The Role of Glutamatergic and Dopaminergic Genes in Resistant Schizophrenia: A Systematic Review

Psychosis is a heterogeneous disorder, with approximately one-third of patients experiencing treatment resistance, predominantly among individuals diagnosed with Schizophrenia. Treatment-resistant schizophrenia (TRS) may stem from a distinct biological signature, involving abnormalities in the dopaminergic and glutamatergic systems. However, generalizing research findings has been challenged by inconsistent definition of resistance. Following PRISMA guidelines, a systematic literature search was conducted across four databases (PubMed, Embase, PsycINFO, and Medline) utilizing the treatment response and resistance in psychosis criteria to standardize the definition of resistance. The objective was to identify concordant genetic findings in key dopaminergic and glutamatergic pathways related to TRS, ultimately seeking genetic markers for diagnosis. Eighteen studies of moderate quality were included. The findings tentatively implicate specific glutamatergic and dopaminergic abnormalities in treatment-resistant patients, particularly involving loci within the DRD2, COMT, and NMDAR genes. Despite this concordance, the generalizability of results remains limited by factors like patient heterogeneity, varied study designs, and differences in treatment protocols. Candidate gene studies implicated genes from both dopaminergic and glutamatergic pathways in TRS but demonstrated genetic heterogeneity. Future research should advance beyond candidate-gene studies to use more robust methods, such as polygenic risk scoring, to improve the predictive accuracy of markers characterizing the TRS diagnosis.