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

Nordström, Anna-Lena; Farde, Lars; Wiesel, Frits‐Axel; Forslund, Kaj; Pauli, Stefan; Halldin, Christer; Uppfeldt, Gunilla

doi:10.1016/0006-3223(93)90288-o

Cited by 482 publications

(253 citation statements)

References 36 publications

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“…This reflects the asymptotic nonlinear relationship that is known to exist between plasma concentrations and D 2 receptor occupancy with atypical and typical antipsychotic drugs, including olanzapine (Tauscher et al, 2002). These changes were mirrored by seven patients receiving oral supplementation within the first four injection cycles, suggesting central D 2 occupancy generally required for antipsychotic efficacy (Nordström et al, 1993) was not attained in these patients until steadystate plasma concentrations were reached. Overall, the results of this study appear to support 4-week dosing intervals for 300 mg of OP depot, although some oral supplementation or alternative dosing strategy may be necessary to maintain adequate therapeutic response during the first few injections cycles.…”

Section: Discussionmentioning

confidence: 86%

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

Mamo

Kapur

Keshavan

et al. 2007

Neuropsychopharmacol

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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 D 2 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 D 2 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 treatmentemergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D 2 receptor occupancy, as measured by [ 11 C]-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, D 2 receptor occupancy and plasma olanzapine concentrations were significantly correlated (r ¼ 0.76, Pp0.001). OP depot resulted in mean D 2 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.

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Section: Discussionmentioning

confidence: 86%

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

Mamo

Kapur

Keshavan

et al. 2007

Neuropsychopharmacol

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“…Using the analogy of dopamine D 2 receptor occupancy, a threshold of 60%-70% receptor occupancy has been suggested for therapeutic efficacy on the symptoms of psychosis (Nordström et al 1993;Heinz et al 1996). A similar threshold has not been established for anticholinergic properties.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated a dose dependent, moderate to high degree of Dopamine D 2 receptor occupancy in subjects treated with olanzapine (Raedler et al 1999a). For typical antipsychotics, dopamine D 2 receptor occupancy levels of more than 75%-80% have been associated with increased incidence of extrapyramidal side effects (Farde et al 1992;Nordström et al 1993). The lack of obvious extrapyramidal side effects, despite relatively high levels of D 2 receptor occupancy, suggests that other mechanisms may mitigate the development of these side effects in patients treated with olanzapine.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Raedler

Knable

Jones

et al. 2000

Neuropsychopharmacology

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“…A moderate affinity (K I values between 10 and 100 nM) was observed for ␣ 2C (K I 16.2 nM), 5-HT 1A (93.1 nM) and 5-HT 6 (63.1 nM) receptors and bovine 5-HT 1B/1D receptors (89.1 nM). Since antipsychotic compounds are dosed until a significant occupation (50-80%) of D 2 receptors is obtained (Nordström et al 1993;Kapur et al 2000), one can assume that therapeutic doses of iloperidone will result in relevant occupancy of D 3 , 5-HT 2A , 5-HT 2C , ␣ 1 and ␣ 2C receptors. Whether 5-HT 1A , The displacement curves were established with eight concentrations (10-fold dilution steps) of iloperidone.…”

Section: Discussionmentioning

confidence: 99%

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Kalkman

Subramanian

Hoyer

2001

Neuropsychopharmacology

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Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al. 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al. (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al. 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels. It is postulated that dopamine D 2 receptor blockade is the mechanism by which antipsychotic activity is achieved (Creese et al. 1976;Seeman et al. 1976 Conley et al. 1999;Taylor and Duncan-McConnell 2000). The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al. 1996;Hertel et al. 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1). Iloperidone was selected from a large series of piperidinyl-benzisoxazoles because it showed a 300-fold greater potency in a test for limbic activity (inhibition of apomorphine-induced climbing) than in a test for nigrostriatal activity (inhibition of apomorphine-induced stereotypy) . The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al. 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio. The aim of the present study was to determine the receptor affinity profile of iloperidone at a wider range of human neurotransmitter receptors. In resemblance to clozapine, it was noted that iloperidone possesses high affinity for norepinephrine ␣ 1 -and ␣ 2C adrenergic receptors. METHODSThe radioligand receptor binding assays are listed in Table 1. MaterialsRadioligands were purchased from NEN Life Science Products, USA, except for 3 H-RX821002 and 3 H-Mesulergine, which were obtained from Amersham Pharmacia Biotech Ltd, UK, and 125 I-GTI which was obtained from ANAWA, Switzerland. Iloperidone was synthesized by Hoechst Marion Roussel. Unless speci...

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

Cited by 482 publications

References 36 publications

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

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