Details of a Researcher - Uchida, Hiroyuki

Papers - Uchida, Hiroyuki

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Lack of Early Improvement with Antipsychotics is a Marker for Subsequent Nonresponse in Behavioral and Psychological Symptoms of Dementia

Yoshida Kazunari, Roberts Rachel, Suzuki Takefumi, Lebowitz Barry, Reeves Suzanne, Howard Robert, Abe Takayuki, Mimura Masaru, Uchida Hiroyuki

American Journal of Geriatric Psychiatry 2016.09

ISSN 1064-7481

Objective: Prediction of response or nonresponse to antipsychotics is especially important in patients with behavioral and psychological symptoms of dementia (BPSD) in whom antipsychotic exposure increases risks of death. This study examined whether the presence or absence of early improvement of BPSD with antipsychotics is associated with subsequent response or nonresponse. Methods: In a post-hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) study (2001-2004) (clinicaltrials.gov; NCT00015548) in 45 U.S. sites, 245 subjects (olanzapine, N = 90; quetiapine, N = 81; risperidone, N = 74) with a DSM-IV diagnosis of dementia of the Alzheimer type who presented with a score of 1 or more in the Brief Psychiatric Rating Scale (BPRS) at baseline (phase I of CATIE-AD) were randomly assigned to treatment with olanzapine, quetiapine, risperidone, or placebo in a double-blind manner. Associations were examined between response at week 8 and demographic and clinical characteristics, including BPRS total score reduction at week 2, using logistic regression analyses. Prediction performance of binary classification (presence or absence) of improvement or no improvement at week 2 for response at week 8 was examined. Results: BPRS total score reduction at week 2 (mean percentage score reduction: 12.6%) was significantly associated with response at week 8 (odds ratio: 1.18; 95% CI: 1.11-1.26). The 5% score reduction cut-off at week 2 showed the highest accuracy (0.71), with sensitivity, specificity, and positive and negative predictivevalues of 0.76, 0.65, 0.69, and 0.72, respectively. Conclusion: Lack of even a very small early improvement with antipsychotic treatment may be a marker of subsequent nonresponse in BPSD.

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Plasma levels and estimated dopamine D₂ receptor occupancy of long-acting injectable risperidone during maintenance treatment of schizophrenia

Ikai Saeko, Suzuki Takefumi, Mimura Masaru, Uchida Hiroyuki

Psychopharmacology 1 - 8 2016.09

ISSN 0033-3158

Introduction: Dopamine D₂ receptor occupancy levels needed for the maintenance treatment of schizophrenia remain to be elucidated. We examined 3-year clinical outcomes of patients with schizophrenia who received long-acting injectable risperidone (LAI risperidone) at baseline and investigated their dopamine D₂ receptor occupancy levels, estimated from plasma drug concentrations. Methods: A chart review of 52 outpatients with schizophrenia who participated in the original cross-sectional study was conducted to examine their 3-year clinical outcomes between April and September 2015. Patients who continued outpatient treatment with LAI risperidone without any usage of concomitant chlorpromazine equivalent antipsychotic dosage at >200 mg/day for the 3-year period were asked to participate in the follow-up assessments that included the Brief Psychiatric Rating Scale (BPRS) and estimated dopamine D₂ receptor occupancy levels at trough, using plasma concentrations of risperidone plus 9-hydroxyrisperidone. Data were compared with the same patients collected 3 years earlier. Results: Among the original 52 participants, 14 participants (27 %) continued outpatient treatment with LAI risperidone. Ten participants (19 %) provided plasma samples; mean ± SD measured trough concentration of risperidone plus 9-hydroxyrisperidone significantly increased from 22.9 ± 15.6 to 31.8 ± 17.5 ng/mL (P = 0.02). Estimated dopamine D₂ receptor occupancy numerically increased from 63.0 ± 10.9 to 69.0 ± 11.0 % (P = 0.12). A significant worsening was observed in the BPRS total score among these patients (mean ± SD, 34.3 ± 12.7 to 46.5 ± 16.9, P = 0.003). Conclusion: Paradoxically, the increased plasma concentration was found to be associated with a significant worsening of the clinical outcome. More investigations are indicated to shed further light on optimal levels of D₂ blockade in the maintenance treatment of schizophrenia.

