Abstract
Rationale
The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.
Objectives
To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D2 receptor occupancy and changes in working memory.
Methods
Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride and [18 F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [18 F]FDG scan.
Results
The mean (±SD) D2 receptor occupancies were 22.2 ± 16.0 % in the 2 mg group, 35.5 ± 3.6 % in the 5 mg group, 63.2 ± 9.9 % in the 10 mg group and 72.8 ± 2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t = 2.705, df = 14, p = 0.017). Greater striatal D2 receptor occupancy was related to greater decrease in frontal metabolism (r = −0.659, p = 0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r = −0.597, p = 0.019) under the greatest task load.
Conclusions
Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D2 receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.
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References
Barch DM, Smith E (2008) The cognitive neuroscience of working memory: relevance to CNTRICS and schizophrenia. Biol Psychiatry 64:11–17
Bartlett EJ, Brodie JD, Simkowitz P, Schlosser R, Dewey SL, Lindenmayer JP, Rusinek H, Wolkin A, Cancro R, Schiffer W (1998) Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients. Am J Psychiatry 155:337–343
Brozoski TJ, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–932
Buchsbaum MS, Haznedar MM, Aronowitz J, Brickman AM, Newmark RE, Bloom R, Brand J, Goldstein KE, Heath D, Starson M, Hazlett EA (2007) FDG-PET in never-previously medicated psychotic adolescents treated with olanzapine or haloperidol. Schizophr Res 94:293–305
Calzavara R, Mailly P, Haber SN (2007) Relationship between the corticostriatal terminals from areas 9 and 46, and those from area 8A, dorsal and rostral premotor cortex and area 24c: an anatomical substrate for cognition to action. Eur J Neurosci 26:2005–2024
Castner SA, Goldman-Rakic PS, Williams GV (2004) Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology (Berl) 174:111–125
Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486
Eblen F, Graybiel AM (1995) Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. J Neurosci 15:5999–6013
First MB, Spitzer RL, Miriam G, Williams BWJ (2002) Structured clinical interview for DSM–IV–TR axis I disorders, Research version, Non-patient edition. (SCID-I/NP). Biometrics Research, New York State Psychiatry Institute, New York
Frankle WG, Laruelle M, Haber SN (2006) Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection. Neuropsychopharmacology 31:1627–1636
Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Grasby PM, McGuire PK (2010) Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry 67:683–691
Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Montgomery AJ, Grasby PM, McGuire P (2011) Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Mol Psychiatry 16:67–75
Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV (2004) Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 174:3–16
Hirose T, Kikuchi T (2005) Aripiprazole, a novel antipsychotic agent: dopamine D2 receptor partial agonist. J Med Invest 52(Suppl):284–290
Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D, Valmaggia L, Allen P, Murray R, McGuire P (2011a) Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry 16:885–886
Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P (2011b) Dopamine synthesis capacity before onset of psychosis: a prospective [18 F]-DOPA PET imaging study. Am J Psychiatry 168:1311–1317
Howes OD, Egerton A, Allan V, McGuire P, Stokes P, Kapur S (2009a) Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Curr Pharm Des 15:2550–2559
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69:776–786
Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM (2009b) Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 66:13–20
Ito H, Hietala J, Blomqvist G, Halldin C, Farde L (1998) Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [11C]raclopride binding. J Cereb Blood Flow Metab 18:941–950
Ito H, Takahashi H, Arakawa R, Takano H, Suhara T (2008) Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography. NeuroImage 39:555–565
Jaeggi SM, Buschkuehl M, Perrig WJ, Meier B (2010) The concurrent validity of the N-back task as a working memory measure. Memory 18:394–412
Kang KW, Lee DS, Cho JH, Lee JS, Yeo JS, Lee SK, Chung JK, Lee MC (2001) Quantification of F-18 FDG PET images in temporal lobe epilepsy patients using probabilistic brain atlas. NeuroImage 14:1–6
Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T (2003) Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol 6:325–337
Keefe RS, Silva SG, Perkins DO, Lieberman JA (1999) The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 25:201–222
Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A (2008) Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18 F]fallypride. Neuropsychopharmacology 33:3111–3125
Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49:603–615
Kim E, Howes OD, Kim BH, Jeong JM, Lee JS, Jang IJ, Shin SG, Turkheimer FE, Kapur S, Kwon JS (2012) Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship. J Cereb Blood Flow Metab 32:759–768
Kim E, Kwon JS, Shin YW, Lee JS, Kang WJ, Jo HJ, Lee JM, Yu KS, Kang DH, Cho JY, Jang IJ, Shin SG (2008) Taq1A polymorphism in the dopamine D2 receptor gene predicts brain metabolic response to aripiprazole in healthy male volunteers. Pharmacogenet Genomics 18:91–97
Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4:153–158
Lane CJ, Ngan ET, Yatham LN, Ruth TJ, Liddle PF (2004) Immediate effects of risperidone on cerebral activity in healthy subjects: a comparison with subjects with first-episode schizophrenia. J Psychiatry Neurosci 29:30–37
Lee JS, Lee DS (2005) Analysis of functional brain images using population-based probabilistic atlas. Curr Med Imaging Rev 1:81–87
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ et al (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10:740–747
Magistretti PJ, Pellerin L (1996) The contribution of astrocytes to the 18 F-2-deoxyglucose signal in PET activation studies. Mol Psychiatry 1:445–452
Magistretti PJ, Pellerin L (1999) Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci 354:1155–1163
Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–271
Molina V, Gispert JD, Reig S, Pascau J, Martinez R, Sanz J, Palomo T, Desco M (2005a) Olanzapine-induced cerebral metabolic changes related to symptom improvement in schizophrenia. Int Clin Psychopharmacol 20:13–18
Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Desco M, Palomo T (2005b) Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement. Psychopharmacology (Berl) 178:17–26
Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Palomo T, Desco M (2003) Cerebral metabolism and risperidone treatment in schizophrenia. Schizophr Res 60:1–7
Ngan ET, Lane CJ, Ruth TJ, Liddle PF (2002) Immediate and delayed effects of risperidone on cerebral metabolism in neuroleptic naive schizophrenic patients: correlations with symptom change. J Neurol Neurosurg Psychiatry 72:106–110
Nyberg S, Olsson H, Nilsson U, Maehlum E, Halldin C, Farde L (2002) Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole. Psychopharmacology (Berl) 162:37–41
Olsson H, Farde L (2001) Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy—a simulation study based on experimental data. NeuroImage 14:936–945
Owen AM, McMillan KM, Laird AR, Bullmore E (2005) N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp 25:46–59
Potkin SG, Buchsbaum MS, Jin Y, Tang C, Telford J, Friedman G, Lottenberg S, Najafi A, Gulasekaram B, Costa J et al (1994) Clozapine effects on glucose metabolic rate in striatum and frontal cortex. J Clin Psychiatry 55(B):63–66
Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR (2003) Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 60:681–690
Reep RL, Cheatwood JL, Corwin JV (2003) The associative striatum: organization of cortical projections to the dorsocentral striatum in rats. J Comp Neurol 467:271–292
Schlagenhauf F, Dinges M, Beck A, Wustenberg T, Friedel E, Dembler T, Sarkar R, Wrase J, Gallinat J, Juckel G, Heinz A (2010) Switching schizophrenia patients from typical neuroleptics to aripiprazole: effects on working memory dependent functional activation. Schizophr Res 118:189–200
Simpson EH, Kellendonk C, Kandel E (2010) A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65:585–596
Suzuki H, Gen K, Inoue Y (2011) An unblinded comparison of the clinical and cognitive effects of switching from first-generation antipsychotics to aripiprazole, perospirone or olanzapine in patients with chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35:161–168
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376–384
Yasui-Furukori N, Kaneda A, Sugawara N, Tomita T, Kaneko S (2012) Effect of adjunctive treatment with aripiprazole to atypical antipsychotics on cognitive function in schizophrenia patients. J Psychopharmacol 26:806–812
Acknowledgements
We thank professor Sohee Park for kind and insightful comments. We also thank JaeWoo Kim, Wi Hoon Jung, Ji-young Lee and Soo Jin Kwon for their kind assistance. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A070001). Dr. Oliver Howes is funded by grant U.1200.04.007.00001.01 from the Medical Research Council (MRC) UK.
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Kim, E., Howes, O.D., Turkheimer, F.E. et al. The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory. Psychopharmacology 227, 221–229 (2013). https://doi.org/10.1007/s00213-012-2953-0
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DOI: https://doi.org/10.1007/s00213-012-2953-0