Multimodal Imaging Group

Toronto, Canada

Multimodal Imaging Group

Toronto, Canada

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Uchida H.,Keio University | Uchida H.,Center for Addiction and Mental Health | Takeuchi H.,Keio University | Graff-Guerrero A.,Center for Addiction and Mental Health | And 9 more authors.
Journal of Clinical Psychopharmacology | Year: 2011

Measuring dopamine D2 receptor occupancy levels using positron emission tomography (PET) is still widely unavailable. The objective of this study was to evaluate the accuracy of predicting D2 occupancy from the antipsychotic plasma level in patients with schizophrenia. Positron emission tomographic studies that measured plasma levels of antipsychotics and their corresponding D2 occupancy levels were identified, using MEDLINE and EMBASE (last search: March 2010). Antipsychotics that were investigated in a total of 20 subjects or more were included. All data points for each antipsychotic were fit to a one-site binding model to estimate the total plasma concentration of each antipsychotic associated with a 50% occupancy (ED50) of brain D2 receptors. The mean prediction error and the root mean squared prediction error were used to measure the predictive performance of individual D2 receptor occupancies from plasma drug levels derived from a one-site occupancy model using an ED50 value calculated for each data point. A total of 34 treatment arms from 23 studies involving 281 subjects were included. The mean (95% confidence interval) prediction errors and root squared prediction errors were as low as 0.0 (-1.8 to 1.8) and 8.9 (7.6-10.2) for risperidone (n = 98); 0.0 (-3.5 to 3.5) and 15.1 (12.9-17.3) for clozapine (n = 75); -0.1 (-1.2 to 1.2), 0.0 (-1.9 to 1.9), and 4.6 (3.5-5.8) for olanzapine (n = 42); 0.1 (-3.4 to 3.5) and 9.9 (7.3-12.5) for haloperidol (n = 35); and -0.1 (-3.3 to 3.1) and 12.3 (8.8-15.7) for ziprasidone (n = 31), respectively. These findings suggest that D2 occupancy of antipsychotics could be estimated with a high degree of accuracy using widely available plasma levels. © 2011 Lippincott Williams & Wilkins.

Uchida H.,Keio University | Uchida H.,Center for Addiction and Mental Health | Suzuki T.,Center for Addiction and Mental Health | Suzuki T.,Multimodal Imaging Group | And 6 more authors.
Schizophrenia Bulletin | Year: 2011

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. Data source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). Data extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. Data synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P =. 05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia. © The Author 2011. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

Shinagawa S.,University of California at San Francisco | Shinagawa S.,Jikei University School of Medicine | Nakajima S.,Keio University | Nakajima S.,Center for Addiction and Mental Health | And 10 more authors.
Journal of Alzheimer's Disease | Year: 2014

Frontotemporal dementia (FTD) is a neurodegenerative disorder, associated with a progressive decline in behavior caused by focal degeneration of the frontal lobes. Psychosis was an underestimated symptom of FTD, however, recent genetic research has revealed a high prevalence of psychosis in certain genetic groups. The primary objective of this work is to review the literature on psychosis in FTD and to propose directions for future research, with reference to findings on psychosis in schizophrenia. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", "psychosis", "schizophreni∗", "psychotic symptoms", "hallucinations", and "delusions", and it identified 122 articles. Results revealed: 1) prevalence is approximately 10%, 2) TDP-43 type B and FUS pathologies might have relatively high frequency of psychosis, 3) psychosis in FTD is higher with genetic mutations of C9ORF72 and GRN, 4) imaging researches did not achieve conclusive results, and 5) no treatment for psychosis in FTD is currently available. A limitation of this systematic review is that it includes a small number of studies specifically examining psychosis in FTD. It is suggested that a possible overlap exists between FTD and schizophrenia. This potential overlap indicates a vulnerability to psychosis due to brain systems and pathways shared by these disorders. © 2014 - IOS Press and the authors. All rights reserved.

Gerretsen P.,Center for Addiction and Mental Health | Gerretsen P.,University of Toronto | Gerretsen P.,Multimodal Imaging Group | Pollock B.G.,Center for Addiction and Mental Health | Pollock B.G.,University of Toronto
Expert Opinion on Drug Safety | Year: 2011

Many commonly used drugs have primary or secondary anticholinergic effects contributing to adverse outcomes ranging from mild-to-severe to potentially lethal. Anticholinergic adverse effects frequently occur with medications prescribed with other intended mechanisms of action, including antihistamines, antidepressants, and antipsychotics. Anticholinergic drugs are also the principal treatments of clinical conditions, such as urinary incontinence, that tend to occur in the elderly. Older patients and those with mental illness are particularly vulnerable to the adverse neuropsychiatric effects of anticholinergics as they may already have cognitive impairment. Areas covered: Medline and Pubmed literature searches (1966 - the present) were performed using 'anticholinergic' and 'drug safety'. Abstracts were assessed and references scanned for appropriate articles. Here, the authors i) describe the neural pathways of the cholinergic system; ii) outline the main clinical uses and adverse effects of anticholinergic agents with a focus on cognitive impairment; and iii) discuss anticholinergic safety monitoring. Expert opinion: Prescribers need to be vigilant for adverse anticholinergic effects, particularly in older patients. The symptoms may range from subtle cognitive impairment to delirium and may be due to the cumulative effect of multiple medications of modest antimuscarinic activity. The Anticholinergic Drug Scale and tables listing drugs with known anticholinergic properties may help in guiding clinical decision-making to reduce anticholinergic burden. © 2011 Informa UK, Ltd.

Gerretsen P.,Multimodal Imaging Group | Gerretsen P.,Center for Addiction and Mental Health | Gerretsen P.,University of Toronto | Chakravarty M.M.,Rotman Research Institute | And 15 more authors.
Human Brain Mapping | Year: 2013

Introduction: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. Methods: Both voxel-based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation-based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. Results: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation-based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01). Conclusion: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume-based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations. © 2012 Wiley Periodicals, Inc.

Sakurai H.,Keio University | Bies R.R.,Center for Addiction and Mental Health | Bies R.R.,Indiana University | Bies R.R.,Clinical Translational Science Institute | And 14 more authors.
Schizophrenia Bulletin | Year: 2013

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment. © 2012 The Author.

PubMed | Multimodal Imaging Group, Campbell Family Mental Health Research Institute and Center for Addiction and Mental Health
Type: Journal Article | Journal: Psychopharmacology | Year: 2016

Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial.The objective of this study was to examine the relationship between antipsychotic-related dopamine DForty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [No significant relationship was found between antipsychotic-related dopamine DOur cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

Uchida H.,Keio University | Uchida H.,PET Center | Takeuchi H.,Keio University | Graff-Guerrero A.,PET Center | And 9 more authors.
Journal of Clinical Psychopharmacology | Year: 2011

Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative)/Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window. © 2011 Lippincott Williams & Wilkins.

PubMed | Multimodal Imaging Group, University of Toronto, University of Malta and Keio University
Type: Journal Article | Journal: The Journal of clinical psychiatry | Year: 2017

Although hyperprolactinemia carries a long-term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean SD age = 60.2 6.7 years) taking olanzapine or risperidone. Subjects underwent [C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels.The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests.Prolactin levels decreased following dose reduction (mean SD = 24.1 30.2 ng/mL to 17.2 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender ( = .32, P = .006, vs male), antipsychotics ( = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy ( = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers.Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse identifier: NCT00716755.

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