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

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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.

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, 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, 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, Takeuchi et al., 2013). However, it should be noted that these observations are derived from cross-sectional data (Ikai et al., 2012, Mizuno et al., 2012), post-hoc analyses of prospective clinical trials (Uchida et al., 2008, Moriguchi et al., 2013, 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.

Section snippets

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

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, Table 3. Sixty-six subjects were diagnosed with schizophrenia, one

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

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

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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