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Transmission Disequilibrium Test (TDT)-based methods have been advocated by several authors
for testing that a marker-phenotype association is actually due to linkage and not to uncontrolled
stratification. As a pre-requisite of TDT-type methods is the presence of an association between
marker and phenotype, one may wish to first investigate the association using a classical association
study, and then to check by a TDT approach whether this association is actually due to linkage. We
propose an estimating equation (EE) procedure, to compute analytically the minimum sample size
of sibship data required to detect the association between a marker and a quantitative phenotype,
and that required to confirm it by two TDT methods. We show that, when the marker allele
frequency is low or high, the number of informative sibs needed in TDT-type methods can be lower
than the number required in an association analysis, and even more so when the familial clustering
is strong. However, in all cases, the number of sibs that need to be sampled to get the appropriate
number of informative sibs for analysis is always larger for TDT methods than for an association
study. In a phenotype-first strategy, this number may be critical when investigating costly
Selective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects.
To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo.
The high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients (n=6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared.
Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300–700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics.
Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.
The dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.
To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.
[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.
Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.
Typical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
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