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Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia: An analysis of the CATIE data

Schizophrenia Research, 2-3, 150, pages 373 - 379

Abstract

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.

Keywords: Antipsychotics, Dopamine, Drug attitude, Schizophrenia, Subjective experience.

1. Introduction

Negative subjective experience is one of the critical adverse events induced by both atypical and typical antipsychotics ( de Visser et al., 2001 ); it has consistently been demonstrated that negative experiences lead to poor medication adherence, quality of life, and clinical outcome (Lacro et al, 2002, Chue, 2006, and Vothknecht et al, 2011). Efforts to better capture this side effect have led to the development of rating scales such as the Drug Attitude Inventory (DAI) ( Hogan et al., 1983 ) that consists of two components of subjective experience and attitude toward medication. This scale has been incorporated in large clinical trials in schizophrenia, including the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) ( Lieberman et al., 2005 ) as well as the European First Episode Schizophrenia Trial (EUFEST) ( Kahn et al., 2008 ). It has been found that subjective experience/drug attitude predicted subsequent treatment outcomes in both first-episode and chronic schizophrenia. In the CATIE trial, increases in DAI total scores were associated with improvements in psychopathology, functioning, and medication adherence ( Mohamed et al., 2009 ). In the EUFEST trial, DAI total scores represented one of the significant predictors of treatment discontinuation ( Gaebel et al., 2010 ).

Recent neuroimaging studies indicated a close association between excessive dopaminergic blockade with antipsychotics and negative subjective experience (de Haan et al, 2000, de Haan et al, 2003, de Haan et al, 2005, Mizrahi et al, 2007, and Kim et al, 2011). However, limitations of these previous studies include small sample sizes of up to 50, and a lack of longitudinal data examining the relationship between dopamine D2 receptor occupancy and patients' subjective experience. To our knowledge, there has been only one study to assess the relationship between DAI total scores and dopaminergic function, and it employed a dopamine depletion paradigm using alpha-methyl-p-tyrosine (AMPT) in drug-free schizophrenia ( Voruganti et al., 2001 ). In this investigation, patients with low baseline dopamine function were found to be at an increased risk for negative subjective experience/drug attitude. To date, though, there have been no studies examining the relationship between patients' subjective experience/drug attitude and D2 occupancy with antipsychotics.

Given that neuroimaging is not widely available, we have developed a model with which the dopamine D2 receptor occupancy of various antipsychotics, including risperidone, olanzapine, and ziprasidone, can be reliably estimated from their plasma concentrations ( Uchida et al., 2011 ). In addition, recent advances in nonlinear, mixed-effects population pharmacokinetic methods have made it possible to estimate individual pharmacokinetic parameters for antipsychotics, including peak and trough plasma drug concentrations, using two or more sparsely collected blood samples ( Bigos et al., 2006 ). By combining these models, it is now possible to reliably estimate D2 occupancy levels at any given point in time using the measurement of plasma antipsychotic concentrations at two separate random time points ( Uchida et al., 2009 ).

The CATIE project ( Stroup et al., 2003 ) provides an ideal dataset to carry out such work in light of its unprecedented large sample size and availability of plasma antipsychotic concentrations for which population pharmacokinetic models have already been developed with respect to risperidone ( Feng et al., 2008 ), olanzapine ( Bigos et al., 2008 ), and ziprasidone ( Wessels et al., 2011 ). With these backgrounds, in the present study, we evaluated the impact of estimated dopamine D2 receptor occupancy, using both cross-sectional and longitudinal data, on subjective experience/drug attitude in patients with schizophrenia receiving one of these three antipsychotic drugs.

2. Methods

2.1. Study design

The CATIE, funded by the National Institute of Mental Health, compared the effectiveness of atypical antipsychotics and perphenazine in patients with schizophrenia; details of the study have been reported elsewhere (Stroup et al, 2003 and Lieberman et al, 2005). Briefly, 1493 patients with schizophrenia were initially randomized to olanzapine (7.5–30 mg/day), risperidone (1.5–6.0 mg/day), ziprasidone (40–160 mg/day), quetiapine (200–800 mg/day), or perphenazine (8–32 mg/day) under double-blind conditions, and received treatment for up to 18 months or until treatment was discontinued for any reason (phase 1).

