Abstract
Positron emission tomography (PET) and the high affinity D2/3 radiotracer [18F]fallypride allow the assessment of D2/3 receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D2 agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6±5.5% at 2 mg/day to 96.8±5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D2 occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.
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Acknowledgements
We thank Bristol-Myers Squibb for financial support; Erica Scher, Elisa Reich, and Erica Meyers for technical support; and Jonathan Javitch for fruitful scientific discussions.
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DISCLOSURE/CONFLICTS OF INTEREST
Dr Kegeles has received research support from Pfizer. Dr Slifstein has received research support from GSK and is a consultant for GSK and Amgen. Dr Frankle has received research support from GSK and Sepracor, is a consultant or advisory board member for Sepracor, BMS, Transcept, Eli Lilly, and member of the Speaker's Bureau for BMS and Otsuka pharmaceuticals. Dr Abi-Dargham has received research support from Eli Lilly, BMS, and GSK, is a consultant or advisory board member for Sanofi-Aventis, BMS, Wanda, Eli Lilly, Intracellular Therapeutics, and member of the Speaker's Bureau for Sanofi-Aventis, BMS and, Otsuka pharmaceuticals.
Appendix
Appendix
Throughout the Appendix, the nomenclature of Innis et al (2007) is used: CS (specifically bound compartment concentration), CND (nondisplaceable compartment concentration), and fND (tissue free fraction) are as defined in that reference and BPP and BPND are as defined in the reference and in the Methods section above.
A.1: DERIVATION OF DOPAMINE OCCUPANCY RATIOS FROM REGIONAL DIFFERENCES IN ED80
The assumptions in this estimating procedure are that (i) aripiprazole has the same affinity for all D2-like receptors in all regions, (ii) the concentration of dopamine in the proximity of the receptors is not substantially changed following aripiprazole treatment compared to baseline, and (iii) ED80 ratios between regions are equivalent to EC80 ratios between regions.
Let RA,S, RA,E, RDA,S, and RDA,E be the ratio of concentration to inhibition constant for aripiprazole (A) and dopamine (DA) in striatum (S) and extrastriatal regions (E). Then, occupancy in both region types is equal to
Let ED80(ROI) be the estimated ED80 for a given ROI type, striatal (STR) or extrastriatal (EXT). Then, at the ED80 concentrations, RDA,E is given by the affine function (line with non-zero intercept) of RDA,S
Figure 8 is a plot of RDA,E vs RDA,S for a range of RDA,S values using the ED80 ratio value of .693 observed in this data set generated from BPND values from 2TCM (Figure 4).
A.2: DRUG OCCUPANCY MEASURED BY PET WHEN DRUG CONCENTRATION IS CHANGING DURING THE SCAN
Theory
An underlying assumption used to derive aripiprazole occupancy from the fractional change in BP is that the bound drug concentration is constant during the scanning period. If this quantity is changing during the course of the scan, the apparent occupancy will then be a weighted sum of the dynamically changing occupancy over the course of the scan, and the weights will be influenced by time-varying free concentration of the radioligand. Free radioligand concentration will be different across brain regions, due to the ability of the receptor pool to act like a capacitance, removing ligand from the free compartment by specific binding in the early scan phase when free ligand exceeds the equilibrium binding point, and returning ligand to the free compartment in the later phase when specifically bound ligand exceeds the equilibrium point. The phenomenon will be more pronounced in high receptor density regions (striatum) than in low receptor density regions (cortex and limbic regions), leading to different weights in the estimated occupancies. In particular, if receptor-bound drug was in an approximately exponentially decreasing phase during the course of the scan, the following analysis and simulation show that this phenomenon could cause apparent differences in occupancy in the absence of true differences.
In addition to the standard modeling assumptions regarding rapid equilibration of radioligand free fractions and constant VND (nonspecific distribution volume) across regions, we also assume here that arterial plasma clearance of the radioligand is the same across conditions. This is only for computational simplification, and does not materially affect the result.
