0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Article   |    
Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [18F]Fallypride PET Study
Gerhard Gründer, M.D.; Christine Fellows, M.D.; Hildegard Janouschek, M.D.; Tanja Veselinovic, M.D.; Christian Boy, M.D.; Anno Bröcheler, M.D.; Katrin M. Kirschbaum, Ph.D.; Sandra Hellmann; Katja M. Spreckelmeyer, Ph.D.; Christoph Hiemke, Ph.D.; Frank Rösch, Ph.D.; Wolfgang M. Schaefer, M.D., Ph.D.; Ingo Vernaleken, M.D.
Am J Psychiatry 2008;165:988-995. doi:10.1176/appi.ajp.2008.07101574

Abstract

Objective: Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D2/D3) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D2/D3 antagonist [ 18F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia. Method: Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [ 18F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole. Results: Mean dopamine D2/D3 receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (Emax) values close to saturation. The values for serum concentration predicted to provide 50% of Emax (EC50) were in the range of 5–10 ng/ml in all brain regions. The D2/D3 receptors were completely saturated when serum aripiprazole concentration exceeded 100–150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142). Conclusions: Because of its high affinity for D2/D3 receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D2/D3 receptors must remain nearly saturated for as long as 1 week after the last dose.

Abstract Teaser
Figures in this Article

It is now widely accepted that the antipsychotic effects of dopamine receptor antagonists occur within a “therapeutic window” between 60% and 80% of striatal dopamine 2 and 3 (D2/D3) receptor occupancy. The incidence of extrapyramidal side effects increases when occupancy exceeds the 80% threshold (1). This rule seems to apply also for most of the second-generation antipsychotics (2). However, in a [ 11C]raclopride positron emission tomography (PET) study in normal volunteers to determine the optimal dose of aripiprazole for clinical trials in schizophrenia, it was shown that aripiprazole occupies more than 90% of striatal D2/D3 receptors at clinically effective doses (3). This finding was recently confirmed in patients with schizophrenia (4). On the basis of these findings, we concluded that the original conception of a “therapeutic window” of antipsychotic drug action applies to antagonists only (5).

However, all the above-mentioned observations were made with reference to receptor occupancy in striatal structures only. With the advent of high-affinity radiotracers belonging to the class of substituted benzamides, it became possible to quantify extrastriatal dopamine receptors. While earlier PET studies with the moderate-affinity D2/D3 antagonist [11C]raclopride demonstrated that the second-generation antipsychotics clozapine and quetiapine occupy striatal D2/D3 receptors to a significantly lesser extent than do other antipsychotics (2, 6, 7), it was later consistently shown in studies with high-affinity ligands that these two compounds nonetheless occupy a significantly higher proportion of temporolimbic than striatal D2/D3 receptors (8, 9). We demonstrated that the clinical antipsychotic efficacy of clozapine is likely more related to its binding in the temporal cortex than to its striatal binding (8). This “preferential” extrastriatal binding of second-generation antipsychotics, which was initially observed by Pilowsky et al. (10), has since been shown for several other second-generation antipsychotics, at least to a modest extent (11, 12). On the other hand, a recent PET study by Agid et al. found that striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic receptor occupancy (13). The potential reasons for some controversial aspects of this phenomenon (14) have been discussed previously (8, 15).

One of the most widely used radiotracers for the quantification of extrastriatal D2/D3 receptors is [18F]fallypride (16, 17). This ligand displays similarly high affinities for D2 and D3 receptors and negligible affinity for any other common neuroreceptor (18). Its fluorine-18 label offers the advantage of a longer physical half-life compared with, for example, the carbon-11 label of [11C]raclopride. [18F]Fallypride is an ideal tracer for the study of both striatal and extrastriatal receptors in a single PET scan. Human studies have consistently demonstrated that a 180-minute dynamic scan allows for establishment of a transient equilibrium both in extrastriatal regions of low receptor abundance and in the striatum (16, 17).

To further characterize aripiprazole’s extrastriatal binding and temporal changes in its binding in relation to its serum concentration, we conducted PET studies with [18F]fallypride in patients with schizophrenia at varying time points after the last drug administration. Furthermore, to determine the clinical relevance of the serum concentration/occupancy relationship, we measured the serum concentration of aripiprazole in a large sample of patients with schizophrenia who were treated with this drug under clinical conditions.

The study was approved by the ethics committee of the Medical Faculty of the RWTH Aachen University, Aachen, Germany, and the German radiation safety authorities. Twenty-four patients with schizophrenia were enrolled in the study after giving written informed consent. Sixteen patients underwent scanning while being treated with aripiprazole, and eight patients who were drug-free on admission to the hospital served as a comparison group. All PET investigations were performed in the Department of Nuclear Medicine of the RWTH Aachen University. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) who were treated with aripiprazole. These patients were treated in the Department of Psychiatry of the University of Mainz, Mainz, Germany.

