrapolation of these findings to other antipsychotic drugs and/or other ethnic populations must be made within this context.

In conclusion, the findings from this pilot study suggest that sustained dopamine D2 receptor blockade above 65% may not be necessary in the maintenance treatment of schizophrenia. Going forward, these preliminary findings must be confirmed in future studies using actual measurement of dopamine D2 receptor occupancy levels with brain imaging. Moreover, they have to be confirmed through double-blind, larger scale trials with longer follow-up periods.

Role of funding source

This study was partially funded by Takeda Science Foundation, Kanae Science Foundation, Keio Academic Development Funds, and Research Group for Schizophrenia.

Contributors

Drs. Tsuboi and Uchida designed the study. Drs. Tsuboi, Bies, and Uchida analyzed the data. Dr. Tsuboi wrote the first draft of the manuscript. All authors have contributed to and approved the final manuscript.

Conflict of interest

Dr. Tsuboi has received manuscript fees from Dainippon Sumitomo Pharma and speaker's honoraria from Eli Lilly, Tsumura, Yoshitomi Yakuhin, Dainippon Sumitomo Pharma, Kracie Pharma and Mitsubishi Tanabe Pharma within the past two years.

Dr. Suzuki has received manuscript fees or speaker's honoraria from Dainippon Sumitomo Pharma, Astellas Pharma, Novartis Pharma, Eli Lilly and Meiji Seika Pharma within the past two years.

Dr. Bies has received research support from Indiana CTSI through a gift from Eli Lilly and Company, travel support from Roche and the International Society for Pharmacometrics, and grant support from Merck and Company through Regenstrief Institute.

Dr. Remington has received research support from the Canadian Diabetes Association, the Canadian Institutes of Health Research, Medicure, Neurocrine Biosciences, Novartis, Research Hospital Fund—Canada Foundation for Innovation, and the Schizophrenia Society of Ontario and has served as a consultant or speaker for Novartis, Laboratorios Farmacéuticos Rovi, Synchroneuron, and Roche.

Dr. Pollock receives research support from the National Institute of Health, Canadian Institutes of Health Research, Brain Canada, and the Foundation of the Centre for Addiction and Mental Health. Within the past five years he has been a member of the advisory board of Lundbeck Canada (final meeting was May 2009) and was also a faculty member of the Lundbeck International Neuroscience Foundation (LINF) (final meeting was April 2010).

Dr. Mimura has received grants, consultant fees and/or speaker's honoraria from Asahi Kasei, Astellas Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji-Seika Pharma, Mochida Pharmaceutical, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, and Yoshitomi Yakuhin within the past two years.

Dr. Uchida has received grants from Astellas Pharmaceutical, Eisai, Otsuka Pharmaceutical, GlaxoSmithKline, Shionogi, Dainippon-Sumitomo Pharma, Eli Lilly, Mochida Pharmaceutical, Meiji-Seika Pharma, Janssen Pharmaceutical, and Yoshitomi Yakuhin and speaker's honoraria from Otsuka Pharmaceutical, Eli Lilly, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, Abbvie, and Janssen Pharmaceutical within the past two years.

Acknowledgments

We thank the patients with schizophrenia who participated in this study. We thank Ms. Aki Endo for her role in the randomization and Ms. Ai Otani for her administrative support.

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Footnotes

a Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

b Department of Psychiatry, Inokashira Hospital, Tokyo, Japan

c Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA

d Indiana Clinical and Translational Sciences Institute, Indianapolis, IN, USA

e Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada

f Department of Psychiatry, University of Toronto, Toronto, ON, Canada

g Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada

Corresponding author at: Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: + 81 3 5363 3829; fax: + 81 3 5379 0187.