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,
K
i images, that were matched to a common brain atlas. A significant overall increase of the
K
i values was found in the schizophrenic group as compared with healthy controls.
Results: In particular, significantly higher
K
i 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
K
i 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.
The long-term safety and efficacy of long-acting injectable risperidone, the first long-acting second-generation antipsychotic, were evaluated in stable patients with schizophrenia.
After a 2-week ...run-in period during which patients with DSM-IV schizophrenia received flexible doses of 1 to 6 mg of oral risperidone, patients received injections of 25 mg, 50 mg, or 75 mg of long-acting risperidone every 2 weeks for 12 months. Severity of extrapyramidal symptoms was assessed with the Extrapyramidal Symptom Rating Scale (ESRS), and efficacy was assessed with the Positive and Negative Syndrome Scale (PANSS). This study was conducted from March 29, 1999 to July 19, 2000.
The subjects were 615 patients with schizophrenia who received at least 1 injection of long-acting risperidone. The 12-month trial was completed by 65% of patients. Treatment was discontinued because of adverse events in 5% of patients. Extrapyramidal symptoms as adverse events were reported by 25% of the patients. Severity of extrapyramidal symptoms (according to ESRS scores) was low at baseline and decreased in each of the groups during the 12 months. The other most common adverse events were anxiety in 24%, insomnia in 21%, psychosis in 17%, and depression in 14% of the patients. Little pain was associated with the injections. Severity of symptoms of schizophrenia was improved in each group, with significant reductions in PANSS total scores (p <.01) and positive (p <.01) and negative (p <.001) factor scores.
In terms of both safety and efficacy, symptomatically stable patients with schizophrenia benefit from being switched to long-acting injectable risperidone.
Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 receptor occupancy was assessed with 11Craclopride 2 wk after the last ...(fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone+9-hydroxyrisperidone) after the fourth injection. Steady-state plasma concentrations were maintained for 4–5 wk after the last injection and then declined rapidly. After injections of 25, 50 and 75 mg on day 44 or day 71, D2 receptor occupancy ranged from 25–48%, 59–83% and 62–72% respectively, while plasma active-moiety levels ranged from 4.4–8.8, 15.0–31.1 and 22.5–26.3 ng/ml respectively. The results indicate that brain D2 receptor occupancy at steady state after injections of long-acting risperidone was in the range found in patients effectively treated with 2–6 mg of oral risperidone.
Positron emission tomography (PET) has been shown to be of great importance in elucidating the mechanism of action of antipsychotic drugs. In psychotic patients L‐11CDOPA PET has been used to ...demonstrate some differences in dopaminergic activity compared with that in healthy volunteers. Ten healthy volunteers were investigated with PET and L‐11CDOPA. Ten drug‐free patients with psychosis, nine stable schizophrenics treated with clozapine, and nine stable patients treated with classical antipsychotics were also investigated with L‐11CDOPA. Principal‐component analysis was employed for the analysis of L‐11CDOPA Ki values across a number of corticostriatal brain regions. These data revealed a significant three‐component model with clear‐cut separation between healthy controls and patients with unmedicated schizophrenia. Stable optimal treatment with either classical neuroleptics or clozapine partially, albeit differentially, reversed the aberrant patterns seen in drug‐free schizophrenia. It can thus be concluded that schizophrenia is associated with abnormal patterns of L‐11CDOPA utilization in corticostriatal systems. Treatment with clozapine or classical neuroleptics induces partial, albeit differential, normalization of the abnormal patterns seen in untreated schizophrenia.
The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D
2 dopamine receptor was investigated using the PET tracers
11Craclopride and
N-
11Cmethylspiperone 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 D
2 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
11Craclopride (
P<0.01), no such trend was apparent for
N-
11Cmethylspiperone (
P>0.09, maximal occupancy values were 2% ±3%, measured for the group of three patients on 450 mg). The study suggests that
N-
11Cmethylspiperone cannot be used for the assessment of D
2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants.
Objective: Quetiapine is a novel antipsychotic agent with many atypical features, including low D
2 and higher 5HT
2A affinity in vitro, low propensity to induce extra-pyramidal side effects and ...minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D
2 and 5HT
2A receptors in schizophrenic patients.
Methods: Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D
2 and 5HT
2A occupancies were determined using
11C raclopride and
11C
N-methylspiperone as ligands, respectively, and PET imaging.
Results: Mean D
2 receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT
2A receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study.
Conclusions: In clinically effective doses, quetiapine induced low occupancy at D
2 receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.
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