+

Participants

The comparison group consisted of eight patients 18 to 58 years of age (mean=31 years, SD=14) suffering from schizophrenia as defined by DSM-IV criteria. They had been free of any psychotropic medication for at least 6 months, with the exception of small doses of lorazepam in some instances. All comparison subjects received a physical examination, a mental state examination, blood and urine analysis, electroencephalography, electrocardiography, and cerebral MRI.

The patient group consisted of 16 medicated patients (15 of them male; mean age=30 years, SD=10, range=19–50) who were diagnosed with either schizophrenia or schizoaffective disorder according to DSM-IV criteria. The mean age of the medicated patients did not significantly differ from that of the unmedicated participants. All patients had received an ongoing stable daily dose of aripiprazole (5–30 mg/day) according to clinical needs for at least 4 weeks prior to scanning. Seven patients received concomitant antidepressant medication, three patients were treated with zopiclone for insomnia, and five patients received lorazepam.

+

Clinical Sample

The large clinical patient sample consisted of 128 patients (34% women; mean age=33.8 years, SD=10.7), from whom a total of 203 serum samples were collected. The mean dose of aripiprazole was 20 mg/day (SD=9, median=15, range=10–60). Blood samples were taken at trough levels at 8 a.m. before administration of aripiprazole.

+

Radiochemistry

The [18F]fallypride was synthesized at the Institute for Nuclear Chemistry of the University of Mainz as described in detail elsewhere for its congener [18F]desmethoxyfallypride (19). The tosylated precursor, ((S)-N-[(1-allyl)-2-pyrrolidinyl)-methyl]-5-(3-toluenesulfonyloxypropyl)-2,3-dimethoxybenzamide (5 mg, 10 mmol), was dissolved in 1 ml acetonitrile, treated for 5 minutes at 85°C with potassium carbonate (5 mg, 36 mmol), and subsequently reacted with [18F]fluoride for 20 minutes at 85°C. [18F]Fallypride was isolated using high-performance liquid chromatography and adsorbed on a C18 cartridge, and the product was eluted with 1 ml ethanol. The final fraction was diluted with 9 ml of an isotonic sodium chloride solution and sterilized by ultrafiltration.

+

Data Acquisition and Analysis

Images were acquired on a Siemens ECAT EXACT whole-body PET scanner. Data acquisition comprised a series of 39 time frames (3×20 seconds, 3×1 minute, 3×2 minutes, 3×3 minutes, 21×5 minutes, 2×8 minutes, and 4×10 minutes) for a total scan duration of 180 minutes. After a 15-minute transmission scan, a mean of 207 MBq (SD=48) of [18F]fallypride was injected as a bolus intravenously. The specific activity at the time of injection was 194 GBq/μmol (SD=484), corresponding to an injected mass of 2.3 μg (SD=2.6). Neither specific activities (unmedicated patients: 101 GBq/μmole [SD=103]; medicated patients: 235 GBq/μmole [SD=577]) nor injected mass (unmedicated patients: 2.1 μg [SD=1.7]; medicated patients: 2.7 μg [SD=3.0]) differed significantly between unmedicated patients and patients treated with aripiprazole. The injected mass did not correlate with the measured binding potentials (BP) in any region in the unmedicated subjects. Thus, it is unlikely that the radiotracer occupied a significant proportion (>5%) of receptors even in brain regions with low receptor density.

The magnitude of BP was calculated on a voxelwise basis using the Lammertsma simplified reference tissue model, which is based on a two-tissue compartment model (19, 20). The cerebellum was chosen as a reference region because it is generally considered to be nearly devoid of dopamine receptors. We cannot exclude the possibility that the occupancy values in our study were slightly underestimated because of a small degree of specific binding in the cerebellum (21). However, Kessler et al. (22) compared regional binding potentials obtained with Logan plots with metabolite-corrected plasma input function with those obtained with the reference region method and found a correlation coefficient greater than 0.99 with a slope of 1.0 (22). Furthermore, these authors did not detect any differences between cerebellar and white matter binding in the ratio of unblocked versus blocked states. Thus, underestimation should be less than 5 percent at the occupancies obtained in our study (23). For determination of D2/D3 receptor occupancy, the averaged BPs of eight unmedicated patients were used as the common baseline value. Images were reconstructed with filtered backprojection using a Ramp filter and a Hamming filter (filter width=4 mm). After attenuation and motion corrections, the whole dynamic emission recording was stereotactically normalized into Montreal Neurological Institute coordinates using a predefined ligand-specific D2/D3 template. To this end, a polynomial warping algorithm implemented in the MEDx software, version 3.43 (Medical Numerics, Germantown, Md.), was used.

