Dopamine D2 Receptor Occupancy and Clinical Effects (original) (raw)
Related papers
Estimating Dopamine D2 Receptor Occupancy for Doses of 8 Antipsychotics
Journal of Clinical Psychopharmacology, 2013
Rationale: Dose equivalents based on dopamine D 2 receptor occupancy can be used to compare antipsychotics on D 2 receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data. Objectives: To model the relationship between dose and D 2 receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data.
Estimating dopamine D(2) receptor occupancy for doses of 8 antipsychotics: a meta-analysis: a reply
Journal of clinical psychopharmacology, 2014
Rationale: Dose equivalents based on dopamine D 2 receptor occupancy can be used to compare antipsychotics on D 2 receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data. Objectives: To model the relationship between dose and D 2 receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data.
Neuropsychopharmacology, 2007
Blockade of dopamine D 2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D 2 receptors may be more critical to antipsychotic response than the striatal dopamine D 2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D 2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D 2 occupancy levels across subjects. Clinical response, side effects, striatal ([ 11 C]-raclopride-positron emission tomography (PET)), and extrastriatal ([ 11 C]-FLB 457-PET) D 2 receptors were evaluated after treatment. The measured D 2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D 2 occupancy predicted response in positive psychotic symptoms (r ¼ 0.62, p ¼ 0.01), but not for negative symptoms (r ¼ 0.2, p ¼ 0.5). Extrastriatal D 2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D 2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D 2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2012
In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean ± SD age, 48.8 ± 13.8 years; male [N = 14]; Asians [N = 23], Caucasians [N = 12]; risperidone [N = 20] at 3.2 ± 2.3 mg/day, and olanzapine [N = 15] at 9.2 ± 4.9 mg/day) between September and December 2010. 48.6% (N = 17) did not achieve a continuous blockade of ≥ 65%. Moreover, 11.4% (N = 4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥ 65%. The results suggest that sustained D2 receptor occupancy levels of ≥ 65% may not always be necessary for the maintenance treatment of schizophrenia.
Predicting Dopamine D2 Receptor Occupancy From Plasma Levels of Antipsychotic Drugs
Journal of Clinical Psychopharmacology, 2011
Measuring dopamine D 2 receptor occupancy levels using positron emission tomography (PET) is still widely unavailable. The objective of this study was to evaluate the accuracy of predicting D 2 occupancy from the antipsychotic plasma level in patients with schizophrenia. Positron emission tomographic studies that measured plasma levels of antipsychotics and their corresponding D 2 occupancy levels were identified, using MEDLINE and EMBASE (last search: March 2010). Antipsychotics that were investigated in a total of 20 subjects or more were included. All data points for each antipsychotic were fit to a one-site binding model to estimate the total plasma concentration of each antipsychotic associated with a 50% occupancy (ED 50) of brain D 2 receptors. The mean prediction error and the root mean squared prediction error were used to measure the predictive performance of individual D 2 receptor occupancies from plasma drug levels derived from a one-site occupancy model using an ED 50 value calculated for each data point. A total of 34 treatment arms from 23 studies involving 281 subjects were included. The mean (95% confidence interval) prediction errors and root squared prediction errors were as low as 0.0 (j1.8 to 1.8) and 8.9 (7.6Y10.2) for risperidone (n = 98); 0.0 (j3.5 to 3.5) and 15.1 (12.9Y17.3) for clozapine (n = 75); j0.1 (j1.2 to 1.2), 0.0 (j1.9 to 1.9), and 4.6 (3.5Y5.8) for olanzapine (n = 42); 0.1 (j3.4 to 3.5) and 9.9 (7.3Y12.5) for haloperidol (n = 35); and j0.1 (j3.3 to 3.1) and 12.3 (8.8Y15.7) for ziprasidone (n = 31), respectively. These findings suggest that D 2 occupancy of antipsychotics could be estimated with a high degree of accuracy using widely available plasma levels.
Psychiatry Research, 1993
Positron emission tomography (PET) with 'IC-IV-methylspiperone as the radioligand was carried out in 25 chronic schizophrenic patients to determine dopamine D, receptor density estimates in the corpus striatum. The sample included 18 neuroleptic-naive and 7 neuroleptic-free patients. Dopamine D, receptor density estimates (BmaX) were obtained using a two-scan/four-compartment model. The B,,, estimates for the entire group (33.39 + 3.43 pmole/g) were significantly elevated when compared with estimates for the control group (&ax = 15.63 f_ 2.38). The B,,, values for the entire group of schizophrenic patients showed a significant decline as a function of age. The I&,,, values were significantly related to duration of illness (y = 13.2 f 10.3795x -0.7931~2; r = 0.48). Thirteen patients and seven control subjects were added to our original publication sample (Wong et al., 1986~). The patients' Ema, values, when adjusted for age and sex effects, were significantly different compared with those of control subjects. Clinical data from the entire group were compared with published data from other research groups that have estimated dopamine D, receptor density using different radioligands and different methods of data analysis. Comparisons of the clinical characteristics of the published studies show significant differences in patient populations, suggesting that discrepancies among published studies may reflect, in part, heterogeneity among groups of schizophrenic patients. The Dz receptor abnormality described in this study may be a late manifestation of disease, and the implications of this observation are discussed.
The AAPS Journal, 2010
For currently available antipsychotic drugs, blockade of dopamine D2 receptors is a critical component for achieving antipsychotic efficacy, but it is also a driving factor in the development of extrapyramidal symptoms (EPS). To inform the clinical development of asenapine, generic mathematical models have been developed for predicting antipsychotic efficacy and EPS tolerability based on D2 receptor occupancy. Clinical data on pharmacokinetics, D2 receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from in-house trials. D2 receptor occupancy data were restricted to published positron emission tomography studies that included blood sampling for pharmacokinetics. Clinical efficacy data were restricted to group mean endpoint data from short-term placebo-controlled trials, whereas EPS evaluation also included some non-placebo-controlled trials. A generally applicable model connecting antipsychotic dose, pha...
The British Journal of Psychiatry, 2001
Background Both traditional and atypical antipsychotics have been hypothesised to be effective in schizophrenia through limbic and cortical D2 dopamine receptor blockade. Aims To investigate this hypothesis with the D2/D3-selective positron emission tomography (PET) probe [76Br]-FLB457. Method PETscans were performed on 6 controls and 18 patients with schizophreniatreated with haloperidol or with risperidone, clozapine, amisulpride or olanzapine. Results The D2 dopamine receptor blockade was high in the temporal cortex with both haloperidol and atypical antipsychotics. The atypicals, however, induced a significantly lower D2 binding index than haloperidol in the thalamus and in the striatum. Conclusions Results suggest that cortical D2 dopamine receptors are a common target of traditional and atypical antipsychotics for therapeutic action. Higher in vivo binding to the D2 receptors in the cortex than in the basal ganglia is suggested as an indicator of favourable profile for a putat...
Psychopharmacology, 2004
To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according ...