S43. A PROOF-OF-MECHANISM STUDY OF THE PDE10 INHIBITOR RG7203 IN PATIENTS WITH PROBING REWARD FUNCTIONS WITH IMAGING AND BEHAVIORAL APPROACHES

Abstract

Background: The enzyme phosphodiesterase 10 is highly expressed in the striatum where it modulates both dopamine D2 and D1 dependent signaling. Its inhibition leads to a suppression of D2 mediated signaling ‐similar to effects of D2 antagonists ‐ and an enhancement of D1 dependent signaling. D1‐dependent signaling has been implicated in reward based learning. Its deficient activation may be a key factor underlying deficient reward functions including reward anticipation and reward based learning that have been implicated as a major driver of negative symptoms of schizophrenia. Therefore, inhibition of PDE10 could be a way to ameliorate such a deficit. In healthy volunteers, the PDE10 inhibitor RG7203 indeed enhanced performance in tasks that probed reward functioning suggestive of its potential utility to enhance reward functions and by extension treat negative symptoms in schizophrenia. We therefore tested the hypothesis that it should enhance imaging and behavioral markers of reward functions in patients with moderate negative symptoms in order to establish mechanistic proof of its utility as treatment of negative symptoms. Methods: In a three‐way cross‐over study we investigated the effects of two doses of RG7203 (5 mg and 15 mg) and placebo given as adjunctive treatment to stable background antipsychotic treatment on reward functioning and rewardbased effortful behavior using the monetary incentive delay (MID) task during fMRI and the effort choice task in patients with chronic schizophrenia and moderate levels of negative symptoms. Patients had to show a score of at least 18 points on the PANSS negative symptom factor score at screening. Each treatment period lasted three weeks followed by a 2‐ week washout period. fMRI and behavioral tasks were administered at the end of each treatment period. Key outcome measures were the differential BOLD activity during reward anticipation versus control condition in the MID task, overall BOLD activity during the MID task and the percentage of high‐effort high‐reward choices when the probability of reward was 100% during the effort choice task. Results: Thirty‐three patients with schizophrenia (30 male; 21 B, 9 W, 3 A; mean age 36.6 +/‐7 y) were recruited at three study centers in the US. At study entry PANSS NSFS was 22.8 (+/‐1.4). Twenty‐four subjects finished the entire study. Two patients dropped out due to adverse events (dystonic reactions), seven due to non‐safety related issues. Patients were able to do the fMRI and behavioral tasks. RG7203 at 5 mg significantly increased differential BOLD activity during reward anticipation relative to control condition in the MID task. However, this enhancement occurred in the context of a significant overall decrease of BOLD activity during the MID task observed across all conditions. RG7203 significantly worsened reward‐based effortful behavior in the effort choice task, that is during treatment with PDE10 patients chose the high‐effort high‐reward significantly less often than during placebo treatment (67% for both doses of RG7203 versus 73% for placebo). A multiple regression revealed that the decrease in effortful behavior was significantly related to the decrease in overall BOLD activity during the MID task and not related to the relative increase of BOLD activity during reward anticipation observed at 5 mg. Conclusions: In contrast to our expectation and previous results in healthy volunteers, RG7203 worsened indices of reward functions likely due to a further enhancement of D2 antagonistic activity. The results do not support the utility of a PDE10 inhibitor as adjunctive treatment for negative symptoms in patients with schizophrenia. Given the previous observation that RG7203 enhanced reward functions in healthy volunteers who were not treated with D2 antagonist, the results of our studies point to potentially deleterious effects of D2 blockade on reward functions and by extension on negative symptoms of schizophrenia and raise the question if the presence of D2 antagonistic treatment curtails the potential of any adjunctive treatment for negative symptoms.