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.
"Although the specific reasons for such gradual evolution in dosage patterns are not clear, clinical trials may include subjects with somewhat less diagnostic heterogeneity, comorbidity and illness severity than patients encountered in clinical practice settings (Seeman, 2001). In addition, since D 2 receptor occupancy rates show a significant degree of inter-individual variability at a given dose (Kapur et al., 2000; Mamo et al., 2004; Catafau et al., 2009), higher daily doses may be required in some patients to ensure that adequate steady-state plasma and CNS concentrations are reached. From a practical standpoint, dose escalation is one of the most frequently used treatment strategies for patients with more severe illness and those who do not respond to initial treatment at lower therapeutic doses (Kinon et al., 2004; Schwartz and Stahl, 2011). "
[Show abstract][Hide abstract] 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. DOI:10.1016/j.schres.2013.01.009 · 3.92 Impact Factor
"Involvement of 5-HT 2A and mGlu 2 in schizophrenia Dopamine, glutamate and serotonin are the three major neurotransmitters playing a role in the pathophysiology/treatment of schizophrenia. Almost all marketed antipsychotic drugs are potent dopamine D 2 receptor antagonists and increased striatal dopamine release is observed in medication-free first-break or relapsing schizophrenic patients (Carlsson and Lindqvist, 1963; Catafau et al., 2009; Creese et al., 1976; Howes et al., 2012; Seeman et al., 1976). "
[Show abstract][Hide abstract] ABSTRACT: Important functional interactions between the metabotropic glutamate 2 (mGlu2) and 5-hydroxytryptamine 2A (5-HT2A) neurotransmitter receptors have been established based on electrophysiological, biochemical and behavioral evidence. Over the last several years, dimerization between 5-HT2A and mGlu2 receptors has been proposed to account for the functional cross-talk between these two receptors in the prefrontal cortex. The pros and cons for the existence of a heteromeric complex between 5-HT2A and mGlu2 receptors will be reviewed here. First, the fundamental criteria needing to establish evidence for heteromeric complexes will be reviewed. Then, the in vitro evidence for and against heteromeric complexes between 5-HT2A and mGlu2 receptors will be discussed in regard to physical and functional interactions. Finally, the data with native in situ mGlu2 and 5-HT2A receptors will be discussed with respect to whether heteromeric complexes or a simple functional interaction between two distinct GPCRs based on brain network activity is the more simple explanation for a range of in vivo data.
"The desired methylation reaction consisted of introducing a methyl unit in the phenol moiety of compound 1; thus, similar reaction conditions to those reported in the literature for the preparation of [ 11 C]Raclopride were used (Catafau et al., 2009). In a first set of experiments, DMSO was used as a solvent and different amounts of 5 M NaOH aqueous solution were added to a solution of precursor (1 mg) in DMSO (100 mL). "
[Show abstract][Hide abstract] ABSTRACT: In the present paper, the synthesis of (11)C-labeled Kendine 91 (a HDAC inhibitor which has shown in vitro and in vivo activity in HCT 116 and MOLT 4 human cancer cell lines) is described for the first time. The radiosynthesis has been approached by reaction of the non-radioactive precursor 6-((3-(4-hydroxyphenyl)-5-phenyl-1H-pyrrole-2-carboxamide))hexanehydroxamic acid with [(11)C]CH(3)I in basic media. Despite the presence of more than one reactive site in the chemical structure of the precursor, acceptable radiochemical yield (8.2±2.1%, decay corrected to the end of bombardment), specific activity (28.2±9.4 GBq/μmol) and radiochemical purity values (>95%) were obtained in reasonably short preparation times (~40 min). Despite the moderate radiochemical yield, final radioactivity and radioactivity concentration values (1.8±0.3 GBq and 180 MBq/ml, respectively) should be sufficient for putative in vivo studies in animals.
Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 06/2012; 70(10):2552-7. DOI:10.1016/j.apradiso.2012.05.016 · 1.23 Impact Factor
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