In this study, occupancy is measured as
where drug and baseline refer to the scan conditions. Based on the assumptions above and the fact that compartmental distribution volumes are equivalent to the ratio of the AUC to infinity of the compartment to the AUC of the arterial plasma, and denoting the specifically bound compartment CS, the right-hand side of this expression simplifies to
This is an identity when the modeling assumptions are met exactly. If receptor availability is changing over the course of the scan during the drug condition, the equation is an approximation in the sense that the fitting procedure will find the closest curve to the data from the set of all curves that fit the model equations by least squares minimization, and AUC(CS) of this curve will be influenced by, although not necessarily identical to, AUC(CS) of the data. The AUCs can be derived from the linearized mass action laws for the conditions. Denoting the nondisplaceable compartment as CND,
The parameter k3 equals the constant fND kon Bmax during the baseline condition. Its explicit time dependence applies during the drug occupancy condition. The effect of the drug is represented as a multiplicative factor (k3(t)) due to tracer conditions for the radioligand, so that the drug concentration is not perturbed by the presence of the tracer, and tracer ‘sees’ a time-varying receptor availability. The solution to this differential equation is
for the baseline condition and
for the drug condition, where ⊗ is the convolution operator and D(t) is 1−the fractional occupancy of receptors by the drug at time t. Using the stated assumptions and the properties of convolutions, the occupancy simplifies to
For the case that the bound drug is decreasing exponentially,
where occ0 is the occupancy at the beginning of the scan and the rate constant is λ=ln(2)/τ where τ is the half-life of the drug washout from the receptors. Substituting for D and simplifying leads to
Finally, noting AUC(CND(baseline)) is equal across regions, it can be seen that it is possible for occ0 to be the same across regions, but still have regional differences in estimated occupancy due to differences in AUC(e−λtCND(drug)). Apparent occupancy will therefore be affected by three factors: occ0 and the regional difference in Bmax, each of which influences the shape of CND during the drug condition, and τ, the half-life of the drug.
Simulations
To test the predictive power of this analysis, simulations were performed. Time activity curves were generated using a plasma input function and kinetic parameters similar to human [18F]fallypride parameters in anterior putamen and hippocampus for baseline conditions and for drug occupancy with exponential washout as above. Initial occupancy was tested at 60, 75, and 90%. Based on Figure 2 in Mallikaarjun et al (2004) (also see discussion section), drug off-rates were tested in the range of 10–20 h. For each initial occupancy and washout rate combination, 1000 pairs of curves were generated in each region with Gaussian noise according to the formula C(t) × (1+0.05z), where z was sampled from a standard normal distribution and C(t) was the noise-free time activity curve. Data were then fitted and occupancy computed according to the methods used in the study. Results (Table A1) show that both for the AUC-based prediction and the simulations, striatum occupancy was slightly but consistently less than hippocampus. The results also show that the AUC analysis is numerically closer to striatum fits than hippocampus; in hippocampus, the estimated occupancies are closer to the initial values than the AUC equation predicts. The differences are greatest at high (90%) initial occupancy, where the simulated regional differences are comparable to those seen in the aripiprazole study.
A.3: EFFECT OF D2/3 RECEPTORS IN THE REFERENCE REGION
This section of the Appendix shows that the presence of D2/3 receptors in the reference region would not differentially affect ROIs of low compared with high D2/3 receptor density. Let us assume the null hypothesis that there are a small amount of D2/3 receptors in the reference region, and that after aripiprizole, all regions have the same fractional occupancy by aripiprizole. Let α=1−occupancy, that is, if the baseline binding potential is BP, then after aripiprizole, it becomes αBP. Then at baseline,
and after drug,
and the apparent occupancy is
so that there is a bias (true occupancy=1−α) but it affects all regions to the same extent.
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Kegeles, L., Slifstein, M., Frankle, W. et al. Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D2 Receptors by Aripiprazole in Schizophrenia with PET and [18F]Fallypride. Neuropsychopharmacol 33, 3111–3125 (2008). https://doi.org/10.1038/npp.2008.33
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DOI: https://doi.org/10.1038/npp.2008.33
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