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Umbricht, Daniel [Author]; Abt, Markus [Author]; Gertsik, Lev [Author]; Sevigny, Jeff [Author]; Keswani, Sanjay [Author]; Dukart, Juergen [Author]; Tamburri, Paul [Author]; Chatham, Christopher [Author]; Holiga, Štefan [Author]; Frank, Michael J. [Author]; Collins, Anne G. E. [Author]; Walling, David P. [Author]; Mofsen, Rick [Author]; Gruener, Daniel [Author]

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

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  • Media type: E-Article
  • Title: Proof-of-Mechanism Study of the Phosphodiesterase 10 Inhibitor RG7203 in Patients With Schizophrenia and Negative Symptoms
  • Contributor: Umbricht, Daniel [Author]; Abt, Markus [Author]; Gertsik, Lev [Author]; Sevigny, Jeff [Author]; Keswani, Sanjay [Author]; Dukart, Juergen [Author]; Tamburri, Paul [Author]; Chatham, Christopher [Author]; Holiga, Štefan [Author]; Frank, Michael J. [Author]; Collins, Anne G. E. [Author]; Walling, David P. [Author]; Mofsen, Rick [Author]; Gruener, Daniel [Author]
  • imprint: Elsevier Science, 2021
  • Published in: Biological psychiatry 1(1), 70 - 77 (2021). doi:10.1016/j.bpsgos.2021.03.001
  • Language: English
  • DOI: https://doi.org/10.1016/j.bpsgos.2021.03.001
  • ISSN: 0006-3223
  • Origination:
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  • Description: BACKGROUND:Reduced activation of dopamine D1receptor signaling may be implicated in reward functioning as apotential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highlyexpressed in the striatum, modulates both dopamine D2- and D1-dependent signaling.METHODS:We assessed whether augmentation of D1signaling by the PDE10 inhibitor RG7203 enhances imagingand 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 asadjunctive treatment to stable background antipsychotic treatment in patients with chronic schizophrenia withmoderate levels of negative symptoms. Effects on reward functioning and reward-based effortful behavior wereevaluated 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 age6SD 36.667.0 years; Positive and Negative Syndrome Scalenegative symptom factor score 23.063.5 at screening) were assessed at three study centers in the United States; 24patients completed the study. RG7203 at 5 mg significantly increased reward expectation–related activity in themonetary 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 andindices of reward learning. The results do not support the utility of RG7203 as adjunctive treatment for negativesymptoms in patients with schizophrenia.
  • Access State: Open Access