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Prescription patterns for depression among consultation–liaison psychiatrists and non-psychiatrists

Ikai Saeko, Suzuki Takefumi, Uchida Hiroyuki, Saito Hisaaki, Mimura Masaru, Takeuchi Hiroyoshi

International Journal of Geriatric Psychiatry 31 ( 9 ) 1084 - 1085 2016.09

ISSN 0885-6230

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Psychological dependence on antidepressants in patients with panic disorder

Fujii Kazuhito, Suzuki Takefumi, Mimura Masaru, Uchida Hiroyuki

International Clinical Psychopharmacology 2016.08

ISSN 0268-1315

No study has investigated psychological dependence on antidepressants in patients with panic disorder, which was addressed in this study. This study was carried out in four psychiatric clinics in Tokyo, Japan. Individuals were eligible if they were outpatients aged 18 years or older and fulfilled the diagnostic criteria for panic disorder (ICD-10). Assessments included the Japanese Versions of the Severity of Dependence Scale (SDS), the Self-Report Version of Panic Disorder Severity Scale (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report. Eighty-four individuals were included; of these, 30 patients (35.7%) showed psychological dependence on antidepressants (i.e. a total score of ≥5 in the SDS). A multiple regression analysis showed that PDSS scores and illness duration were correlated positively with SDS total scores. A binary regression model showed that absence of remission (i.e. a total score of ≥5 in the PDSS) and longer duration of illness increased the risk of dependence on antidepressants. Approximately one-third of the patients with panic disorder, receiving antidepressants, fulfilled the criteria for psychological dependence on these drugs. The results underscore the need for close monitoring, especially for those who present severe symptomatology or have a chronic course of the illness.

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Clinical and biological correlates of resilience in patients with schizophrenia and bipolar disorder: A cross-sectional study

Mizuno Y., Hofer A., Suzuki T., Frajo-Apor B., Wartelsteiner F., Kemmler G., Saruta J., Tsukinoki K., Mimura M., Fleischhacker W., Uchida H.

Schizophrenia Research (Schizophrenia Research) 175 ( 1-3 ) 148 - 153 2016.08

ISSN 09209964

© 2016 Elsevier B.V. Objective The concept of resilience is relevant in understanding the heterogeneous outcomes noted in schizophrenia and bipolar disorder. However, clinical and biological correlates of resilience in these populations have rarely been investigated. We aimed to identify key correlates of subjective resilience in such patients using comprehensive assessments and to explore associations between resilience levels and peripheral biomarkers. Method 180 subjects with DSM-IV schizophrenia, bipolar disorder, and healthy controls (60 per group) were included. Demographic and clinical variables were assessed by means of interview and various psychometric scales. Furthermore, blood and saliva samples were obtained for the assessment of brain-derived neurotrophic factor, adrenocorticotropic hormone, cortisol, high sensitivity C-reactive protein, and alpha-amylase levels. Cross-sectional associations with resilience, as assessed by the 25-item Resilience Scale were sought. Results Resilience Scale total scores were significantly higher in healthy individuals (130.1, 95% confidence intervals (CI): 124.8–135.4) compared to subjects with schizophrenia (109.9, 95% CI: 104.6–115.2, p < 0.001) and bipolar disorder (119.0, 95% CI: 113.8–124.3, p = 0.012), while the difference between patient groups was non-significant (p = 0.055). Self-esteem, spirituality, quality of life, and hopelessness were correlated with resilience in all three groups. In addition, internalized stigma and depression were relevant factors in the schizophrenia and bipolar disorder group, respectively. Correlations between resilience levels and peripheral biomarkers did not reach significance. Conclusion Although causal relationships must be confirmed in prospective studies, our results have implications in developing psychological interventions to enhance resilience in patients with schizophrenia and bipolar disorder. The biological correlates of resilience in these populations warrant further investigations.

