Impactos farmacogenéticos de polimorfismos do sistema endocanabinoide em pacientes com esquizofrenia

Abstract

Schizophrenia (SCZ) is a chronic and highly debilitating psychiatric disorder affecting approximately 24 million people worldwide, including 1.6 million in Brazil. Therefore, it has a significant economic impact. Among patients, 34% constitute a group that does not respond well to conventional antipsychotics, individuals with treatment-resistant schizophrenia (TRS). In these cases, the gold-standard treatment is clozapine (CLZ), even though it is often underutilized. The pathophysiology of SCZ, as well as its causes, is not fully elucidated and remains under study. The endocannabinoid system (ECS) has been identified as a mediator of the stress and inflammation that occur in SCZ, as well as in other psychiatric disorders. This study aimed to investigate the association between polymorphisms in ECS genes and the use of CLZ in patients with SCZ, as an indicator of TRS. We evaluated Ninety-five patients followed up in a specialized outpatient clinic, diagnosed with SCZ and using antipsychotics. Clinical and sociodemographic data were obtained, and symptomatic severity was assessed using the Positive and Negative Syndrome Scale (PANSS). Peripheral blood samples were used for genotyping of the rs7766029 (CNR1), rs35761398 (CNR2), and rs324420 (FAAH) polymorphisms by real-time PCR with TaqMan™ probes. Genotypes were compared between users (n=12) and non-users of CLZ (n=83) using association and logistic regression tests. There was an association between the CNR1 or CNR2 polymorphisms and CLZ use in a recessive inheritance pattern (p < 0.05). In an adjusted logistic regression model, the homozygous mutant genotype of CNR1 (CC) was associated with an increased chance of using CLZ (OR = 11.5; p = 0.001; 95% CI: 2.81 - 47.39), as well as a trend towards increased use in the homozygous mutant genotype of CNR2 (OR = 3.55; p = 0.08; 95% CI: 0.85 - 14.77). The FAAH polymorphism did not show a significant association. Despite sample limitations and the absence of functional analyses, the findings suggest that variants in SEC genes may be related to treatment refractoriness in SCZ, reinforcing the potential of this system as a target for personalized therapeutic approaches.