The present analysis was performed with both the cross-sectional and longitudinal datasets. The cross-sectional dataset was derived from patients receiving risperidone, olanzapine, or ziprasidone, who completed DAI-10 assessments at six months and also provided plasma samples for antipsychotic concentrations. The three antipsychotic drugs were chosen because the nonlinear mixed-effect models have already been established for each using data from other CATIE studies (Bigos et al, 2008, Feng et al, 2008, and Wessels et al, 2011). Among the patients included in the cross-sectional dataset, those who experienced an increase in antipsychotic dosage between six and 12 months and also completed DAI-10 assessments at both time points, constituted the longitudinal dataset. The rationale for concentrating on these patients was two-fold: (1) peak and trough plasma drug concentrations would only change in proportion to the doses in a population pharmacokinetic model; and (2) only 15 patients experienced an antipsychotic dose decrease (nine for risperidone, three for olanzapine, and three for ziprasidone), precluding meaningful statistical analyses.

2.2. Outcome measures

Patients' subjective experience/drug attitude was assessed using the DAI-10 ( Hogan et al., 1983 ). Each total score ranges from − 10 to 10, and a higher score indicates a more positive subjective experience/drug attitude. Insight was evaluated using the Insight and Treatment Attitudes Questionnaire (ITAQ) ( McEvoy et al., 1989 ); clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS) ( Kay et al., 1987 ) and the Calgary Depression Scale for Schizophrenia (CDSS) ( Addington et al., 1990 ); extrapyramidal symptoms were assessed with the Simpson–Angus Scale (SAS) ( Simpson and Angus, 1970 ). All assessments were performed at both six and 12 months.

2.3. Population pharmacokinetic analysis

Patients in the CATIE provided plasma samples for the measurement of concentrations of risperidone plus 9-hydroxyrisperidone (active moiety), olanzapine, and ziprasidone, at more than one time point. Using these samples, individual-specific pharmacokinetic parameters were obtained as Empirical Bayes Estimates (Sheiner et al, 1977 and Cha et al, 1992), through taking the following covariates into account: age for 9-hydroxyrisperidone ( Feng et al., 2008 ), sex, race, and smoking for olanzapine ( Bigos et al., 2008 ), and none for ziprasidone ( Wessels et al., 2011 ). Using these pharmacokinetic parameters, plasma antipsychotic concentrations at peak and trough that corresponded to the dose given on the day of DAI-10 assessments were calculated for each individual using the NONMEM software. The model-predicted values of the plasma antipsychotic concentrations were then used to calculate the peak and trough dopamine D2 receptor occupancy levels for each individual on the day of DAI-10 assessments. The precision and reliability of this estimation have recently been confirmed in a population pharmacokinetic study ( Uchida et al., 2012 ).

2.4. Estimation of dopamine D2 receptor occupancy

Using the predicted plasma antipsychotic concentrations at peak and trough on the day of DAI-10 assessments, corresponding dopamine D2 receptor occupancy levels were estimated using the model we developed ( Uchida et al., 2011 ). Briefly, D2 occupancy levels were calculated by incorporating the predicted plasma concentration of risperidone active moiety, olanzapine, or ziprasidone into the following one-site binding model: occupancy (%) = a × [plasma level / (plasma level + ED50)], where a is the maximum receptor occupancy attributable to the antipsychotic drug and ED50 is the estimated plasma concentration of the antipsychotic drug associated with 50% receptor occupancy; the values were obtained in the systematic review and pooled analysis (risperidone active moiety: a = 88.0%, ED50 = 4.9 ng/ml; olanzapine: a = 90.7%, ED50 = 7.1 ng/ml; and ziprasidone: a = 88.2%, ED50 = 32.9 ng/ml) ( Uchida et al., 2011 ). The mean values of estimated D2 occupancy levels at peak and trough were obtained for further analyses.