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Incidence of deep vein thrombosis in catatonic patients

Ishida Takuto, Sakurai Hitoshi, Watanabe Koichiro, Iwashita Satoru, Mimura Masaru, Uchida Hiroyuki

Psychiatry Research 241 61 - 65 2016.07

ISSN 0165-1781

Catatonia is a syndrome of motor and psychological disturbances, which is accompanied by blood stasis that increases the risk of deep vein thrombosis (DVT). The aim of this study was to examine the incidence of DVT in catatonic patients in comparison to that in non-catatonic physically restrained patients. We conducted a chart review of involuntarily hospitalized patients from 2010 to 2013 at Sakuragaoka Memorial Hospital in Japan. Routine screening of DVT has been conducted for catatonic patients and restrained patients in this hospital. Catatonic patients were identified based on descriptions of charts and sorted to two subtypes (i.e. retarded and excited forms). A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared among retarded and excited catatonic patients and non-catatonic restrained patients. There were 79 catatonic patients, of whom 42 were retarded. The incidence of DVT was 25.3% (20/79) in the catatonic patients. The retarded catatonic patients demonstrated a significantly higher incidence rate than the restrained non-catatonic patients (35.7% [15/42] vs. 10.6% [31/272], adjusted OR, 4.47). The incidence of DVT in catatonic patients, especially in the retarded form, was considerably high, which suggests the importance of prophylaxis of DVT.

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Incidence of deep vein thrombosis in catatonic patients: A chart review

Ishida T., Sakurai H., Watanabe K., Iwashita S., Mimura M., Uchida H.

Psychiatry Research (Psychiatry Research) 241 61 - 65 2016.07

ISSN 01651781

© 2016 Elsevier Ireland Ltd. Catatonia is a syndrome of motor and psychological disturbances, which is accompanied by blood stasis that increases the risk of deep vein thrombosis (DVT). The aim of this study was to examine the incidence of DVT in catatonic patients in comparison to that in non-catatonic physically restrained patients. We conducted a chart review of involuntarily hospitalized patients from 2010 to 2013 at Sakuragaoka Memorial Hospital in Japan. Routine screening of DVT has been conducted for catatonic patients and restrained patients in this hospital. Catatonic patients were identified based on descriptions of charts and sorted to two subtypes (i.e. retarded and excited forms). A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared among retarded and excited catatonic patients and non-catatonic restrained patients. There were 79 catatonic patients, of whom 42 were retarded. The incidence of DVT was 25.3% (20/79) in the catatonic patients. The retarded catatonic patients demonstrated a significantly higher incidence rate than the restrained non-catatonic patients (35.7% [15/42] vs. 10.6% [31/272], adjusted OR, 4.47). The incidence of DVT in catatonic patients, especially in the retarded form, was considerably high, which suggests the importance of prophylaxis of DVT.

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Analysis of novel Sir3 binding regions in Saccharomyces cerevisiae.

Mitsumori R, Ohashi T, Kugou K, Ichino A, Taniguchi K, Ohta K, Uchida H, Oki M

Journal of biochemistry 160 ( 1 ) 11 - 7 2016.07

ISSN 0021-924X

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Newly developed nomenclature (Neuroscience-based Nomenclature)

Uchida Hiroyuki, Yamawaki Shigeto

Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology (Japanese Journal of Neuropsychopharmacology) 36 ( 3 ) 69 - 71 2016.06

ISSN 1340-2544

The current nomenclature is based on clinical indications; for example, drugs used for mania and psychosis are classified as "mood stabilizers" and "antipsychotic drugs", respectively. This discrepancy between their names and indications often confuses patients and their caregivers and sometimes leads to a misunderstanding of the effects of prescribed medications. In addition, up-to-date scientific knowledge on these drugs has not been reflected in the current nomenclature. To overcome these limitations of the current nomenclature, following an initiative of the European Congress of Neuropsychopharmacology (ECNP), a taskforce for psychotropic nomenclature was established with representatives from 5 international organizations, including the Asian College of Neuropsychopharmacology (AsCNP). The mission of this taskforce is to provide a pharmacologically-driven (rather than indication-based) nomenclature, which is now referred to as Neuroscience-based Nomenclature (NbN). The NbN project has just started. Since it always takes time to change the culture, we understand the transition will likely involve some expected and unexpected responses from the field. However, we believe that such responses and feedback will surely improve the quality of the NbN, which in turn will be beneficial for clinicians, researchers, and patients as well as their caregivers.

