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.

Funding/Support This study was funded and supported by F. Hoffmann-La Roche Ltd. Additionally, P. Homan was supported by a NARSAD grant from the Brain & Behavior Research Foundation (28445) and by a Research Grant from the Novartis Foundation (20A058). Disclosures/Conflicts of interest P. Homan has received grants and honoraria from Novartis, Lundbeck, Mepha, Janssen, Boehringer Ingelheim, Neurolite outside of this work. No further disclosures were reported.

NCT02824055

Funding/Support This study was funded and supported by F. Hoffmann-La Roche Ltd. Additionally, P. Homan was supported by a NARSAD grant from the Brain & Behavior Research Foundation (28445) and by a Research Grant from the Novartis Foundation (20A058). Disclosures/Conflicts of interest P. Homan has received grants and honoraria from Novartis, Lundbeck, Mepha, Janssen, Boehringer Ingelheim, Neurolite outside of this work. No further disclosures were reported.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The research protocol was registered on ClinicalTrials.gov (NCT02824055). All responsible ethics oversight bodies gave approval to the study: Copernicus Group IRB, P.O. Box 110605, Research Triangle Park, NC 27709, approval given on May 27th 2016; Washington University in St. Louis, Human Protection Office, 660 South Euclid Ave., Campus Box 8089, St. Louis, MO 63110, approval given on 5th August 2016; Alpha IRB, 1001 Avenida Pico, Suite C#497, San Clemente, CA 92673, approval given on 8th July 2016; Integ Review IRB, 3815 S. Capital of Texas Hwy, Suite 320, Austin, TX 78704, approval given on 27th May 2016.

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All data produced in the present study are available upon reasonable request to the authors.