2.5. Statistical analysis

Statistical analyses were performed in all patients collectively as well as by each of the three antipsychotic groups. Spearman's rank correlations were performed to evaluate the bivariate associations of DAI-10 total scores with estimated dopamine D2 receptor occupancy levels for cross-sectional and longitudinal datasets. If the association between DAI-10 total scores and estimated D2 occupancy was statistically significant, multiple regression analysis was employed using DAI-10 total scores as an independent variable, and significant variables identified by Spearman's rank correlations, including age, years of education, years of treatment, ITAQ, PANSS, CDSS, and SAS total scores as dependent variables for both datasets. For the longitudinal analysis, absolute changes in all variables were considered.

A two-tailed P-value of < 0.05 was considered statistically significant for all tests. Bonferroni correction was applied to the association between DAI total scores and estimated D2 occupancy (i.e. P values multiplied by four: one whole plus three antipsychotic groups). All statistical analyses were conducted using the IBM SPSS Statistics version 19 (IBM Corporation, Armonk, NY).

3. Results

3.1. Baseline demographic and clinical characteristics of patients

3.1.1. Cross-sectional dataset

A total of 371 patients were included in the cross-sectional dataset. Baseline demographic and clinical characteristics are summarized in Table 1 . Estimated dopamine D2 receptor occupancy levels significantly differed between the three antipsychotic groups (F = 214, df = 2, P < 0.001), with no significant differences found on any other variables except PANSS total score (F = 3.48, df = 2, P = 0.032).

Table 1 Baseline demographic and clinical characteristics of patients in cross-sectional dataset.

  All antipsychotics (N = 371) Risperidone (N = 135) Olanzapine (N = 170) Ziprasidone (N = 66)
  N % N % N % N %
Male 272 73.3 100 74.1 124 72.9 48 72.7
White 220 59.3 80 59.3 99 58.2 41 62.1
Married 41 11.1 19 14.1 17 10.0 5 7.6
Employed 56 15.1 22 16.3 24 14.1 10 15.2
 
  Mean SD Mean SD Mean SD Mean SD
Age (years) 41.7 11.2 41.4 11.6 42.0 10.8 41.5 11.5
Duration of education (years) 12.1 2.2 12.2 2.1 12.1 1.9 11.9 3.1
Duration of treatment (years) 17.5 11.8 17.8 12.2 17.9 11.7 15.7 11.4
DAI-10 total score 6.6 2.9 6.3 3.1 6.6 2.9 6.8 2.8
ITAQ total score 18.7 4.5 18.4 4.8 18.9 4.4 19.0 4.2
PANSS total score a 65.3 16.7 68.0 16.0 63.0 16.8 66.1 17.2
CDSS total score 3.1 3.7 3.3 3.8 2.8 3.7 3.5 3.8
SAS total score 0.2 0.3 0.2 0.3 0.2 0.3 0.3 0.4
Dose (mg/day) N/A N/A 4.2 1.5 20.4 7.3 120.0 36.5
Estimated D2 occupancy (%) a 68.3 13.1 72.3 7.7 73.1 8.2 47.7 12.6

a Significant difference among the three antipsychotic groups.

Fisher's exact test for categorical variables or one-way analysis of variance (ANOVA) for continuous variables was used to compare among the three antipsychotic groups.

Abbreviation: DAI; Drug Attitude Inventory, ITAQ; Insight and Treatment Attitudes Questionnaire, PANSS; Positive and Negative SyndromeScale, CDSS; Calgary Depression Scale for Schizophrenia, SAS; Simpson–Angus Scale.

3.1.2. Longitudinal dataset

A total of 45 patients were included in the longitudinal dataset; baseline characteristics are detailed in Table 2 . No significant differences were found between groups on all variables except estimated D2 occupancy (F = 12.4, df = 2, P < 0.001).