+

Calculation of D2/D3 Receptor Occupancy

The individual participant’s receptor occupancy was defined as percentage reduction of BP relative to the baseline BP according to the following equation:

Predefined templates of polygonal volumes of interest were used to calculate time activity curves for the cerebellum (2.38 cm3), the caudate nucleus (0.52 cm3), the putamen (1.14 cm3), the thalamus (2.50 cm3), the amygdala (0.31 cm3), and the inferior temporal cortex (3.61 cm3). The inferior temporal cortex (anterior and medial parts) was used as representative of cortical binding because the D2/D3 receptor density in this region is highest compared with all other cortical regions. A mean BPUnmedicated value for each volume of interest was then calculated by averaging BP values from eight unmedicated patients. BPMedicated was calculated in an identical manner for the 16 patient studies.

+

Aripiprazole Pharmacokinetic Data

Aripiprazole was administered in single doses in the morning in all cases. Dosing details for individual patients in relation to tracer injection are provided in Table 1. Blood samples were collected at 8 a.m. (immediately before ingestion of aripiprazole) and again immediately before [18F]fallypride bolus injection. The PET scans were started between 1 p.m. and 6 p.m. Aripiprazole serum concentrations were determined according to a previously published method (24) with high-performance liquid chromatography including column switching with online sample cleanup and online ultraviolet detection of aripiprazole and its main metabolite, dehydroaripiprazole (24). The within-run and between-run imprecision of the assay was below 15%, and the limits of quantification were below 50 ng/ml for both analytes.

+

Statistical Analyses

Statistical analyses were carried out with SPSS, version 14.0 (SPSS, Inc., Chicago). Means and standard deviations were calculated for serum concentrations and occupancy values. Unpaired t tests were used to compare D2/D3 BP values for the groups of unmedicated and aripiprazole-treated patients. A general linear model for repeated measures with within-subjects factor at five levels was applied to compare D2/D3 receptor occupancy in the five regions evaluated: putamen, caudate nucleus, thalamus, amygdala, and inferior temporal cortex. Spearman rank correlations were calculated for relationships between aripiprazole doses and serum concentrations and brain D2/D3 receptor occupancy values. Serum concentrations (trough serum levels in the morning and levels at the time of injection) and D2/D3 receptor occupancy values were fitted to a one-site ligand binding model by nonlinear regression analysis using Sigma Plot, version 9.0 (Systat, San Jose, Calif.), using the following equation:

where Emax is the maximum attainable receptor occupancy, EC50 is the serum concentration predicted to provide 50% of the maximum attainable receptor occupancy, and CAri is the serum concentration of aripiprazole. In all analyses, the two-tailed level of statistical significance was set at α=0.05.

The entire group of aripiprazole-treated patients had statistically significantly lower mean D2/D3 receptor BP values than did the unmedicated patients in the putamen (mean=4.1 [SD=2.7] compared with mean=24.1 [SD=3.6], respectively; t=15.2, df=22, p<0.001), the caudate nucleus (mean=3.4 [SD=2.3] compared with mean=21.8 [SD=3.2]; t=16.3, df=22, p<0.001), the thalamus (mean=0.36 [SD=0.17] compared with mean=2.36 [SD=0.43]; t=16.4, df=22, p<0.001), the amygdala (mean=0.51 [SD=0.21] compared with mean=3.39 [SD=1.47]; t=7.8, df=22, p<0.001), and the inferior temporal cortex (mean=0.15 [SD=0.08] compared with mean=0.87 [SD=0.12]; t=17.7, df=22, p<0.001).

Aripiprazole occupied high proportions of D2/D3 receptors to a similar extent throughout the brain, with mean occupancy values close to complete saturation (see Tables 1 and 2 and Figure 1). A repeated-measures analysis of variance with within-subjects factor at five levels revealed no significant difference in D2/D3 receptor occupancy across the five regions examined (Table 2, Figure 1).

The mean aripiprazole serum concentration at the time of radiotracer injection was 245 ng/ml (SD=307, range=27–1144). The mean dehydroaripiprazole serum level at the time of injection was 58 ng/ml (SD=60, range=0–210). Trough serum concentrations determined in the morning before aripiprazole administration were similar to those obtained at the time of the PET scan (aripiprazole: 282 ng/ml [SD=267, range=50–862]; dehydroaripiprazole: 76 ng/ml [SD=84, range=0–261; data missing for five subjects]). The mean administered aripiprazole dose was 18.8 mg/day (SD=7.2, range=5–30). The daily aripiprazole dose did not correlate significantly with either the trough aripiprazole serum concentration or the serum concentration at the time of tracer injection. There was also no correlation between daily dose of aripiprazole and D2/D3 receptor occupancy in any brain region investigated.

In the large clinical sample, in which aripiprazole serum concentrations were collected independently from the PET study, the mean level was 228 ng/ml (SD=142, median=196, 25th to 75th percentile range=134–294). Here, blood levels correlated significantly with doses (r=0.510, p<0.01; Figure 2).

