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The Relationship Between Antipsychotic D2 Occupancy And Psychopharmacology (2013) 227:221–229 DOI 10.1007/s00213-012-2953-0 ORIGINAL INVESTIGATION The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory A dual [11C]raclopride and [18F]FDG imaging study with aripiprazole Euitae Kim & Oliver D. Howes & Federico E. Turkheimer & Bo-Hyung Kim & Jae Min Jeong & Ji Who Kim & Jae Sung Lee & In-Jin Jang & Sang-Goo Shin & Shitij Kapur & Jun Soo Kwon Received: 5 September 2012 /Accepted: 10 December 2012 /Published online: 28 December 2012 # Springer-Verlag Berlin Heidelberg 2012 Abstract biomarker relating the drug effect on the brain to change in Rationale The effects of aripiprazole on cognitive function cognitive function. are obscure, possibly due to the difficulty in disentangling Objectives To explore the effect of aripiprazole on cognitive the specific effects on cognitive function from effects sec- function, we measured changes in frontal metabolism as an ondary to the improvement of other schizophrenic symp- intermediate biomarker and sought to determine its relation- toms. This prompts the necessity of using an intermediate ship with D2 receptor occupancy and changes in working memory. Methods E. Kim : J. S. Kwon (*) Fifteen healthy male volunteers participated in the Department of Psychiatry, Seoul National University study. Serial positron emission tomography (PET) scans College of Medicine, 28 Yeongon-dong, with [11C]raclopride and [18F]FDG were conducted 1 day Chongno-gu, Seoul 110-744, South Korea before and 2 days after the administration of aripiprazole. e-mail: [email protected] The subjects performed the N-back task just after finishing 18 E. Kim : O. D. Howes the [ F]FDG scan. Psychiatric Imaging, Medical Research Council Clinical Sciences Results The mean (±SD) D2 receptor occupancies were 22.2 Centre, Imperial College London, Hammersmith Hospital ±16.0 % in the 2 mg group, 35.5±3.6 % in the 5 mg group, Campus, London W12 0NN, UK 63.2±9.9 % in the 10 mg group and 72.8±2.1 % in the E. Kim : O. D. Howes : S. Kapur 30 mg group. The frontal metabolism was significantly King’s College London, Institute of Psychiatry, decreased after the administration of aripiprazole (t=2.705, London SE5 8AF, UK df=14, p=0.017). Greater striatal D2 receptor occupancy r F. E. Turkheimer was related to greater decrease in frontal metabolism ( = Department of Neuroimaging, Institute of Psychiatry, −0.659, p=0.010), and greater reduction in frontal metabo- King’s College London, London SE5 8AF, UK lism was associated with longer reaction times (r=−0.597, p : : =0.019) under the greatest task load. B.-H. Kim I.-J. Jang S.-G. Shin Conclusions Department of Clinical Pharmacology and Therapeutics, Aripiprazole can affect cognitive function and Seoul National University College of Medicine and Hospital, alter frontal metabolic function. The changes in these func- Seoul 110-744, South Korea tions are linked to greater D2 receptor occupancy. This suggests that it may be important to find the lowest effective J. M. Jeong : J. W. Kim : J. S. Lee Department of Nuclear Medicine, Seoul National University dose of aripiprazole in order to prevent adverse cognitive College of Medicine, Seoul 110-744, South Korea effects. J. S. Kwon Keywords Aripiprazole . Working memory . Raclopride Brain and Cognitive Science-WCU program, Seoul National . University College of Natural Sciences, C11 Fluorodeoxyglucose F18 Positron emission Seoul 151-747, South Korea tomography 222 Psychopharmacology (2013) 227:221–229 Introduction cognitive function is closely linked to dopaminergic activity in the frontal cortex (Castner et al. 2004; Goldman-Rakic et al. Aripiprazole acts as a potent partial dopamine D2 receptor 2004). However, there is also evidence from transgenic mice agonist, which is believed to reduce dopaminergic neurotrans- that even relatively small alterations in D2 receptor availability mission in the mesolimbic pathway, where hyperactivity is in the striatum can lead to cognitive impairments in tasks thought to underlie psychotic symptoms in schizophrenia, thought to be subserved by the frontal cortex (Simpson et al. while simultaneously enhancing dopaminergic function in 2010). Thus D2 receptor occupancy either in the frontal cortex cortical regions, where hypodopaminergia is thought to un- or in the striatum may alter frontal metabolism and cognitive derlie negative and cognitive symptoms (see review articles functions that involve the frontal cortex. by Davis et al. 1991; Howes and Kapur 2009). This unique However, it is also possible that the cognitive and metabol- pharmacological profile might predict efficacy against both ic effects of antipsychotics are due to their actions at other cognitive and negative symptoms as well as positive