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Significant Dissociation of Brain and Plasma Kinetics with Antipsychotics Molecular Psychiatry (2002) 7, 317–321 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Significant dissociation of brain and plasma kinetics with antipsychotics J Tauscher1,2,4, C Jones1, G Remington2,3, RB Zipursky2,3 and S Kapur1,2,3 1Schizophrenia-PET Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada; 2Schizophrenia and Continuing Care Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada; 3Department of Psychiatry, University of Toronto, Toronto, Canada; 4Department of General Psychiatry, University of Vienna, Vienna, Austria Keywords: antipsychotics; pharmacokinetics; positron withdrawal from oral doses of conventional neurolep- emission tomography; receptor occupancy; dopamine tics,8 and up to 6 months after depot injection of halo- receptors; serotonin receptors; schizophrenia peridol decanoate.9 Current dosing regimens of psychotropic drugs are We measured the time course of drug plasma levels based on plasma kinetic considerations, although it is and brain D2 receptor occupancy in healthy volunteers unclear whether plasma levels faithfully reflect brain after a single dose of 3–4 mg risperidone (n = 4) or kinetics of drugs.1,2 To examine this, we compared the 15 mg olanzapine (n = 4). We used [11C]raclopride as a kinetics of plasma levels of two widely used antipsy- PET-ligand to estimate central D2 receptor occupancy chotics, olanzapine and risperidone, vs the time course in the striatum,1 and [11C]FLB457 for quantification of of their effects in the brain. We used positron emission extra-striatal D blockade in the thalamus.10 Addition- tomography (PET) and [11C]-labeled ligands to quantify 2 ally, we investigated the time course of plasma levels striatal and extra-striatal dopamine-2 (D2), and cortical and striatal D2 occupancy in five stable patients suffer- serotonin-2A (5-HT2A) receptor occupancy in healthy subjects after a single dose, and in patients chronically ing from schizophrenia. These patients had received a − treated for psychosis. We found a significant dis- monotherapy with olanzapine 15–20 mg day 1 (n = 3) sociation of brain and plasma kinetics. Mean plasma or risperidone 3 mg day−1 (n = 2) for at least one month. elimination half-lives of single doses of olanzapine and We scanned them immediately after withdrawal from risperidone were 24.2 and 10.3 h, respectively, whereas their antipsychotic medication, and again after 24 it took on average 75.2 h with olanzapine, and 66.6 h and 48 h. with risperidone to decline to 50% of their peak striatal In the single-dose experiments in healthy volunteers, D receptor occupancy. We found similar discrepancies 2 mean peak olanzapine plasma levels occurred 6 h after between the time course of plasma levels and extra-stri- intake (23 ng ml−1 ± 4 SD). The plasma elimination atal D2 as well as 5-HT2A receptor occupancy. Our results question the current reliance on plasma kinetics half-life time (t1/2) was 24.2 h (95% confidence interval as the main basis for dosing regimens of antipsy- (CI): 21.2–28.1). After 72 h, plasma levels declined on chotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psycho- tropic medications. Molecular Psychiatry (2002) 7, 317–321. DOI: 10.1038/ sj/mp/4001009 Novel antipsychotics are currently used to treat diverse medical conditions such as schizophrenia, mania, depression, and dementia. It is well established that antagonism of D2 receptors is critical for antipsychotic efficacy,3,4 and that at clinical doses antipsychotics 5 block a substantial proportion of D2 receptors in vivo. Positron emission tomography and selective ligands such as [11C]raclopride have provided valuable insights regarding receptor occupancy during treatment with olanzapine and risperidone.6,7 However, in most stud- ies PET scans were obtained only at a single time point Figure 1 Single dose experiments in controls. Time course after medication intake, typically 12 h post-dose. of plasma levels (olanzapine: , grey dashed line; risperidone Hence, little is known about the time course of brain plus 9-OH-risperidone: , grey solid line), and striatal D2 receptor blockade with these atypical antipsychotics. receptor occupancy (olanzapine: , black dashed line; risperi- This is of particular interest as it has been shown that done: , black solid line). All results are normalized to 100% D2 receptor occupancy can persist up to 15 days after of their peak value. Error bars denote one standard deviation. Significant dissociation of brain and plasma kinetics J Tauscher et al 318 average to 4 ng ml−1, corresponding to 19% of the peak with risperidone. In patients under steady state con- plasma level (Figure 1). The active moiety of risperi- ditions, the brain t1/2 at striatal D2 receptors was 88.4 h done, risperidone plus 9-hydroxyrisperidone, peaked (95% CI: 61.1–159.3) for olanzapine and 45.5 h (95% −1 ± on average after 2 h (37 ng ml 14 SD), reached t1/2 CI: 44.8–46.2) for risperidone. after 10.3 h (95% CI: 8.1–14.3) and declined to 5% of The extra-striatal D2 receptor occupancy, as mea- peak levels within 72 h (Figure 1). The observed sured with [11C]FLB457 and PET in the thalamus, plasma kinetics were in close correspondence to pre- closely resembled the time course seen in the striatum. viously reported results obtained in healthy volun- Single doses of olanzapine or risperidone led to com- 11–13 14 teers and patients with schizophrenia. parably high peak D2 occupancy of extra-striatal D2 Both single doses of risperidone and olanzapine led receptors in the thalamus ranging from 72% to 82% to high striatal D2 receptor blockade, with peak occu- and declining to 51–69% after 24 h, and 27–37% after pancy rates at the time of their respective peak plasma 72 h. Table 1 shows a synopsis of plasma levels and D2 levels ranging from 80–88%. Subsequent serial PET receptor occupancy in healthy volunteers and patients. scans revealed sustained D2 receptor occupancy with Each of the healthy volunteers experienced sedation, both drugs in the range of 71–77% after 24 h, 56–60% which was reversible within hours. Additionally, three after 48 h, and 36–42% after 72 h. Brain t1/2 at the stria- of the four subjects receiving risperidone showed mild tal D2 receptor was 75.2 h (95% CI: 67.9–84.4) for a sin- to moderate akathisia, which spontaneously resolved gle dose of olanzapine and 66.6 h (95% CI: 54.0–86.8) in two cases, and had to be treated with 1 mg of lora- for risperidone. These brain receptor t1/2 values of both zepam in one case. None of the patients reported any drugs, observed after only one single dose, are substan- clinically relevant side effects at the time of the PET tially longer than the currently recommended dosing scans. interval of 24 h with both drugs. To examine whether the brain effects of antipsy- In olanzapine-treated patients, plasma-levels peaked chotics follow a similar time course on other neuro- −1 ± at 66 ng ml ( 4 SD), showed a t1/2 of 19.5 h (95% CI: transmitter receptors, and since 5-HT2A receptors have 12.4–45.9), and declined to 16 ng ml−1 (±3 SD) after been implicated in the genesis and treatment of psy- 48 h, corresponding to 25% of the peak plasma level. chosis,15 we additionally examined the time course of After discontinuation of risperidone in patients, 5-HT2A receptor occupancy in two healthy volunteers plasma levels declined with a t1/2 of 13.4 h (95% CI: receiving a single dose of 4 mg risperidone or 15 mg 9.8–20.8) to 16% of their peak values within 48 h olanzapine. Both drugs led to a complete saturation of (Figure 2). 5-HT2A receptors within 6 h. After 48 h risperidone −1 Continuous treatment with 15–20 mg day olanza- still led to a complete blockade of 5-HT2A receptors and pine or 3 mg day−1 risperidone resulted in high striatal olanzapine to 92% occupancy, indicating a persisting D2 receptor blockade ranging from 81% to 88% at the cortical 5-HT2A receptor blockade, despite the fact that time of peak plasma levels. Subsequent serial PET drug plasma levels had declined to less than 10% of scans after discontinuation of the antipsychotic medi- their peak plasma level with both drugs. cation revealed mean striatal D2 occupancy values of In summary, both single doses of olanzapine and ris- 78% with olanzapine and 66% with risperidone after peridone in healthy volunteers and continuous treat- 24 h, and after 48 h 61% with olanzapine and 42% ment in patients led to substantial and prolonged D2 and 5-HT2A receptor occupancy. Plasma drug levels declined significantly faster than brain receptor occu- pancy. The 95% CI of brain and plasma t1/2 were dis- tinctly different and non-overlapping for both atypical antipsychotics in single-dose experiments in controls and under steady-state conditions in patients. Thus, our study convincingly demonstrates a significant dis- sociation of declining drug plasma levels and the time course of brain effects in healthy volunteers and patients, after single doses or continuous treatment with risperidone or olanzapine, and both, in striatal and extra-striatal brain regions. Several factors may account for the significant differ- ence in the time courses of drug plasma levels and brain receptor occupancy. The relation between plasma drug levels and occupancy is non-linear and can be best described by a rectangular hyperbola.1 In Figure 2 Discontinuation experiments in patients.
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