RESUMEN
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.
RESUMEN
BACKGROUND: As evidence of a biologic determinant of schizophrenia has been elaborated, an interest in the relationship between schizophrenia and autoimmune disorders has become increasingly more developed over the last decade. Pedigree analysis has shown that schizophrenia, like autoimmune disorders, is likely a heritable phenomenon, and a genetic liability in this disorder is hardly disputed. Research has indicated that physiologic connections between IFN-gamma and TNF-alpha are suggestive of a connection between the symptoms associated with schizophrenia and those of hypoglycemic events in IDDM. Autoimmune pathogeneses of schizophrenia have been hypothesized; however, the clinical delineation of a potentially corresponding subset of patients is rarely addressed. CASE REPORT: We treated a 22-year-old white female who carried the concomitant diagnoses of Schizophrenia, IDDM, and Hypothyroidism with quetiapine and risperidone on an acute basis at our inpatient facility, and observed an apparent resolution of her brittle diabetes with the successful treatment of her psychotic disorder. CONCLUSIONS: The well documented link between antipsychotic agents and changes in blood glucose may be of benefit in a subset of patients who suffer from both psychotic and diabetic disorders.