¹Sapporo Medical University, Neuropsychiatry, Sapporo, Japan, ²Sapporo Medical University, Center for Medical Education, Sapporo, Japan, ³Sunagawa City Hospital, Psychiatry, Sunagawa, Japan, ⁴University of Milan, Pharmacology & Biomolecular Science, Milan, Italy, ⁵Sapporo Medical University/Ain Holdings/Nitori Holdings, Palliative Medicine and Supportive Care, Sapporo, Japan, ⁶Sapporo Medical University, Cellular Physiology and Signal Transduction, Sapporo, Japan, ⁷Obihirokosei Hospital, Psychiatry, Obihiro, Japan, ⁸Sapporo Medical University, Occupational Therapy, Sapporo, Japan

Background: The brain pathology underlying social dysfunction in depression and schizophrenia is complex, and directly effective treatment is still under development. Efforts continue to explore methods for restoring occupational and social functioning through the appropriate expression of cognitive/emotional empathy functions. Meanwhile, it has been noted that stress during the fetal period (including infections during pregnancy) and postnatal stress (including adverse childhood experiences) can cause abnormalities in the development and function of brain regions involved in cognitive function, emotional stability, and sociality (such as the prefrontal cortex, limbic system, thalamus, and nucleus accumbens), thereby increasing the risk of developing mental disorders like schizophrenia.

Aims & Objectives: In this study, we have investigated the influences of antipsychotic Lurasidone, on social & empathy behaviors, using two-hit schizophrenic animal model related to stress vulnerability, induced by dual stresses during embryonic and juvenile periods.

Method: We generated a two-hit model rat of schizophrenia by subjecting it to dual stressors: Poly(I:C) administration during the fetal period and social isolation treatment during the postnatal childhood to adolescence period. We investigated behavioral changes related to sociability and empathy and performed a comparative analysis of the effect of Lurasidone, which have been reported to be effective for cognitive and social dysfunction in clinical settings. The study was conducted in accordance with the Sapporo Medical University Animal Experiment Guidelines and Animal Facility Management Regulations, with utmost consideration given to avoid unnecessary suffering to the animals.

Results: In the group subjected to immune-activating stress during the fetal period, and in the group subjected to fetal stress plus social isolation stress during childhood and adolescence, proactive social behavior in the social interaction test was significantly reduced. In contrast, administration of Lurasidone and group housing treatment alone did not have a significant effect, respectively. However, in the group treated with both Lurasidone and group housing, the reduction in social behavior observed in the model animals was significantly improved. Furthermore, in the fetal stress model, empathic spontaneous action (rescue behavior) toward restrained individuals was markedly reduced, and this reduction was even more pronounced in the group exposed to both stresses. In contrast, while neither treatment alone had a significant effect, the group receiving both Lurasidone and group housing showed a significant improvement in the reduction observed in the model animals.

Discussion & Conclusions: The results of this study suggest that lurasidone administration may contribute to improving the appropriate expression of social and empathic functions in schizophrenia patients, thereby potentially aiding in the recovery of occupational functioning. Currently, focusing particularly on the point that Lurasidone's effects are demonstrated when combined with group housing treatment, we are conducting detailed exploratory research. This research centers on analyzing functional variations in the GABAergic and oxytocinergic systems, which are suggested to be deeply involved in the causes of social dysfunction. Our goal is to develop new treatments for treatment-resistant psychiatric disorders by enhancing occupational and social functional recoveries.