Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.