symp- receptor systems, in particular the serotonin (5-HT) system. toms of schizophrenia. The serotonin system also mediates cognitive functions. An- Indeed, it has been demonstrated to be safe and effective imal studies have generally shown that 5-HT2A antagonists in treating psychotic symptoms in schizophrenia (Kasper et impair some aspects of cognitive function, although the effect al. 2003; Potkin et al. 2003) and improvements in cognitive of 5-HT1A agonism on cognition is still debatable (Keefe et al. function have also been reported in patients receiving aripi- 1999). Aripiprazole has high affinities for 5-HT1A and 5-HT2A prazole (Schlagenhauf et al. 2010;Suzukietal.2011). receptors and acts as a partial 5-HT1A agonist and 5-HT2A However, its effects on cognitive function are less clear- antagonist (Hirose and Kikuchi 2005). Thus cognitive effects cut, with some evidence that it can also impair some aspects due to aripiprazole could be mediated by its serotonergic of cognitive performance (Yasui-Furukori et al. 2012). effects as well as its dopaminergic effects. Although the role These discrepant findings with respect to the effects of aripi- of 5-HT in cognition is significant, for the purpose of this prazole on cognition could be due to differences between study, we decided to constrain our inquiry to the dopamine studies in the task parameters used or the baseline perfor- system by focusing on one aspect of cognitive function — mance of subjects and drug occupancy levels in the brain. working memory — that is known to be closely associated Furthermore, it is not easy to disentangle the specific effects of with dopaminergic activity (Barch and Smith 2008). aripiprazole on cognitive function from secondary effects due Thus, to examine the effect of aripiprazole on cognitive to the improvement of other symptoms in schizophrenia. This function, we sought to determine the relationship between prompts the necessity of using an intermediate biomarker D2 receptor occupancy and changes in frontal metabolism relating the drug effect on the brain to change in cognitive and working memory. D2 receptor occupancy would inform function, thereby making it possible to directly explore the us about the pharmacokinetics of aripiprazole in the brain effect of antipsychotic drugs on cognitive function. and the change in frontal metabolism would enable to track It has been reported that antipsychotics, including aripipra- the drug effect on the brain as a pharmacodynamics param- zole, induce metabolic decreases in the frontal lobe (Bartlett et eter. For this, we measured dopamine receptor occupancy al. 1998; Kim et al. 2008;Laneetal.2004;Molinaetal.2003, and frontal metabolic change in healthy volunteers using 2005b) that are related to cognitive function such as working [11C]raclopride and [18F]fluorodeoxyglucose (FDG) posi- memory (Barch and Smith 2008;Owenetal.2005). As brain tron emission tomography (PET) after the administration regional metabolism primarily reflects neuronal activity with- of aripiprazole. At the same time, we related the frontal in the region (Magistretti and Pellerin 1996, 1999), the brain metabolic change to the performance on working memory. metabolic change by antipsychotics can be largely attributed to altered neuronal activity in a given region. Thus the frontal metabolic decrease suggests that antipsychotics are reducing Materials and methods neuronal activity, which in turn is likely to underlie the effects of antipsychotics on cognitive function. This implies that The present study was approved by the Institutional Review frontal metabolic change induced by antipsychotics could be Board of Seoul National University Hospital, Seoul, South a useful intermediate biomarker for investigating antipsychot- Korea, and was carried out in accordance with the Declaration ic effects on cognitive function. of Helsinki. The mechanism that mediates the antipsychotic effect on frontal metabolism and cognitive function is not fully under- Subjects stood, but several lines of evidence suggest it could be sec- ondary to D2 receptor blockade. Firstly, despite their widely Fifteen right-handed, non-smoking, healthy male volunteers varying pharmacology, all antipsychotics block D2 receptors participated in the study. After complete description of the (Howes et al. 2009a). Secondly, animal studies show that study to the subjects, written informed consent was obtained. Psychopharmacology (2013) 227:221–229 223 Screening tests for healthy volunteers included physical ex- the brain activity: the [11C]raclopride scans were performed at 18 amination, vital signs, laboratory tests (hematology, blood 9:30A.M., and the [ F]FDG scans were conducted at 1:30P.M. chemistry, and urinalysis), and a 12-lead electrocardiograms. Blood samples
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