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
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.
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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.
References (38)
- et al.
A depression rating scale for schizophrenics
Schizophr. Res.
(1990) - et al.
Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2012) - et al.
Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia: an analysis of the CATIE data
Schizophr. Res.
(2013) - et al.
Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2013) - et al.
Sensitivity of older patients to antipsychotic motor side effects: a PET study examining potential mechanisms
Am. J. Geriatr. Psychiatry
(2009) A rating scale for drug-induced akathisia
Br. J. Psychiatry
(1989)- et al.
Sex, race, and smoking impact olanzapine exposure
J. Clin. Pharmacol.
(2008) Overview: maintenance therapy in psychiatry: I. Schizophrenia
Am. J. Psychiatry
(1975)- et al.
The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance
Arch. Gen. Psychiatry
(1976) - et al.
Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects
Arch. Gen. Psychiatry
(1992)
Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study
Br. J. Clin. Pharmacol.
ECDEU Assessment Manual for Psychopharmacology
The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia
Acta Psychiatr. Scand. Suppl.
A cross-sectional study of plasma risperidone levels with risperidone long-acting injectable: implications for dopamine D2 receptor occupancy during maintenance treatment in schizophrenia
J. Clin. Psychiatry
Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients
Arch. Gen. Psychiatry
Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia
Am. J. Psychiatry
The positive and negative syndrome scale (PANSS) for schizophrenia
Schizophr. Bull.
A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms
Acta Psychiatr. Scand.
Maintenance treatment with antipsychotic drugs for schizophrenia
Cochrane Database Syst. Rev.
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