Table 2 Baseline demographic and clinical characteristics of patients in longitudinal dataset.

  All antipsychotics (N = 45) Risperidone (N = 20) Olanzapine (N = 22) Ziprasidone (N = 3)
  N % N % N % N %
Male 33 73.3 14 70.0 17 77.3 2 66.7
White 28 62.2 13 65.0 14 63.6 1 33.3
Married 2 4.4 2 10.0 0 0.0 0 0.0
Employed 6 13.3 3 15.0 3 13.6 0 0.0
 
  Mean SD Mean SD Mean SD Mean SD
Age (years) 41.0 10.0 41.5 11.6 41.2 9.0 35.7 3.5
Duration of education (years) 12.0 2.2 11.9 2.8 12.2 1.8 11.7 0.6
Duration of treatment (years) 17.9 11.3 19.5 12.3 15.9 10.5 22.3 11.0
DAI-10 total score 6.4 3.1 7.0 2.5 5.5 3.5 8.0 2.0
ITAQ total score 19.2 4.7 19.6 4.4 18.5 5.2 21.0 1.7
PANSS total score 64.1 16.7 63.8 17.5 65.5 17.1 56.0 6.0
CDSS total score 4.0 4.5 4.0 4.5 3.7 4.6 6.0 5.3
SAS total score 0.2 0.3 0.2 0.4 0.1 0.2 0.1 0.1
Dose (mg/day) N/A N/A 3.2 0.9 17.0 4.7 106.7 23.1
Estimated D2 occupancy (%) a 68.6 9.4 70.2 8.6 69.9 6.0 47.3 12.1

a Significant difference among the three antipsychotic groups.

Fisher's exact test for categorical variables or one-way analysis of variance (ANOVA) for continuous variables was used to compare among the three antipsychotic groups.

Abbreviation: DAI; Drug Attitude Inventory, ITAQ; Insight and Treatment Attitudes Questionnaire, PANSS; Positive and Negative SyndromeScale, CDSS; Calgary Depression Scale for Schizophrenia, SAS; Simpson-Angus Scale.

3.2. Association between estimated dopamine D2 receptor occupancy and DAI-10 total scores

In the olanzapine group, estimated D2 occupancy levels were positively correlated with DAI-10 total scores (rs = 0.160, P = 0.037) in the cross-sectional dataset (i.e. a higher estimated D2 occupancy was related to a more positive subjective experience/drug attitude) ( Fig. 1 A), although it failed to remain significant after Bonferroni correction. DAI-10 total scores were also correlated with ITAQ total scores (rs = 0.191, P = 0.013) and PANSS total scores (rs = − 0.216, P = 0.005). After multiple regression analysis incorporating these variables, only ITAQ and PANSS scores remained significant (β = 0.158, P = 0.037; β = − 0.194, P = 0.010, respectively) (adjusted R2 = 0.071, P = 0.002).

gr1

Fig. 1 Olanzapine: cross-sectional and longitudinal correlations between estimated dopamine D2 receptor occupancy and DAI-10 total scores.

In contrast to the cross-sectional analysis, in the longitudinal dataset, changes in estimated D2 occupancy levels were negatively correlated with changes in DAI-10 total scores (rs = − 0.534, P = 0.010) in the olanzapine group (i.e. an increase in estimated D2 occupancy was related to an increase in negative subjective experience/drug attitude) ( Fig. 1 B), which remained significant after Bonferroni correction. Changes in DAI-10 total scores were not significantly correlated with changes in any other variables.

