The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory

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. 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 D-2 receptor occupancy and changes in working memory. Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [C-11]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. The mean (+/- SD) D-2 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 D-2 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. Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D-2 receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.