Dopamine D2 Receptor Occupancy Research Articles

Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients.

By the use of positron emission tomography (PET), high central dopamine D2 receptor occupancy (70 to 90%) has been demonstrated in patients treated with conventional neuroleptics. In patients treated with the atypical antipsychotic clozapine, the D2 occupancy was low (20 to 67%). The effects of clozapine may thus be mediated by a mechanism distinct from D2 occupancy. The observation that low doses of clozapine (125 to 175 mg daily) induced more than 80% (5-hydroxytryptamine) 5-HT2 occupancy supports the view that 5-HT2 antagonism may be related to the atypical effects of clozapine. Risperidone is a new antipsychotic drug with high affinity in vitro for both central 5-HT2 and D2 receptors. In this study, we determined the D2 and 5-HT2 occupancy induced by clinical treatment with risperidone. Four patients with acute exacerbation of schizophrenia were examined by PET after 4 weeks of treatment with risperidone, 6 mg daily. The D2 occupancy in the striatum was 75 to 80%. The 5-HT2 occupancy in the neocortex was 78 to 88%. This study confirms that, in patients with schizophrenia, treatment with risperidone induces a high D2 and 5-HT2 occupancy. Risperidone is, accordingly, a suitable drug for the examination of the clinical benefit of combined serotonin and dopamine antagonism.

Striatal D2-dopamine receptor occupancy during treatment with typical and atypical neuroleptics

Dopamine D2 receptors can be studied in vivo using Posiuon Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) technique applying the tracers CRaclopride and mIodobenz,onide (mI-IBZM). PET studies demonstrated selective effects of different neuroleptics (NLs) on D2 and DI dopamine receptor occupancy (Sedvall 1992). Farde et al (1989, 1992) reported that clozapine, an atypical neuroleptic (AN) shows a decreased D2 and increased D 1 receptor occupancy compared to typical neuroleptics (TN), such as haloperidol. The lower D2 receptor occupancy by clozapine could be replicated by SPECT technique (Briicke et al 1992). Because the amount of D2 receptor blockade is most likely related to the occurrence of extrapyramidal symptoms (EPMS) side effects (Farde et a11989,1992), it is of considerable interest to investigate whether there exists a different dose-response relation between striatal D2 receptor occupancy and total daily dosage of typical NLs compared to atypical NLs. So far, this has been done only once by SPECT technique (Briicke et al 1992), suggesting a curvilinear dose-response relation for'IN with no such relation for AN. These authors apparently investigated different'INs in a small number of patients, however, and evaluated the dose-response relationship of the different NLs on the basis of cMorpromazine equivalents, a procedure that reduces the accuracy of these data.

D2-dopamine receptor occupancy differs between patients with and without extrapyramidal side effects.

To investigate whether the occurrence of extrapyramidal side effects was related to D2 dopamine receptor occupancy, iodobenzamide single positron emission computed tomography was carried out in 27 schizophrenic patients and 10 controls. Eighteen patients were treated with haloperidol; 9 patients were treated with clozapine. Our data suggest a relationship between D2 receptor occupancy and extrapyramidal side effects as well as the existence of a neuroleptic threshold of a striatal:frontal cortex ratio of 1.2, below which drug-induced exptrapyramidal side effects can be expected.

An open clinical and biochemical study of ritanserin in acute patients with schizophrenia

The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine-antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out.

Antipsychotic medication, D2 dopamine receptor blockade and clinical response: a 123I IBZM SPET (single photon emission tomography) study.

The hypothesis that poor response to antipsychotic medication is due to inadequate occupancy of central D2 receptors was tested in vivo. We assessed striatal D2 dopamine receptor availability for binding with the specific ligand 123I IBZM by single photon emission tomography (SPET) in two groups of DSM-III-R diagnosed schizophrenic patients on typical antipsychotic medication, and a group of healthy controls (N = 20). Patients were characterized by clinical ratings as antipsychotic responders (N = 10) or non-responders (N = 8). Dynamic single slice SPET, at a slice chosen to include the basal ganglia, began immediately following intravenous injection of 185 MBq 123I IBZM. Semiquantitative analysis generated indices of D2 receptor availability for binding. There was no difference in striatal D2 receptor availability between the patient groups, both showing a similar degree of occupancy by antipsychotic medication compared to the control group. Thus, poor clinical response does not appear to be accounted for by differential blockade, or inadequate occupancy of striatal dopamine D2 receptors by antipsychotic medication.