In the ziprasidone group, estimated D2 occupancy levels were positively correlated with DAI-10 total scores (rs = 0.395, P = 0.001) in the cross-sectional dataset (i.e. a higher estimated D2 occupancy was related to a more positive subjective experience/drug attitude) ( Fig. 2 ), which remained significant after Bonferroni correction. DAI-10 total scores were also correlated with ITAQ total scores (rs = 0.301, P = 0.014). After multiple regression analysis incorporating these variables, D2 occupancy remained significant as well as ITAQ total scores (β = 0.333, P = 0.005; β = 0.254, P = 0.029, respectively) (adjusted R2 = 0.165, P = 0.001). Due to a very small number of patients who experienced a dose increase of ziprasidone (N = 3), statistical analyses were not performed for the longitudinal dataset.

gr2

Fig. 2 Ziprasidone: cross-sectional correlation between estimated dopamine D2 receptor occupancy and DAI-10 total scores.

No significant correlations were observed in the risperidone group or the whole sample for both the cross-sectional dataset (rs = 0.025, P = 0.772; rs = 0.069, P = 0.187, respectively) and longitudinal dataset (rs = 0.178, P = 0.453; rs = -0.125, P = 0.412, respectively) ( Fig. 3 A and B).

gr3

Fig. 3 Risperidone: cross-sectional and longitudinal correlations between estimated dopamine D2 receptor occupancy and DAI-10 total scores.

4. Discussion

To the best of our knowledge, this is the first study to examine both cross-sectional and longitudinal relationships between estimated dopamine D2 receptor occupancy with atypical antipsychotics and subjective experience/drug attitude in patients with schizophrenia. Our findings can be summarized as follows: (1) a longitudinal increase in estimated D2 occupancy with olanzapine was associated with an increase in negative subjective experience/drug attitude, (2) a higher estimated D2 occupancy with ziprasidone was associated with a more positive subjective experience/drug attitude cross-sectionally, and (3) no significant associations were found in those receiving risperidone or the whole sample. These findings collectively suggest that the association between dopamine D2 receptor occupancy and patients' subjective experience/drug attitude may differ between antipsychotics, at least those in question here.

The longitudinal dataset indicated that an increase in estimated D2 occupancy was associated with an increase in negative subjective experience/drug attitude in patients who were receiving olanzapine, which emphasizes the need for caution when the dose of olanzapine is increased. Simply put, patients with lower baseline dopaminergic function (i.e. olanzapine-related D2 occupancy) may be exposed to an increased risk of developing negative subjective experience/drug attitude in the face of increased D2 blockade through dose increments ( Voruganti et al., 2001 ).

In contrast, the cross-sectional dataset suggested a positive association between estimated D2 occupancy and subjective experience/drug attitude in patients receiving ziprasidone. This may sound paradoxical in light of a notion that increased D2 occupancy, as occurs with higher doses, generally increases risk of negative subjective experience in patients with schizophrenia (de Haan et al, 2000, de Haan et al, 2003, de Haan et al, 2005, Mizrahi et al, 2007, and Kim et al, 2011). One possible explanation is that the mean ± SD estimated D2 occupancy with ziprasidone in this study was, in line with recent PET data examining multiple time points using within subject design ( Suzuki et al., 2013 ), as low as 47.7 ± 12.6%, suggesting that too low D2 occupancy may not be adequate to counteract patients' negative subjective experience. In contrast, D2 occupancy beyond the therapeutic threshold may exert detrimental effects as we noted in the instance of olanzapine. The use of lower doses of zirasidone in the CATIE trial may be of relevance since as many as 34.8% of patients received lower than the currently recommended dose of 120–160 mg/day (Citrome et al, 2009 and Gardner et al, 2010). In the case of ziprasidone, its risk, albeit modest, of dose-dependent QTc prolongation ( Camm et al., 2012 ) may be an obstacle for dose increments.

