D2 receptor occupancy of olanzapine pamoate depot using positron emission tomography : an open-label study in patients with schizophrenia

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D2 receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D2 occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D2 receptor occupancy, as measured by [11C]-raclopride PET, was 69% on oral olanzapine (5–20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D2 receptor occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, Pless than or equal to0.001). OP depot resulted in mean D2 receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.peer-reviewe

N-[11C]Methylspiperone PET, in contrast to [11C]raclopride, fails to detect D2 receptor occupancy by an atypical neuroleptic

The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D2 dopamine receptor was investigated using the PET tracers [11C]raclopride and N-[11C]methylspiperone in a group of five schizophrenic patients. A steady-state treatment condition was ensured by dosing the patients with 750 mg quetiapine daily during 3 weeks followed by a period of tapering off the dose. For each patient, PET examinations were performed with both tracers at two of the following doses: 750, 450, 300 and/or 150 mg. As control, a group of six healthy untreated volunteers was investigated. The D2 binding potential in the putamen and the caudate nucleus was determined by using an evaluation method based on the method proposed by Patlak and Blasberg. The receptor occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing quetiapine dose (reaching 51%±10% occupancy at the 750 mg dose) was detected with [11C]raclopride (P0.09, maximal occupancy values were 2% ±3%, measured for the group of three patients on 450 mg). The study suggests that N-[11C]methylspiperone cannot be used for the assessment of D2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET

Background: The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. Methods: PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled l-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate l-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. Results: In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of l-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. Conclusions: The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia

Increased synthesis of dopamine in prefrontal cortex and striatum in drug-naive schizophrenic patients studied by use of 11C-labelled L-dopamine and positron emission tomography

The present study was design to test the hypothesis of a deviant dopaminergic activity in schizophrenia by using the positron emission tomography (PET) technique (GE 2048-15B Plus camera) and 11C-labelled L-DOPA as the tracer, which enables calculation of the rate of synthesis (‘utilization’) of dopamine in different brain regions. Twelve first-admitted and never-treated patients with a DSM-IV diagnosis of schizophrenia (10 men and 2 women) were included. Their mean age was 31.6 years. Controls were 10 healthy volunteers (8 male and 2 female) with a mean age of 33 years. Scanning began immediately after injection of 11C-L-DOPA and continued for 60 min. A patlak plot was calculated for each individual, giving the K3 value, which indirectly reflects the enzymatic utilization of L-DOPA and indirectly the synthesis rate for dopamine. The data showed no lateralization for any brain region tested, either in controls or in schizophrenic patients. However, when compared with healthy controls, a significantly increased synthesis of dopamine was found in the putamen (K3, 1.75 versus 1.59, P = 0.01) and in the caudatus (K3, 1.72 versus 1.50, P=0.002). Further, a significantly increased K3 was also seen in the medial prefrontal cortex in schizophrenic patients (K3, 0.84 versus 0.70, P=0.014). The present results indicate an increased synthesis of dopamine in certain brain areas, most interestingly in the frontal lobe, in schizophrenia