0000000000148109
AUTHOR
Dean F. Wong
Mechanism of New Antipsychotic Medications
Antagonism of D 2 -like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80%(striatal) D 2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D 2 -like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is ari…
The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.
Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior tem…
Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone).
To elucidate the Batypicality( of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. ( 18 F)fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel ( 11 C)raclopride-PET stu…
The applicability of SRTM in [18F]fallypride PET investigations: Impact of scan durations
The high-affinity radioligand [18F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential ( BPND) of the putamen, thalamus, and temporal cortex w…
Time Course of 5-HT2A Receptor Occupancy in the Human Brain after a Single Oral Dose of the Putative Antipsychotic Drug MDL 100,907 Measured by Positron Emission Tomography
MDL 100,907 is a potent and selective antagonist of 5-HT2A serotonin receptors. Animals studies suggest that MDL 100,907 may behave as an atypical antipsychotic drug. Positron emission tomograph (PET) using [11C]NMSP as the radiotracer was used to define the time course of 5-HT2 receptor occupancy in the human frontal cerebral cortex after a single oral dose of MDL 100,907 (10 or 20 mg) in nine healthy subjects. After the baseline scan each subject was studied three times post dosing at various time points. 5-HT2 occupancies were in the range of 70 and 90% after each dose. While the occupancy remains in this range over 24 hours after 20 mg MDL 100,907, it decreases by about 20% at 24 hours …
Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo
Udgivelsesdato: 2003-Apr The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D(2)-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[(18)F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activi…