This opposite direction of the impact on subjective experience/drug attitude between olanzapine and ziprasidone may be attributable to pharmacodynamic and pharmacokinetic characteristics. For instance, one study demonstrated a significant interaction between dopamine D2 receptor binding profiles of antipsychotics (loose vs. tight) and estimated D2 occupancy with regard to subjective experience ( Lataster et al., 2011 ). Furthermore, a recent PET study showed that ziprasidone has a relatively short central half-life with respect to D2 occupancy across the brain regions ( Suzuki et al., 2013 ), which stands in contrast to olanzapine ( Tauscher et al., 2002 ). Note that the distributions of estimated D2 occupancy differed between the two drugs in the present study (i.e. mean ± SD 73.1 ± 8.2 for olanzapine and 47.7 ± 12.6 for ziprasidone) ( Figs. 1 A and 2 ). These factors appear to have some influence on subjective experience, although the exact mechanisms still remain elusive.

Unlike olanzapine and ziprasidone, no association was found between estimated D2 occupancy and subjective experience/drug attitude in patients receiving risperidone. In fact, data regarding risperidone have not been consistent. Mizrahi et al. reported a significant relationship between D2 occupancy and subjective experience with risperidone in five patients ( Mizrahi et al., 2007 ). In contrast, de Haan et al. demonstrated no significant association between D2 occupancy and subjective experience in seven patients receiving risperidone ( de Haan et al., 2000 ). It is noteworthy that the sample for the first study was drug-naïve ( Mizrahi et al., 2007 ); whether this might account for the differences is not clear, but there is evidence indicating susceptibility to side effects in the early stages of antipsychotic treatment ( Emsley, 2009 ). Unfortunately, there have been few studies examining the relationship between D2 occupancy with specific atypical antipsychotics and subjective experience in patients with schizophrenia.

There are limitations to the present study that must be noted. First, only patients receiving risperidone, olanzapine, or ziprasidone were included in this study since both the population pharmacokinetic models (Bigos et al, 2008, Feng et al, 2008, and Wessels et al, 2011) and the prediction model of dopamine D2 receptor occupancy levels from plasma antipsychotic concentrations ( Uchida et al., 2011 ) were available only for three drugs. Although these drugs represent commonly prescribed atypical antipsychotics, any extrapolation of the findings to other antipsychotics must be made caution. Second, the number of patients in the longitudinal dataset was relatively small compared to the cross-sectional dataset, which limits interpretation of the former. In fact, for ziprasidone, only three patients experienced a dose increase, which did not allow for statistical analysis. Nevertheless, the results on 60 patients (45 increased plus 15 decreased) whose antipsychotic doses were changed were essentially similar (data not shown). Third, peak and trough plasma antipsychotic concentrations were calculated from actual plasma antipsychotic concentrations using population pharmacokinetic model and D2 occupancy levels used herein were not directly measured but, instead, estimated based on the results from a pooled-analysis study ( Uchida et al., 2011 ). Moreover, the region of interest in 97% of the PET data used for the development of this prediction model was the striatum ( Uchida et al., 2011 ). Thus, the findings in the present study need to be replicated in future investigations, using high-affinity radiotracers that enable visualization and quantification of extrastriatal dopamine receptors as well. Fourth, the present analysis focused on D2 occupancy with antipsychotics. It is likely that neurotransmitters other than dopamine (e.g. histamine) are also involved in subjective experience ( Yanai et al., 2011 ). It is further important to point out that attitude toward medication has a strong ‘personal’ dimension that may defy a simplified D2-occupancy theory. Finally, it may be preferable to assess patients' subjective experience to antipsychotics by using more comprehensive scales such as the Subjective Well-being under Neuroleptic treatment (SWN) ( Naber, 1995 ), which has been used in other studies (de Haan et al, 2000, de Haan et al, 2003, de Haan et al, 2005, and Mizrahi et al, 2007). More data on the longitudinal relationship between D2 occupancy with antipsychotics and various domains of subjective experience are needed to not only replicate our preliminary findings, but also better establish whether there is threshold that delineates increased risk of negative subjective experience (in the same fashion as what we have witnessed with clinical response and extrapyramidal symptoms).

