Background
Treatment-resistant schizophrenia (TRS) occurs when patients do not respond adequately to standard treatments, leading to a significant burden on individuals and healthcare systems. Clozapine is the only approved medication for TRS and is more effective at managing symptoms than other antipsychotic drugs. Risperidone, another widely used antipsychotic, works differently and is often prescribed for schizophrenia that is not considered treatment-resistant.
This study aimed to investigate whether genetic differences influence TRS by comparing patients treated with clozapine (TRS group) to those treated with risperidone (non-TRS group). Researchers analysed genetic data from 1,286 patients who had undergone routine therapeutic drug monitoring between 2005 and 2022.
Results
A specific genetic variant in the LINC00523 gene was identified as potentially linked to TRS, though its significance was just below the threshold needed for definitive conclusions. Additionally, patients with a higher polygenic risk score (PRS) for schizophrenia were significantly more likely to have TRS. Further analysis of brain tissue from schizophrenia patients suggested that this genetic variant might influence the regulation of GPR88, a gene involved in brain signalling, and PUDP, which is linked to intellectual disability.
Conclusions
This study provides new evidence that genetic factors may contribute to TRS. The identified genetic variant could be a promising target for future research to better understand the biological mechanisms behind TRS. These findings highlight the potential of both single-gene and polygenic analyses in predicting which patients may develop treatment resistance, which could help improve personalised treatment approaches for schizophrenia.
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