When aripiprazole serum concentrations and occupancy values were related to each other according to the law of mass action (see Statistical Analyses in the Method section), serum concentrations were significantly positively correlated with D2/D3 receptor occupancy values for all regions evaluated. Positive correlations were found between aripiprazole serum concentrations and occupancy values in the putamen (r=0.62, df=14, p<0.0001; Figure 1), the caudate nucleus (r=0.61, df=14, p<0.0001), the thalamus (r=0.62, df=14, p<0.0001), the amygdala (r=0.51, df=14, p<0.0001), and the inferior temporal cortex (r=0.57, df=14, p<0.0001; Figure 1). Figure 1 shows the relationship between aripiprazole serum concentration and receptor occupancy in the putamen and the inferior temporal cortex. D2/D3 dopamine receptors were almost completely occupied homogeneously throughout the brain at aripiprazole serum concentrations above approximately 100–150 ng/ml. There were only marginal differences in EC50 values between the analyzed brain regions (range=4–10 ng/ml; Table 2).

Correlations between receptor occupancies and serum concentrations were slightly better in four of the five brain regions when values for aripiprazole and the active main metabolite dehydroaripiprazole were added (putamen: r=0.67, df=14, Emax=95%, EC50=20 ng/ml, p<0.0001; caudate nucleus: r=0.67, df=14, Emax=95%, EC50=18 ng/ml, p<0.0001; thalamus: r=0.70, df=14, Emax=92%, EC50=12 ng/ml, p<0.0001; amygdala: r=0.50, df=14, Emax=89%, EC50=7 ng/ml, p<0.0001; inferior temporal cortex: r=0.60, df=14, Emax=92%, EC50=15 ng/ml, p<0.0001).

The PET scans were performed at a range of time points after the last drug administration (range=4–78 hours; Table 1). Aripiprazole occupancy of D2/D3 dopamine receptors persisted for several days after the last dosing (Table 1). Figure 3 shows parametric BP images of a patient who was treated with a daily aripiprazole dose of 30 mg. He was withdrawn from medication and underwent scanning approximately 78 hours after the last dose. Even after 3 days off medication, the D2/D3 dopamine receptor occupancy in this patient’s brain was close to 80% (putamen, 81%; caudate nucleus, 83%; thalamus, 75%; amygdala, 75%; inferior temporal cortex, 64%). Regardless of the time of the PET scan relative to the last drug administration, serum concentrations and occupancy values could be described by one single concentration/occupancy curve (Figure 1).

In this study, we demonstrated that aripiprazole almost completely saturates both striatal and extrastriatal D2/D3 receptors over a wide range of serum levels typical of those obtained in clinical practice. With regard to aripiprazole’s striatal binding, our results are entirely concordant with our earlier observations in a PET study with [11C]raclopride in normal volunteers (3, 5), a finding that was recently confirmed in patients with schizophrenia (4). In addition, we could not detect any preferential extrastriatal binding of aripiprazole. This feature of aripiprazole stands in contrast to the preferential extrastriatal binding of other second-generation antipsychotics. Furthermore, this study showed that the rate of aripiprazole’s dissociation from D2/D3 receptors is very low. Taking into account aripiprazole’s long serum elimination half-life of about 72 hours, our observation of almost complete D2/D3 receptor occupancy above a serum concentration of approximately 100–150 ng/ml suggests that in patients treated with aripiprazole under clinical conditions, D2/D3 receptors remain almost saturated for as long as 1 week after the last drug administration. Our findings have important theoretical and clinical implications, as discussed below.

Although this is the third study demonstrating striatal D2/D3 receptor occupancies above 80% under clinically used dosages of aripiprazole (3, 5), it is the first to clearly show a relationship between aripiprazole serum concentrations under clinical conditions and D2/D3 receptor occupancy in striatum and extrastriatal regions. While D2/D3 receptor occupancy by aripiprazole reaches a plateau of almost complete D2/D3 receptor saturation at serum concentrations of approximately 100–150 ng/ml, the mean aripiprazole serum concentration in the larger clinical sample of 128 patients was above 200 ng/ml. Considerably higher serum concentrations, in some cases even above 1000 ng/ml, were not rare in the clinically established dosage range (Table 1, Figure 2). In a recent study with 164 patients treated with aripiprazole, the mean serum aripiprazole concentration was 214 ng/ml (25). In a subsample of 75 patients receiving aripiprazole monotherapy, it was demonstrated that clinical improvement was optimal at serum concentrations between 150 and 300 ng/ml and that side effects were rare below 250 ng/ml (25). This clearly confirms the view that the very high D2/D3 receptor occupancy associated with aripiprazole not only is innoxious but also represents a requirement for effective treatment (5). This unique characteristic of aripiprazole is most likely due to its particular pharmacological profile, namely, partial agonism or “functional selectivity” at D2-like dopamine receptors (26). Extrapyramidal side effects are rare even under very high aripiprazole serum concentrations (25), and even the highest serum concentrations in our patient sample were not associated with significant extrapyramidal side effects. Taken together, these observations suggest that there is a serum concentration threshold of 100–150 ng/ml for antipsychotic efficacy. Furthermore, the therapeutic index of aripiprazole is evidently very broad and not usually limited by the occurrence of extrapyramidal side effects. Individual differences in the sensitivity for prodopaminergic effects of aripiprazole might explain the occasional presentation of the main side effects, which are agitation and sleeplessness.

