Relationship between Striatal Connectivity and Apathy during Phosphodiesterase 10 Inhibition in Schizophrenia

Negative symptoms in schizophrenia remain a challenge with limited therapeutic strategies. The novel compound RG7203 promotes reward learning via dopamine D1-dependent signaling and therefore holds promise to improve especially the apathy dimension of negative symptoms. When tested as add-on to antipsychotic medication apathy did not change significantly with RG7203 versus placebo. However, the response varied across patients, and a subset showed clinically relevant improvement of apathy. It remains unclear if these interindividual differences are related to neurobiological correlates. Due to the predominant binding of RG7203 in the striatum, we asked how apathy changes with RG7203 are related to changes in cortico-striatal connectivity. We focused on cortico-striatal circuits that have been associated with apathy and previously showed connectivity alterations in schizophrenia. In a double-blind, 3-way randomized crossover study, resting state functional magnetic resonance imaging was acquired in 24 individuals with schizophrenia following a 3-week administration of placebo, 5mg or 15mg of RG7203 as add-on to antipsychotics. We found that 5mg or 15mg of RG7203 did not lead to significant changes in striatal connectivity. However, changes in the apathy response across individuals were reflected by striatal connectivity changes. Apathy improvement with 5mg RG7203 vs. placebo was associated with increased connectivity between ventral caudate (vCaud) and paracingulate gyrus (PCG) as well as anterior cingulate cortex (ACC). The same trend was observed for 15mg RG7203 vs. placebo. Importantly, such associations were not observed for the negative symptom dimension of expressive deficits. These findings suggest that the relationship between vCaud-PCG/ACC connectivity and apathy response with RG7203 should be further explored in larger clinical studies. Replication and further elaboration of these findings could help to advance biologically informed treatment options for negative symptoms.