Proof-of-Mechanism Study of the Phosphodiesterase 10 Inhibitor RG7203 in Patients With Schizophrenia and Negative Symptoms

Abstract

Background: Reduced activation of dopamine D₁ receptor signaling may be implicated in reward functioning as a potential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highly expressed in the striatum, modulates both dopamine D₂- and D₁-dependent signaling.

Methods: We assessed whether augmentation of D₁ signaling by the PDE10 inhibitor RG7203 enhances imaging and behavioral markers of reward functions in patients with schizophrenia and negative symptoms. In a 3-period, double-blind, crossover study, we investigated the effects of RG7203 (5 mg and 15 mg doses) and placebo as adjunctive treatment to stable background antipsychotic treatment in patients with chronic schizophrenia with moderate levels of negative symptoms. Effects on reward functioning and reward-based effortful behavior were evaluated using the monetary incentive delay task during functional magnetic resonance imaging and the effort-cost-benefit and working memory reinforcement learning tasks.

Results: Patients (N = 33; 30 male, mean age ± SD 36.6 ± 7.0 years; Positive and Negative Syndrome Scale negative symptom factor score 23.0 ± 3.5 at screening) were assessed at three study centers in the United States; 24 patients completed the study. RG7203 at 5 mg significantly increased reward expectation-related activity in the monetary incentive delay task, but in the context of significantly decreased overall activity across all task conditions.

Conclusions: In contrast to our expectations, RG7203 significantly worsened reward-based effortful behavior and indices of reward learning. The results do not support the utility of RG7203 as adjunctive treatment for negative symptoms in patients with schizophrenia.

Keywords: Negative symptoms; PDE10 inhibitor; Proof-of-mechanism study; RG7203; Reward functioning; Schizophrenia.

Figure 1

Deployed masks and results of hemodynamic response function (HRF) analyses. (A) Ventral striatal monetary incentive delay activation mask extracted from a previous study in healthy volunteers alongside the corresponding HRF for the different task conditions (control = $0, win1 = $0.2, win2 = $2) (28). (B) n-back dorsolateral prefrontal activation mask extracted from a previous study in healthy volunteers alongside the corresponding HRF for the different task conditions (28). (C) HRF for the monetary incentive delay task per treatment and task condition. p values from the paired t test for each task condition vs. placebo are reported. (D) HRF for the n-back task per treatment and task condition. p values from the paired t test for each task condition vs. placebo are reported. The shaded area for all HRFs represents the standard error of mean.

Figure 2

Results of primary and exploratory analyses. (A) Results for the four primary outcomes are displayed per treatment condition. (B) Results for the three secondary end points are displayed. p values are two-sided. Error bars are 95% boot-strapped confidence intervals of the mean. ECBT, effort-cost-benefit task; LP, learning phase; MID, monetary incentive delay; TP, test phase; WMRLT, working memory reinforcement learning task.

Figure 3

Proportion of patients choosing the high effort/high reward option by magnitude of the reward value when receiving the reward was certain. During placebo treatment, patients show only a small increase in high effort choices with increasing reward—a profile typical of patients with negative symptoms. During treatment with either dose of RG7203, patients became less inclined to choose the high effort option—an effect predictive of worsening of negative symptoms. IQR, interquartile range.