Aripiprazole is metabolized via the hepatic cytochrome P450 enzyme system, specifically the isoenzymes CYP2D6 and CYP3A4. Inhibition or induction of these enzymes—for example, through comedication—leads to predictable changes in aripiprazole serum concentrations (25). Mutation in the gene encoding for the CYP2D6 isoenzyme can lead to markedly increased aripiprazole serum concentrations (27, 28). Conversely, CYP2D6 ultrarapid metabolizers would be expected to present with unusually low serum concentrations of aripiprazole. Thus, in many clinical situations, individual assessment of the aripiprazole serum concentration may guide further treatment decisions.

Another finding of this study is that aripiprazole produces prolonged occupancy of cerebral D2/D3 dopamine receptors (Table 1, Figure 3). This observation was expected, given aripiprazole’s high affinity for dopamine receptors and its long plasma elimination half-life (approximately 60–70 hours) (29). We calculate that if aripiprazole were withdrawn in patients with serum levels above 600 ng/ml, the drug would still almost completely occupy D2/D3 receptors for almost 1 week after the last dose. Regardless of the time of the PET scan relative to the last drug administration, the estimated data could be almost perfectly described by a single nonlinear fit according to the law of mass action (Figure 1). These findings seem to contrast somewhat with a recent report that aripiprazole dissociates very rapidly from the D2 receptor (30). However, PET cannot provide information about the temporal dynamics of a pharmaceutical on a microenvironmental synaptic level. Therefore, it is theoretically possible that aripiprazole is slowly released from the D2/D3 receptor from a macroscopic view but still dissociates rapidly if the association rate is comparably high. Nevertheless, our PET studies indicate that “atypicality” in its original sense (absence of extrapyramidal side effects) can be achieved by several mechanisms, such as D2 partial agonism or low D2 affinity (8). We show that transient occupancy of D2/D3 receptors, as seen with some low-affinity second-generation antipsychotics, is not a prerequisite for low liability to extrapyramidal side effects (31). Aripiprazole’s properties as a 5-HT1A agonist and a 5-HT2 antagonist might also contribute to its “atypical” clinical characteristics, although these receptors are occupied to a relatively small extent at clinically used dosages (4).

It has been demonstrated, by us and others (8, 9), that especially low-affinity antipsychotics, such as clozapine and quetiapine, occupy brain D2/D3 receptors to a lesser extent in striatal than in extrastriatal, especially cortical, brain regions. In the present case of aripiprazole, we could not detect regional differences in occupancy. Striatal and cortical binding could be described by virtually identical serum concentration/occupancy curves (Figure 1). A lack of regionally heterogeneous binding and a slow dissociation from D2 receptors have also been described for haloperidol (32, 33). Aripiprazole and haloperidol have in common their high affinity for D2-like dopamine receptors and their long plasma elimination half-life. Therefore, we suggest that the lack of differential regional binding at D2 receptors is not a characteristic that separates first-generation from second-generation antipsychotics. Rather, regional differences in occupancy may occur as a function of affinity of the specific antipsychotic. Compounds with a short half-life and/or a low affinity, such as clozapine, typically present a flat plasma concentration/occupancy curve (8), whereas compounds with a long plasma half-life and/or a high affinity, such as haloperidol, are described by a steep curve. The most likely explanation for differential regional binding of low-affinity compounds is the regionally different competition of these compounds from endogenous dopamine (34). Interstitial dopamine concentrations in animal striatum are significantly higher compared with cortical concentrations when measured with microdialysis (35, 36). Furthermore, there are markedly different kinetics of dopamine release and reuptake across brain regions (37). For compounds that are characterized by a much higher affinity for D2 receptors than dopamine itself, this competition might be irrelevant.

+Presented at the 45th annual meeting of the American College of Neuropsychopharmacology, Dec. 3–7, 2006, Hollywood, Fla. Parts of this work are included in Sandra Hellmann’s doctoral thesis at the Medical Faculty of RWTH Aachen University, Aachen, Germany. Received Oct. 7, 2007; revisions received Nov. 30 and Dec. 21, 2007; accepted Jan. 2, 2008 (doi: 10.1176/appi.ajp.2008.07101574). From the Departments of Psychiatry and Psychotherapy and Nuclear Medicine, RWTH Aachen University; and the Department of Psychiatry and Institute for Nuclear Chemistry, University of Mainz, Mainz, Germany. Address correspondence and reprint requests to Dr. Gründer, Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; ggruender@ukaachen.de (e-mail).

