Within-subject comparison of striatal D2 receptor occupancy measurements using [123I]IBZM SPECT and [11C]Raclopride PET.
ABSTRACT Antipsychotic-induced D2 receptor occupancy values tend to be lower when measured with [(123)I]IBZM SPECT than with [(11)C]Raclopride PET. To clarify this issue, D2 receptor occupancy was measured in the same subjects using both techniques. Twenty patients with schizophrenia on monotherapy with risperidone (n=7; 3-9 mg/d), olanzapine (n=5; 5-20 mg/d) or clozapine (n=8; 150-450 mg/d) at stable doses, and ten healthy volunteers (HV) underwent both a [(123)I]IBZM SPECT and a [(11)C]Raclopride PET examinations in random order on different days within a week. Patients with schizophrenia were scanned at a fixed interval after last dose administration. Quantification of receptor availability was performed using the most conventional methods from the literature: the tissue ratio derived specific uptake ratios (SUR) were used for SPECT, and simplified reference tissue model (SRTM) derived binding potentials (BP(ND)) for PET. Analysis was performed using both occipital cortex and cerebellum as reference regions for both modalities. Striatal D2 receptor occupancy was measured as the percentage reduction of [(123)I]IBZM SUR or [(11)C]Raclopride BP(ND) compared to the population average measured in HV using the same modality. Occupancy values measured by SPECT were lower than those measured with PET, by 12.4% and 13.8% when occipital cortex and cerebellum were used as reference regions. This difference should be taken in consideration when interpreting reported antipsychotic striatal D2 receptor occupancy values from the literature.
Article: Self-organizing analog fields (SOAF)[Show abstract] [Hide abstract]
ABSTRACT: Summary form only given. A neural network paradigm called self-organizing analog fields (SOAF) learns many-to-many, analog (as opposed to winner-take-all, WTA) spatiotemporal mappings. The learning mechanisms employed are unsupervised learning of features and self-organization of connectivity. Homeostasis is defined, providing a necessary extra degree of freedom to solve the credit assignment problem between these two different forms of learning. It is also shown that homeostasis provides a mathematical equivalent to the Lyapunov function for this paradigm. SOAF is hierarchical, allowing unlimited layers for spatiotemporal feature extraction/abstraction. Each SOAF layer is modular and mathematically self-contained, allowing arbitrary connectivity between layers. Empirical results indicate that unsupervised WTA is a degenerate case of SOAF; SOAF's clustering performance is bell-shaped with respect to its primary tuning parameters; and peak clustering performance (top of bell) can be rapidly achieved and the peak broadened and heightened with more layers01/1991;
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ABSTRACT: Dose equivalents based on dopamine D2 receptor occupancy can be used to compare antipsychotics on D2 receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data. To model the relationship between dose and D2 receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data. We conducted a meta-analysis on published D2 receptor occupancy data (positron emission tomography and single-photon emission computed tomography) in patients with schizophrenia treated with antipsychotics. A nonlinear mixed effects model estimated the median D2 receptor occupancy for a given antipsychotic dose. Heterogeneity between studies was investigated by incorporating study as a random effect in the model, in addition to patient- and study-specific explanatory variables. Included were 51 studies, describing 606 patients (mean ± SD age, 32.2 ±10.8 years; 25.7% female). The models described the dose-occupancy relationship with narrow confidence bands around the therapeutic dose range. Maximum occupancy (95% confidence interval [CI]) was estimated for haloperidol (91.9%; 95% CI, 86.1-97.8), risperidone (92.4%; 95% CI, 81.8-100), olanzapine (96.5%; 95% CI, 85.8-100), clozapine (61.7%; 95% CI, 49.2-74.2), quetiapine (49.1%; 95% CI, 18.7-79.6), aripiprazole (86.9%; 95% CI, 78.2-95.7), ziprasidone (82.9%; 95% CI, 44.9-100), and amisulpride (85.0%; 95% CI, 68.5-100). Interindividual differences explained most of the variability in occupancy values, besides significant heterogeneity between studies. Dose-occupancy functions estimated the median level of dopamine D2 receptor occupancy for 8 frequently prescribed antipsychotics in patients with schizophrenia. These dose equivalents can be used to compare antipsychotic effects in epidemiological studies and clinical practice.Journal of clinical psychopharmacology 08/2013; · 5.09 Impact Factor
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ABSTRACT: Objective This study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80 mg/day and 160 mg/day) in the treatment of an acute exacerbation of schizophrenia.Methods Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of fixed-dose, double-blind treatment with lurasidone 80 mg (n = 125), lurasidone 160 mg (n = 121), quetiapine XR 600 mg (QXR-600 mg; n = 119; active control included to test for assay sensitivity), or placebo (n = 121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure).ResultsTreatment with both doses of lurasidone or with QXR-600 mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥ 20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80 mg (65%; p < 0.001), lurasidone 160 mg (79%; p < 0.001), and QXR-600 mg (79%; p < 0.001) compared with placebo (41%). The proportion of patients experiencing ≥ 7% weight gain was 4% for each lurasidone group, 15% for the QXR-600 mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600 mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p < 0.001), LDL cholesterol (p < 0.01), and triglycerides (p < 0.05).Conclusions Lurasidone 80 mg and 160 mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated.Schizophrenia Research 04/2013; 145(s 1–3):101–109. · 4.43 Impact Factor