[Newly developed nomenclature (Neuroscience-based Nomenclature)].

Uchida H, Yamawaki S

Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 36 ( 3 ) 69 - 71 2016.06

ISSN 1340-2544

Neuroscience-based nomenclature (NbN) for clinical psychopharmacology and neuroscience

Uchida Hiroyuki, Yamawaki Shigeto, Bahk Won Myong, Jon Duk In

Clinical Psychopharmacology and Neuroscience 14 ( 2 ) 115 - 116 2016.05

ISSN 1738-1088

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Resilience, internalized stigma, self-esteem, and hopelessness among people with schizophrenia

Hofer Alex, Mizuno Yuya, Frajo-Apor Beatrice, Kemmler Georg, Suzuki Takefumi, Pardeller Silvia, Welte Anna Sophia, Sondermann Catherine, Mimura Masaru, Wartelsteiner Fabienne, Fleischhacker W. Wolfgang, Uchida Hiroyuki

Schizophrenia Research 171 ( 1-3 ) 86 - 91 2016.03

ISSN 0920-9964

Resilience is becoming an important topic in people with schizophrenia since there is evidence that it increases the probability for long-term recovery. The current study investigated transcultural differences in resilience across schizophrenia patients from two different geographical regions, Austria and Japan. Another objective was to examine transcultural differences in internalized stigma, self-esteem, and hopelessness, which can be expected to be relevant in this context, as well as the interrelations between these subjective elements of recovery and symptom severity. To this end, patients from outpatient mental health services in Innsbruck, Austria (= 52) and Tokyo, Japan (= 60) as well as 137 healthy comparison subjects from both countries were included into this cross-sectional study. Notably, we detected a significant country effect with markedly lower resilience (= 74.4, p <0.001) and self-esteem scores (= 226.0, p <0.001) as well as higher hopelessness scores (= 37.4, p <0.001) among Japanese subjects in general. In addition, both Austrian and Japanese patients indicated significantly lower degrees of resilience (= 57.5, p <0.001), self-esteem (= 51.8, p <0.001), and hope (= 29.5, p <0.001) compared to healthy control subjects. The inter-correlations between subjective elements of recovery were comparable in size in the two patient samples, but the inter-correlations between these issues and residual symptoms of schizophrenia as objective domains of recovery were markedly higher in Austrian subjects. This suggests that schizophrenia patients from Western European and Japanese cultures may have different needs to achieve recovery. In conclusion, it will be critical to develop culture-specific psychosocial programs and to examine their feasibility and effectiveness among these patients.

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Resilience in schizophrenia

Yoshida Kazunari, Suzuki Takefumi, Imasaka Yasushi, Kubo Ken ichiro, Mizuno Yuya, Saruta Juri, Tsukinoki Keiichi, Mimura Masaru, Uchida Hiroyuki

Schizophrenia Research 171 ( 1-3 ) 92 - 96 2016.03

ISSN 0920-9964

The resilience levels between patients with schizophrenia residing in a rural island and a metropolitan area in Tokyo, Japan, was compared and the factors associated with resilience were explored. The Resilience Scale (RS) and EuroQol were assessed, together with biological markers and multiple demographic variables. No significant difference was found in the RS scores between the two groups (40 subjects each). However, longer duration of illness and higher EuroQol score were significantly associated with a greater RS score, which indicates that potentially successful adaptation and subjective perspectives appear more pertinent than the degree of urbanicity in determining resilience levels.