+Dr. Gründer has received grant support from, served as a consultant for, or served on the speakers bureau of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Cilag, Johnson & Johnson, Otsuka, and Pfizer. Dr. Hiemke has served as a consultant for Eli Lilly and Servier and has received grant support from Pfizer, Sanofi-Aventis, Roche, and Bio-Rad Laboratories. All other authors report no competing interests.

+Supported in part by Bristol-Myers Squibb KGaA, Munich, Germany.

+The authors thank Sabine Höhnemann and Markus Piel for assistance with synthesis and Dr. Paul Cumming for critical discussion of the manuscript.

1.Farde L, Nordström AL, Wiesel FA, Pauli S, Halldin C, Sedvall G: 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. Arch Gen Psychiatry 1992; 49:538–544
 
2.Kapur S, Zipursky RB, Remington G: Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999; 156:286–293
 
3.Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF: Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 2002; 27248–27259
 
4.Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S: Differential effects of aripiprazole on D2, 5-HT2, and 5-HT1A receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 2007; 164:1411–1417
 
5.Gründer G, Carlsson A, Wong DF: Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry 2003; 60:974–977
 
6.Nordström A-L, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G: D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995; 152:1444–1449
 
7.Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P: A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 2000; 57:553–559
 
8.Gründer G, Landvogt C, Vernaleken I, Buchholz HG, Ondracek J, Siessmeier T, Härtter S, Schreckenberger M, Stoeter P, Hiemke C, Rösch F, Wong DF, Bartenstein P: The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology 2006; 31:1027–1035
 
9.Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY: Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 2006; 31:1991–2001
 
10.Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa DC, Kerwin RW: Limbic selectivity of clozapine. Lancet 1997; 350:490–491
 
11.Bigliani V, Mulligan RS, Acton PD, Ohlsen RI, Pike VW, Ell PJ, Gacinovic S, Kerwin RW, Pilowsky LS: Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study. Psychopharmacology 2000; 150:132–140
 
12.Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS: Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 2003; 23:5–14
 
13.Agid O, Mamo D, Ginovart N, Vitcu I, Wilson AA, Zipursky RB, Kapur S: Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response: a double-blind PET study in schizophrenia. Neuropsychopharmacology 2007; 32:1209–1215
 
14.Talvik M, Nordström A-L, Nyberg S, Olsson H, Halldin C, Farde L: No support for regional selectivity in clozapine-treated patients: a PET study with [11C]raclopride and [11C]FLB 457. Am J Psychiatry 2001; 158:926–930
 
15.Vernaleken I, Siessmeier T, Buchholz H-G, Härtter S, Hiemke C, Stoeter P, Rösch F, Bartenstein P, Gründer G: High striatal occupancy of D2-like dopamine receptors by amisulpride in brain of patients with schizophrenia. Int J Neuropsychopharmacol 2004; 7:421–430
 
16.Siessmeier T, Zhou Y, Buchholz HG, Landvogt C, Vernaleken I, Piel M, Schirrmacher R, Rösch F, Schreckenberger M, Wong DF, Cumming P, Gründer G, Bartenstein P: Parametric mapping of binding in human brain of D2 receptor ligands of different affinities. J Nucl Med 2005; 46:964–972
 
17.Mukherjee J, Christian BT, Dunigan KA, Shi B, Narayanan TK, Satter M, Mantil J: Brain imaging of 18F-fallypride in normal volunteers: blood analysis, distribution, test-retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D2/D3 receptors. Synapse 2002; 46:170–188
 
18.Stark D, Piel M, Hübner H, Gmeiner P, Gründer G, Rösch F: In vitro affinities of various halogenated benzamide derivatives as potential radioligands for non-invasive quantification of D2-like dopamine receptors. Bioorg Med Chem 2007; 15:6819–6829
 
19.Gründer G, Siessmeier T, Piel M, Vernaleken I, Buchholz H-G, Zhou Y, Hiemke C, Wong DF, Rösch F, Bartenstein P: Quantification of D2-like dopamine receptors in the human brain with [18F]desmethoxyfallypride. J Nucl Med 2003; 44109–44116
 
20.Lammertsma AA, Hume SP: Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4(3 Pt 1):153–158
 
21.Mukherjee J, Christian BT, Narayanan TK, Shi B, Mantil J: Evaluation of dopamine D2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride. Neuropsychopharmacology 2001; 25:476–488
 
22.Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY: Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 2005; 30:2283–2289
 
23.Olsson H, Halldin C, Farde L: Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 2004; 22:794–803
 
24.Kirschbaum KM, Muller MJ, Zernig G, Saria A, Mobascher A, Malevani J, Hiemke C: Therapeutic monitoring of aripiprazole by HPLC with column-switching and spectrophotometric detection. Clin Chem 2005; 51:1718–1721
 