D2 dopamine receptor occupancy and response to typical and atypical antipsychotics- A 123I IBZM SPET study

D2 dopamine receptor occupancy and response to typical and atypical antipsychotics- A 123I IBZM SPET study

Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: A double-blind PET study of schizophrenic patients

The relationship between central D2-dopamine receptor occupancy and antipsychotic drug effects was examined in a double-blind study. Raclopride was the compound used to induce a selective occupancy of the D2-dopamine receptors. In addition, 11C-labeled raclopride was the radioligand used to measure occupancy by positron emission tomography (PET). Seventeen schizophrenic patients were randomly assigned to one of three parallel groups treated for 4 weeks with daily doses of 2, 6, or 12 mg of raclopride. D2-receptor occupancy was determined by PET at steady-state conditions in 13 patients who completed the study. A statistically significant relationship was demonstrated between antipsychotic effect and degree of D2-receptor occupancy ( p < 0.05). Patients with extrapyramidal side effects had significantly 3igher D2-receptor occupancy than those without ( p = 0.02). The finding of a relationship between selective occupancy of the D2-dopamine receptors and clinical effects in schizophrenic patients principally provides new support for the dopamine hypothesis of antipsychotic drug action.

PET examination of central D2 dopamine receptor occupancy in relation to extrapyramidal syndromes in patients being treated with neuroleptic drugs.

Positron emission tomography (PET) and suitable radioligands have been used to determine D2 dopamine receptor occupancy in the basal ganglia of patients undergoing neuroleptic drug treatment. The dopamine hypothesis of antipsychotic drug action has been supported by consistent PET findings of a high D2 dopamine receptor occupancy in patients treated with conventional clinical doses of chemically distinct classes of antipsychotic drugs (Farde et al. 1988; Smith et al. 1988; Baron et al. 1989).

Prediction of Therapeutic Doses of Antipsychotic Drugs as Dopamine D2 Receptor Antagonists. Approach Based on Receptor Occupancy Theory.

Antipsychotic drugs have been widely used in humans for the treatment of schizophrenic psychosis. It is widely accepted that the pharmacological activities of antipsychotic drugs are best associated with its dopamine D2 receptor blockade. The usual therapeutic doses vary to a high extent among the antipsychotic drugs with the maximum of about 500-fold difference, despite of the same clinical improvement. In order to clarify the mechanism of this difference, we analyzed retrospectively the pharmacotherapeutic effects of antipsychotic drugs based on the receptor occupancy theory. Since the antipsychotic drugs readily transfer across the brain cell membranes, the dopamine D2 receptor occupancies of various drugs were calculated by using both their unbound concentrations in plasma and dissociation constants(Kd) for dopamine D2 receptor, and then compared with those determined by PET. The calculated dopamine D2 receptor occupancies of antipsychotic drugs which had no active metabolites were almost constant (76.4±15.0%) and corresponded to those determined by PET (80.0±7.6%). On the other hand, the calculated receptor occupancies of antipsychotic drugs which had active metabolites varied between 0.8 to 35% because of no consideration of active metabolites. However, those determined by PET were stable (79.8±4.1%). This finding indicated that the usual doses of antipsychotic drugs allowed to get about 79% as the optimum dopamine D2 receptor occupancy. Furthermore, the simulation of effect-receptor occupancy curves based on the ternary complex model indicated that the large receptor occupancy was necessary for sufficient therapeutic effect of antipsychotic drugs. Based on these findings, we could develop a methodology for estimating the rational usual dose of a newly developed drug by using Kd and data on pharmacokinetics in phase I clinical study.

Savoxepine: striatal dopamine-D2 receptor occupancy in human volunteers measured using positron emission tomography (PET).

The extent and duration of striatal dopamine-D2 receptor occupancy by savoxepine in humans has been studied using positron emission tomography with [11C]-raclopride, in order to investigate why the anticipated favourable ratio between its extrapyramidal and antipsychotic effects was not achieved in practice. After 0.25 mg savoxepine, striatal D2 receptor occupancy peaked at 50-60% after 24-36 h and disappeared within 6 days. After doses of 0.1 mg to 0.5 mg, D2 receptor occupancy in the putamen and caudate nucleus increased from 20 to 70% 3-7 h after administration and amounted to 40 to 75% at the peak time (20-29 h). This suggests that cumulative D2 receptor blockade would occur if equal or increasing doses of savoxepine were given repeatedly. Extrapyramidal adverse-effects would be likely to occur under such circumstances. An adequate test of the theory that preference for hippocampal dopamine D2 receptors with afford a good therapeutic ratio requires an alternative dosing regimen.

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.

Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

PET Analysis Indicates Atypical Central Dopamine Receptor Occupancy in Clozapine-Treated Patients

D1 and D2 dopamine (DA) receptor occupancy was determined by PET in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with classical neuroleptics at conventional doses, the average D2 occupancy was 78% (s.d. 6%). In five patients treated with the prototype atypical antipsychotic drug clozapine, a lower D2 occupancy of 48% (s.d. 11%, P less than 0.01) was found. Accordingly, clozapine is 'atypical' with respect to the striatal D2 DA receptor occupancy induced in patients. No obvious D1 DA receptor occupancy was induced by the classical neuroleptics haloperidol or sulpiride. The thioxanthene flupenthixol induced a 36-44% D1 occupancy in individual patients. In four patients treated with clozapine the D1 occupancy was 38-52%.

Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol.

Central D2-dopamine receptor occupancy was followed by repeated PET experiments after administration of single oral doses of haloperidol to four healthy men. D2-dopamine receptor occupancy was high already 3 h after administration of 4 and 7.5 mg haloperidol and remained high for at least 27 h. Akathisia appeared when D2-dopamine receptor occupancy was maximal. After initiation of neuroleptic drug treatment several days or weeks may elapse before antipsychotic effect is evident. The results of this study do not indicate that any late onset of the antipsychotic effect is related to an insufficient D2-dopamine receptor occupancy during the first days of treatment.

PET Examination of Central D2 dopamine and 5-HT2 Receptor Occupancy by Risperidone

PET Examination of Central D2 dopamine and 5-HT2 Receptor Occupancy by Risperidone

Positron emission tomography with (18F)methylspiperone demonstrates D2 dopamine receptor binding differences of clozapine and haloperidol

Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.

Distribution of remoxipride to the human brain and central D2‐ dopamine receptor binding examined in vivo by PET

Remoxipride is a new antipsychotic drug that binds selectively to the D2-dopamine receptor subtype as demonstrated in animal studies in vitro and in vivo. It is generally assumed that the antipsychotic effect of neuroleptic drugs is mediated by blockade of dopamine receptors. The aim of the present study was to use positron emission tomography (PET) and the ligand [11C] raclopride to examine the central D2-dopamine receptor occupancy in man during oral administration of remoxipride. After oral administration of remoxipride 100 mg three times daily to a healthy male subject there was a 73% central D2-dopamine receptor occupancy. In a schizophrenic patient treated with remoxipride 200 mg twice daily there was a 71% occupancy. These occupancy values are similar to the values of 65-85% previously found in a series of patients treated with neuroleptics representative of all currently used chemical classes. In a separate experiment, remoxipride was labelled with 11C and injected intravenously and the distribution of radioactivity to the brain examined. Radioactivity appeared in the brain during the first minutes after injection and 4.5 min after injection it accounted for 0.8% of the total radioactivity injected, thus indicating that [11C]remoxipride had rapidly passed through the blood-brain barrier.

D1- and D2-dopamine receptor occupancy during treatment with classical and atypical neurpleptics

D1- and D2-dopamine receptor occupancy during treatment with classical and atypical neurpleptics

Central D2receptor blockade and antipsychotic effects of neuroleptics. Preliminary study with positron emission tomography

SummaryThe striatal D2receptor density/affinity index was assessed using positron emission tomography and76Br-Bromolisuride in 15 schizophrenics, first untreated, and afterwards receiving neuroleptics, and in 14 control subjects. The patients received low or conventional doses of neuroleptics. The schizophrenics receiving low doses (n= 6) had preponderant negative symptoms. Mean D2receptor occupancy was 24 ± 20%. Despite this weak central D2receptor blockade, a significant decrease in negative symptoms was observed, a result consistent with the hypothesis of a disinhibitory action of some neuroleptics administered in low doses. The patients treated with conventional doses (n= 9) had mixed positive and negative symptoms, and the mean D2receptor occupancy was 54 ± 13%. Significant decreases in positive symptoms, but also in negative symptoms, were obtained with this treatment. Before treatment, there was no significant difference in the striatal D2receptor density/affinity index between: 1) patients and controls, 2) negative and mixed schizophrenics, and 3) the subsequent responder and non-responder patients. In addition, the D2dopamine receptor occupancy by neuroleptics did not significantly differ in responder or nonresponder patients, suggesting that the central D2dopamine receptor blockade is a necessary, but insufficient condition to account for the antipsychotic effect of neuroleptics.

Clinical melperone treatment blocks D2‐dopamine receptors in the human brain as determined by PET

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.

Dopamine Receptor Occupancy and Plasma Haloperidol Levels-Reply

<h3>In Reply.—</h3> Our finding of a 65% to 85% D2-dopamine receptor occupancy in schizophrenic patients treated with chemically distinct antipsychotic drugs represents strong support for the hypothesis that the antipsychotic effect is mediated by blockade of D2-dopamine receptors.¹The theoretically expected curvilinear relationship between neuroleptic drug concentration in plasma and D2-dopamine receptor occupancy has now been confirmed in several PET studies of patients receiving neuroleptic therapy.^1,2However, caution must be exercised before accepting the conclusions reached by Wolkin et al regarding the clinical utility of plasma levels. In their letter, Wolkin et al comment on their curve between plasma haloperidol levels and receptor occupancy: "The lack of scatter about the curve implies a close relationship between plasma level and receptor blockade. This is a strong argument for the clinical utility of plasma neuroleptic drug levels." Despite a large number of studies, a generally confirmed relationship between plasma drug concentrations