A scoping review of genetic studies of treatment-resistant schizophrenia

This scoping review synthesized the current evidence on the genetic architecture of treatment-resistant schizophrenia (TRS). TRS is typically characterized by an inadequate response to antipsychotic treatment in individuals with schizophrenia. Approximately 30% of individuals with schizophrenia develop treatment resistance, which is associated with greater disability, poorer prognosis, and increased mortality compared to treatment-responsive schizophrenia. Numerous studies have explored various genetic aspects of TRS; therefore, a scoping review was needed to summarize findings and consistent patterns, clarify the current level of understanding, and highlight remaining knowledge gaps.

A systematic search was conducted in PubMed up to March 2025. This scoping review followed PRISMA-ScR guidelines. Studies were included if they reported on genetic factors of TRS and its related constructs (clozapine resistance). Data on treatment resistance, study design, population characteristics, and genetic findings were extracted and synthesized.

A total of 102 studies were included. Definitions of TRS varied across studies, with most using proxies such as clozapine use, antipsychotic polypharmacy, or they used presence of symptoms despite antipsychotic treatment. Most studies compared TRS with treatment-responsive schizophrenia and predominately included participants of European genetic ancestry. Genetic findings spanned common variants (e.g., identified from genome-wide association studies or in cumulative measures such as polygenic risk scores [PRS]), rare variants, and copy number variants and functional genomics such as gene expression and epigenetic markers. Common variants dominated the literature but explained only a small proportion of TRS liability. Higher schizophrenia PRS, specific rare variants, and copy number variants were associated with TRS, while TRS-specific PRS remain in development. GWAS largely focused on schizophrenia broadly, with substantial genetic overlap between TRS and schizophrenia. Transcriptomic and epigenomic data provide additional but limited insights, often confounded by drug exposure.

Heterogeneous TRS definitions and limited ancestry diversity constrain progress, and robust TRS-specific genetic markers remain scarce. Harmonized criteria and larger, diverse cohorts are needed. Integrating genetic, epigenetic, and clinical data could improve early risk identification and guide precision treatment strategies.