25.Kirschbaum KM, Muller MJ, Malevani J, Mobascher A, Burchardt C, Piel M, Hiemke C: Serum levels of aripiprazole and dehydroaripiprazole, clinical response, and side effects. World J Biol Psychiatry (E-pub ahead of print, May 11, 2007)
 
26.Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB: Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20:612–627
 
27.Oosterhuis M, Van De Kraats G, Tenback D: Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient (letter). Am J Psychiatry 2007; 164:175
 
28.Hendset M, Hermann M, Lunde H, Refsum H, Molden E: Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol 2007; 63:1147–1151
 
29.Mallikaarjun S, Salazar DE, Bramer SL: Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 2004; 44:179–187
 
30.Seeman P: An update of fast-off dopamine D2 atypical antipsychotics (letter). Am J Psychiatry 2005; 162:1984–1985
 
31.Kapur S, Seeman P: Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? a new hypothesis. Am J Psychiatry 2001; 158:360–369
 
32.Xiberas X, Martinot JL, Mallet L, Artiges E, Loc’h C, Maziere B, Paillere-Martinot ML: Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 2001; 179:503–508
 
33.Nordström AL, Farde L, Halldin C: Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology (Berl) 1992; 106:433–438
 
34.Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; 47:27–38
 
35.Brown RM, Crane AM, Goldman PS: Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: concentrations and in vivo synthesis rates. Brain Res 1979; 168:133–150
 
36.Pehek EA: Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum. J Pharmacol Exp Ther 1999; 289:14–23
 
37.Garris PA, Wightman RM: Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J Neurosci 1994; 14:442–450
 
 
Figure 1. Relationship Between Aripiprazole Serum Levels and Dopamine D2/D3 Receptor Occupancy in the Putamen and the Inferior Temporal Cortex in 16 Patients With Schizophrenia and Schizoaffective Disorder Receiving Therapeutic Doses of Aripiprazolea

aNote that the relationships for these two brain regions are described by exactly the same regression line.

 
Figure 2. Dose-Related Serum Aripiprazole Concentrations in a Large Sample of Patients With Schizophrenia (N=128) Treated With Aripiprazolea

aThe regression line shows the significant association between aripiprazole dose and serum concentration (r=0.510, p<0.01).

 
Figure 3. Sagittal, Transverse, and Coronal Slices From a PET Study in a Patient With Schizophrenia Treated With Aripiprazole Who Received His Last Dose 78 Hours Prior to the PET Scana

aThe mean striatal D2/D 3 receptor occupancy was 82%, and the aripiprazole serum concentration at the time of the PET scan was 106 ng/ml.

Figure 1. Relationship Between Aripiprazole Serum Levels and Dopamine D2/D3 Receptor Occupancy in the Putamen and the Inferior Temporal Cortex in 16 Patients With Schizophrenia and Schizoaffective Disorder Receiving Therapeutic Doses of Aripiprazolea

aNote that the relationships for these two brain regions are described by exactly the same regression line.

Figure 2. Dose-Related Serum Aripiprazole Concentrations in a Large Sample of Patients With Schizophrenia (N=128) Treated With Aripiprazolea

aThe regression line shows the significant association between aripiprazole dose and serum concentration (r=0.510, p<0.01).

Figure 3. Sagittal, Transverse, and Coronal Slices From a PET Study in a Patient With Schizophrenia Treated With Aripiprazole Who Received His Last Dose 78 Hours Prior to the PET Scana

aThe mean striatal D2/D 3 receptor occupancy was 82%, and the aripiprazole serum concentration at the time of the PET scan was 106 ng/ml.

+

References

1.Farde L, Nordström AL, Wiesel FA, Pauli S, Halldin C, Sedvall G: 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. Arch Gen Psychiatry 1992; 49:538–544
 
2.Kapur S, Zipursky RB, Remington G: Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999; 156:286–293
 
3.Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF: Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 2002; 27248–27259
 
4.Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S: Differential effects of aripiprazole on D2, 5-HT2, and 5-HT1A receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 2007; 164:1411–1417
 
5.Gründer G, Carlsson A, Wong DF: Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry 2003; 60:974–977
 
6.Nordström A-L, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G: D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995; 152:1444–1449
 
7.Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P: A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 2000; 57:553–559
 
8.Gründer G, Landvogt C, Vernaleken I, Buchholz HG, Ondracek J, Siessmeier T, Härtter S, Schreckenberger M, Stoeter P, Hiemke C, Rösch F, Wong DF, Bartenstein P: The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology 2006; 31:1027–1035
 
9.Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY: Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 2006; 31:1991–2001
 
10.Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa DC, Kerwin RW: Limbic selectivity of clozapine. Lancet 1997; 350:490–491
 
11.Bigliani V, Mulligan RS, Acton PD, Ohlsen RI, Pike VW, Ell PJ, Gacinovic S, Kerwin RW, Pilowsky LS: Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study. Psychopharmacology 2000; 150:132–140
 
