Apathy, a lack of motivation and reduced goal-directed behavior, is a core negative symptom of schizophrenia that significantly impairs daily functioning. Despite its impact, effective treatments for apathy remain limited. Wolfgang Omlor and Philipp Homan from the Department of Adult Psychiatry and Psychotherapy at the University of Zurich and others explored whether changes in brain connectivity could explain individual differences in response to a novel compound.
The drug RG7203 is designed to enhance dopamine D1 signaling and potentially improve reward processing. It works by blocking an enzyme called PDE10A, which helps to control how brain cells respond to dopamine – a chemical involved in motivation and goal-directed behavior.
In a randomized, double-blind crossover study, 24 individuals with schizophrenia received placebo, 5 mg, or 15 mg of RG7203, each for three weeks, alongside their regular antipsychotic medication. Resting-state functional MRI scans were conducted to assess brain activity.
While RG7203 did not lead to overall improvements in apathy for the whole group, some participants did show clear benefits. These improvements were linked to stronger communication between the striatum, a brain area important for reward and motivation, and two other regions called the paracingulate cortex and anterior cingulate cortex, which are associated with decision-making and staying motivated. Participants who had weaker connections between these areas at the beginning of the study experienced the biggest reductions in apathy during treatment with RG7203.
These findings suggest that brain connectivity patterns may help identify individuals who could benefit from treatments like RG7203. Further research with larger samples is needed to confirm these results and advance personalized treatment approaches for negative symptoms in schizophrenia.
Reference: Omlor, W., Cecere, G., Huang, GY. et al. Exploratory analysis of the relationship between striatal connectivity and apathy during phosphodiesterase 10 inhibition in schizophrenia: findings from a randomized crossover trial. BMC Med 23, 187 (2025). https://doi.org/10.1186/s12916-025-04004-2
Useful links:
- Wolfgang and Philipp’s Website: https://www.dapp.uzh.ch/en/cfpr/researchgroups/researchgroups/individual-differences-in-psychosis/team.html
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