In conclusion, the present findings suggest that dopamine D2 receptor occupancy may have some impact on subjective experience/drug attitude in patients with schizophrenia. Given the body of evidence linking D2 occupancy to adverse effects, we encourage more studies to encompass subjective perspectives particularly given the limited efforts to date. Side effects including negative subjective experience have been clearly implicated in antipsychotic nonadherence, and information that can better guide clinicians in optimizing antipsychotic dosing to treatment response while minimizing adverse events, represents a critical advance in the field.

Role of funding source

None.

Contributors

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

Conflict of interest

Dr. Takeuchi has received fellowship grants from the Japanese Society of Clinical Neuropsychopharmacology and Astellas Foundation for Research on Metabolic Disorders, speaker's honoraria from Dainippon Sumitomo Pharma, Eli Lilly, GlaxoSmithKlein, Janssen Pharmaceutical, Meiji Seika Pharma, and Otsuka Pharmaceutical, and manuscript fees from Dainippon Sumitomo Pharma within the past 5 years.

Dr. Suzuki has received fellowship grants from the Japanese Society of Clinical Neuropsychopharmacology, Government of Canada Post-Doctoral Research Fellowships, Kanae Foundation, and Mochida Memorial Foundation, and speaker's honoraria or manuscript fees from Astellas Pharma, Dainippon Sumitomo Pharma, Eli Lilly, Meiji Seika Pharma, and Novartis.

Dr. Bies has received grants from Eli Lilly through the Indiana CTSI as well as from Merck and Company through Regenstrief Institute within the past 5 years.

Dr. Remington has received research support from Novartis, Medicure, and Neurocrine Bioscience, consultant fees from Roche, and speaker's fees from Novartis. He holds no commercial investments in any pharmaceutical company within the past 5 years.

Dr. Mamo has no competing interests to disclose.

Dr. Pollock receives research support from the National Institute of Health, Canadian Institutes of Health Research, American Psychiatric Association, 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 Forest Laboratories (final meeting was March 2008). Dr. Pollock has served one time as a consultant for Wyeth (October 2008) and Takeda (July 2007). He was also a faculty member of the Lundbeck International Neuroscience Foundation (LINF) (final meeting was April 2010).

Dr. Mimura has received grants or consultant fees from Astellas Pharma, Eisai, GlaxoSmithKline, and Meiji Seika Pharma, and speaker's honoraria from Astellas Pharma, Dainippon Sumitomo Pharma, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji Seika Pharma, Otsuka Pharmaceutical, Pfizer Japan, and Yoshitomiyakuhin within the past 5 years.

Dr. Uchida has received grants from Astellas Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji Seika Pharma, Mochida Pharmaceutical, Otsuka Pharmaceutical, Pfizer Japan, Shionogi, and Yoshitomiyakuhin, and speaker's honoraria from Dainippon Sumitomo Pharma, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Novartis Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomiyakuhin within the past 5 years.

Acknowledgment

Data used in the preparation of this article were obtained from the limited access datasets distributed from the NIH-supported “Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia” (CATIE-Sz). This is a multisite, clinical trial of persons with schizophrenia, comparing the effectiveness of randomly assigned medication treatment. The study was supported by NIMH Contract #N01MH90001 to the University of North Carolina at Chapel Hill. The ClinicalTrials.gov identifier is NCT00014001 . The version of the dataset used was 1.0. This study was also supported by grant R01MH064173 from the National Institute of Mental Health and was ancillary to Clinical Antipsychotic Trials of Intervention Effectiveness, N01MH90001, from the National Institute of Mental Health.

This manuscript reflects the views of the authors and may not reflect the opinions or views of the CATIE-Sz Study Investigators or the NIH. No funding was provided for the present analysis.

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Footnotes

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

b Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, ON, Canada

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

d Department of Psychiatry, Inokashira Hospital, Tokyo, Japan

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

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

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

h Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

lowast Corresponding author at: Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, ON, Canada, 250 College Street, Toronto, Ontario M5T 1R8, Canada. Tel.: + 1 416 535 8501x30547; fax: + 1 416 979 4292.