12.Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS: Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 2003; 23:5–14
 
13.Agid O, Mamo D, Ginovart N, Vitcu I, Wilson AA, Zipursky RB, Kapur S: Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response: a double-blind PET study in schizophrenia. Neuropsychopharmacology 2007; 32:1209–1215
 
14.Talvik M, Nordström A-L, Nyberg S, Olsson H, Halldin C, Farde L: No support for regional selectivity in clozapine-treated patients: a PET study with [11C]raclopride and [11C]FLB 457. Am J Psychiatry 2001; 158:926–930
 
15.Vernaleken I, Siessmeier T, Buchholz H-G, Härtter S, Hiemke C, Stoeter P, Rösch F, Bartenstein P, Gründer G: High striatal occupancy of D2-like dopamine receptors by amisulpride in brain of patients with schizophrenia. Int J Neuropsychopharmacol 2004; 7:421–430
 
16.Siessmeier T, Zhou Y, Buchholz HG, Landvogt C, Vernaleken I, Piel M, Schirrmacher R, Rösch F, Schreckenberger M, Wong DF, Cumming P, Gründer G, Bartenstein P: Parametric mapping of binding in human brain of D2 receptor ligands of different affinities. J Nucl Med 2005; 46:964–972
 
17.Mukherjee J, Christian BT, Dunigan KA, Shi B, Narayanan TK, Satter M, Mantil J: Brain imaging of 18F-fallypride in normal volunteers: blood analysis, distribution, test-retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D2/D3 receptors. Synapse 2002; 46:170–188
 
18.Stark D, Piel M, Hübner H, Gmeiner P, Gründer G, Rösch F: In vitro affinities of various halogenated benzamide derivatives as potential radioligands for non-invasive quantification of D2-like dopamine receptors. Bioorg Med Chem 2007; 15:6819–6829
 
19.Gründer G, Siessmeier T, Piel M, Vernaleken I, Buchholz H-G, Zhou Y, Hiemke C, Wong DF, Rösch F, Bartenstein P: Quantification of D2-like dopamine receptors in the human brain with [18F]desmethoxyfallypride. J Nucl Med 2003; 44109–44116
 
20.Lammertsma AA, Hume SP: Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4(3 Pt 1):153–158
 
21.Mukherjee J, Christian BT, Narayanan TK, Shi B, Mantil J: Evaluation of dopamine D2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride. Neuropsychopharmacology 2001; 25:476–488
 
22.Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY: Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 2005; 30:2283–2289
 
23.Olsson H, Halldin C, Farde L: Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 2004; 22:794–803
 
24.Kirschbaum KM, Muller MJ, Zernig G, Saria A, Mobascher A, Malevani J, Hiemke C: Therapeutic monitoring of aripiprazole by HPLC with column-switching and spectrophotometric detection. Clin Chem 2005; 51:1718–1721
 
25.Kirschbaum KM, Muller MJ, Malevani J, Mobascher A, Burchardt C, Piel M, Hiemke C: Serum levels of aripiprazole and dehydroaripiprazole, clinical response, and side effects. World J Biol Psychiatry (E-pub ahead of print, May 11, 2007)
 
26.Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB: Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20:612–627
 
27.Oosterhuis M, Van De Kraats G, Tenback D: Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient (letter). Am J Psychiatry 2007; 164:175
 
28.Hendset M, Hermann M, Lunde H, Refsum H, Molden E: Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol 2007; 63:1147–1151
 
29.Mallikaarjun S, Salazar DE, Bramer SL: Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 2004; 44:179–187
 
30.Seeman P: An update of fast-off dopamine D2 atypical antipsychotics (letter). Am J Psychiatry 2005; 162:1984–1985
 
31.Kapur S, Seeman P: Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? a new hypothesis. Am J Psychiatry 2001; 158:360–369
 
32.Xiberas X, Martinot JL, Mallet L, Artiges E, Loc’h C, Maziere B, Paillere-Martinot ML: Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 2001; 179:503–508
 
33.Nordström AL, Farde L, Halldin C: Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology (Berl) 1992; 106:433–438
 
34.Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; 47:27–38
 
35.Brown RM, Crane AM, Goldman PS: Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: concentrations and in vivo synthesis rates. Brain Res 1979; 168:133–150
 
36.Pehek EA: Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum. J Pharmacol Exp Ther 1999; 289:14–23
 
37.Garris PA, Wightman RM: Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J Neurosci 1994; 14:442–450
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 68

Related Content
Articles
Books
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 1.  >
Gabbard's Treatments of Psychiatric Disorders, 4th Edition > Chapter 20.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 26.  >
Dulcan's Textbook of Child and Adolescent Psychiatry > Chapter 52.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 31.  >
Topic Collections
Psychiatric News
Read more at Psychiatric News >>
APA Guidelines
PubMed Articles