Abstract
Aripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.
Highlights
We reported that striatal dopamine D2/3 (D2/3) receptor occupancies by aripiprazole were related to working memory in healthy volunteers[6]
A post hoc analysis found that error rates were significantly correlated with all memory-loaded tasks (1-back, ß = –2.131, t = −4.137, df = 18.341, and p = 0.001; 2-back, ß = –3.111, t = −5.943, df = 13.454, and p = 0.001; and 3-back, ß = −1.512, t = −2.332, df = 17.878, and p = 0.032) (Supplementary Figure 1), while reaction times were significantly related with the D2/3 receptor occupancy in the two-back condition (1-back, ß = −5.752, t = −1.560, df = 16.938, and p = 0.137; 2-back, ß = −21.453, t = −3.153, df = 16.623, and p = 0.006; and 3-back, ß = −13.311, t = −1.533, df = 18.347, and p = 0.142) (Supplementary Figure 2). To our knowledge, this is the first report of the relationship between the D2/3 receptor occupancy by aripiprazole and working-memory performance in patients with schizophrenia
These results indicate that aripiprazole’s occupancy of striatal D2/3 receptors is related to improvements in cognitive function, and suggest that it has potential to treat cognitive dysfunction in patients with schizophrenia
Summary
This pharmacological profile has been proposed to offer efficacy against the cognitive and negative symptoms of schizophrenia, as well as positive symptoms[1]. It has been reported that aripiprazole is safe and effective in improving cognitive and negative symptoms, as well as positive symptoms of schizophrenia[2,3,4]. We reported that striatal dopamine D2/3 (D2/3) receptor occupancies by aripiprazole were related to working memory in healthy volunteers[6]. We focused on the primary effects of aripiprazole on cognitive function and controlled the baseline performance by serial measurements of the relationship in the healthy volunteers. We found that greater striatal D2/3 receptor occupancy by aripiprazole was related to decreased performance in working-memory tasks.
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