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Resilience in schizophrenia: A comparative study between a remote island and an urban area in Japan

Yoshida K., Suzuki T., Imasaka Y., Kubo K.i., Mizuno Y., Saruta J., Tsukinoki K., Mimura M., Uchida H.

Schizophrenia Research (Schizophrenia Research) 171 ( 1-3 ) 92 - 96 2016.03

ISSN 09209964

© 2016 Elsevier B.V. The resilience levels between patients with schizophrenia residing in a rural island and a metropolitan area in Tokyo, Japan, was compared and the factors associated with resilience were explored. The Resilience Scale (RS) and EuroQol were assessed, together with biological markers and multiple demographic variables. No significant difference was found in the RS scores between the two groups (40 subjects each). However, longer duration of illness and higher EuroQol score were significantly associated with a greater RS score, which indicates that potentially successful adaptation and subjective perspectives appear more pertinent than the degree of urbanicity in determining resilience levels.

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Resilience, internalized stigma, self-esteem, and hopelessness among people with schizophrenia: Cultural comparison in Austria and Japan

Hofer A., Mizuno Y., Frajo-Apor B., Kemmler G., Suzuki T., Pardeller S., Welte A., Sondermann C., Mimura M., Wartelsteiner F., Fleischhacker W., Uchida H.

Schizophrenia Research (Schizophrenia Research) 171 ( 1-3 ) 86 - 91 2016.03

ISSN 09209964

© 2016 Elsevier B.V. Resilience is becoming an important topic in people with schizophrenia since there is evidence that it increases the probability for long-term recovery. The current study investigated transcultural differences in resilience across schizophrenia patients from two different geographical regions, Austria and Japan. Another objective was to examine transcultural differences in internalized stigma, self-esteem, and hopelessness, which can be expected to be relevant in this context, as well as the interrelations between these subjective elements of recovery and symptom severity. To this end, patients from outpatient mental health services in Innsbruck, Austria (= 52) and Tokyo, Japan (= 60) as well as 137 healthy comparison subjects from both countries were included into this cross-sectional study. Notably, we detected a significant country effect with markedly lower resilience (= 74.4, p < 0.001) and self-esteem scores (= 226.0, p < 0.001) as well as higher hopelessness scores (= 37.4, p < 0.001) among Japanese subjects in general. In addition, both Austrian and Japanese patients indicated significantly lower degrees of resilience (= 57.5, p < 0.001), self-esteem (= 51.8, p < 0.001), and hope (= 29.5, p < 0.001) compared to healthy control subjects. The inter-correlations between subjective elements of recovery were comparable in size in the two patient samples, but the inter-correlations between these issues and residual symptoms of schizophrenia as objective domains of recovery were markedly higher in Austrian subjects. This suggests that schizophrenia patients from Western European and Japanese cultures may have different needs to achieve recovery. In conclusion, it will be critical to develop culture-specific psychosocial programs and to examine their feasibility and effectiveness among these patients.

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Postural sway and flexibility in patients with schizophrenia-spectrum disorders

Ikai Saeko, Uchida Hiroyuki, Suzuki Takefumi, Tsunoda Kenichi, Fujii Yasuo, Mimura Masaru

Asian Journal of Psychiatry 19 14 - 18 2016.02

ISSN 1876-2018

Coordinated bodily balance is necessary to prevent falls, where postural sway and/or body inflexibility should be relevant. We aimed to assess postural sway and flexibility in patients with schizophrenia and identify clinical characteristics. Postural sway (length and range of trunk motion, and Romberg ratio) and flexibility (anteflexion in sitting) were measured in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Drug Induced Extrapyramidal Symptoms Scale (DIEPSS) were used for the assessment of psychopathology and extrapyramidal symptoms, respectively. Characteristics associated with postural sway and flexibility were examined with regression analysis. A total of 100 patients (68 men, mean ± S.D. age: 49.3 ± 13.8 years, PANSS score: 83.4 ± 15.1, DIEPSS score: 2.2 ± 2.2) participated in this study. The anteflexion in sitting was not significantly correlated with length of trunk motion, range of trunk motion, or Romberg ratio. Postural instability was associated with higher DIEPSS overall severity score and PANSS positive symptoms. A significant correlation was also found between less flexibility and increased PANSS negative symptoms. In conclusion, flexibility and postural stability might be regarded as separate elements of physical fitness in schizophrenia. Prospective exercise intervention would be worthy of investigation to enhance postural stability and flexibility in an effort to prevent falls.

