WHEN ANTIPSYCHOTICS FAIL: MITORESILIENCE AS POTENTIAL MECHANISM UNDERLYING TREATMENT-RESISTANT SCHIZOPHRENIA IN AN ANIMAL MODEL

Schizophrenia is a complex psychiatric disorder that affects thought, perception, and behavior. Despite advances in pharmacotherapy, approximately 30% of patients develop treatment-resistant schizophrenia (TRS). In this context, mitochondrial function has recently emerged as a promising area of research. Mitochondria play a central role in the cellular response to stress and directly influence key neurobiological processes, including neuronal plasticity, oxidative stress, and the response to antipsychotic treatments. Thus, exploring the interplay between mitochondrial function and TRS is crucial for the development of more effective therapeutic strategies. The aim of this study is to evaluate mitochondrial function and dynamics in a neurodevelopmental model of schizophrenia, as well as their potential differential regulation in treatment-responsive and treatment-resistant animals. To this end, a double-hit model was employed, consisting of maternal immune activation via poly I:C injection (4 mg/kg, i.v.) followed by social isolation for seven weeks after weaning. Additionally, during the last 14 days of isolation, animals were treated with clozapine (5 mg/kg/day), the gold-standard antipsychotic for TRS. Preliminary results show differential behavioral outcomes among experimental groups, with animals subjected to the model displaying a schizophrenia-like phenotype, thereby validating the model. Moreover, parameters related to mitochondrial function and dynamics, as well as oxidative stress markers, were differentially regulated across experimental groups. Taken together, these findings highlight the important role of mitochondrial dysfunction in schizophrenia and treatment resistance, opening new avenues for investigating the mechanisms underlying this phenomenon.