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Postural sway and flexibility in patients with schizophrenia-spectrum disorders: A cross-sectional study

Ikai S., Uchida H., Suzuki T., Tsunoda K., Fujii Y., Mimura M.

Asian Journal of Psychiatry (Asian Journal of Psychiatry) 19 14 - 18 2016.02

ISSN 18762018

© 2015 Elsevier B.V. Coordinated bodily balance is necessary to prevent falls, where postural sway and/or body inflexibility should be relevant. We aimed to assess postural sway and flexibility in patients with schizophrenia and identify clinical characteristics. Postural sway (length and range of trunk motion, and Romberg ratio) and flexibility (anteflexion in sitting) were measured in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Drug Induced Extrapyramidal Symptoms Scale (DIEPSS) were used for the assessment of psychopathology and extrapyramidal symptoms, respectively. Characteristics associated with postural sway and flexibility were examined with regression analysis. A total of 100 patients (68 men, mean ± S.D. age: 49.3 ± 13.8 years, PANSS score: 83.4 ± 15.1, DIEPSS score: 2.2 ± 2.2) participated in this study. The anteflexion in sitting was not significantly correlated with length of trunk motion, range of trunk motion, or Romberg ratio. Postural instability was associated with higher DIEPSS overall severity score and PANSS positive symptoms. A significant correlation was also found between less flexibility and increased PANSS negative symptoms. In conclusion, flexibility and postural stability might be regarded as separate elements of physical fitness in schizophrenia. Prospective exercise intervention would be worthy of investigation to enhance postural stability and flexibility in an effort to prevent falls.

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Relapse of ileus in patients with psychiatric disorders

Kitahata Ryosuke, Nakajima Shinichiro, Suzuki Takefumi, Plitman Eric, Mimura Masaru, Uchida Hiroyuki

General Hospital Psychiatry 38 31 - 36 2016.01

ISSN 0163-8343

Objective: To explore risk factors for relapse of paralytic ileus in a psychiatric population. Method: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. Results: Sixty-three subjects (38 women; age, 66.0±11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P = .03, odds ratio=4.34, 95% CI=1.15-16.42) and duration of psychiatric disorders (P = .02, odds ratio=1.00, 95% CI=1.00-1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P = .01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P = .02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. Conclusions: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus.

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Dopamine D_2/3 Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations

Nakajima Shinichiro, Uchida Hiroyuki, Bies Robert R., Caravaggio Fernando, Suzuki Takefumi, Plitman Eric, Mar Wanna, Gerretsen Philip, Pollock Bruce G., Mulsant Benoit H., Mamo David C., Graff-Guerrero Ariel

Schizophrenia Bulletin 42 ( 1 ) 212 - 219 2016.01

ISSN 0586-7614

Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D_2/3 receptors (D_2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [¹¹C]-raclopride positron emission tomography scan to measure D_2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D_2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D_2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D_2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D_2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D_2/3R occupancy on an individual basis.

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Dopamine D<inf>2/3</inf> Receptor Occupancy Following Dose Reduction Is Predictable with Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial

Nakajima S., Uchida H., Bies R., Caravaggio F., Suzuki T., Plitman E., Mar W., Gerretsen P., Pollock B., Mulsant B., Mamo D., Graff-Guerrero A.

Schizophrenia Bulletin (Schizophrenia Bulletin) 42 ( 1 ) 212 - 219 2016.01

ISSN 05867614

© 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com. Background. Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested. Methods. Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1±7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [11C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value. Results. The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P =. 001 for olanzapine; r = 0.67, P =. 02 for risperidone). Conclusions. D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.

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