Treatment-Resistant Schizophrenia May Have Genetic Cause

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The results of a genome-wide association study may help researchers develop more tailored treatments to help patients who don’t respond to conventional antipsychotic medications.

Treatment-resistant schizophrenia (TRS) may have genetic underpinnings according to a genome-wide association study (GWAS) published in JAMA Psychiatry. The results of the study may help researchers develop more tailored treatments to help patients who don’t respond to conventional antipsychotic medications.

The GWAS aimed to identify genetic variants associated with TRS. They used samples from large genomic schizophrenia studies, many recruited based on clozapine use.

The study included 85,490 total participants (48,635 male) in the GWAS stage and 1,380 participants (859 male) in the polygenic risk score (PRS) profiling validation stage. The researchers found a common, heritable genetic signal for TRS, showing that it may be categorically distinct from treatment-responsive schizophrenia. However, the variance was modest with a small associated area under the curve values.

That TRS is an under-reported diagnosis is one of the study’s limitations, as some individuals with TRS may not appear in that data set. Imperfect phenotyping and potential misclassification may also have affected the results.

Overall, “TRS had a small but detectable heritability associated with common risk alleles,” the researchers stated. “Altogether, these results highlight the usefulness of well-controlled clinical phenotype data in psychiatric genetics to explore beyond diagnostic classifications and into treatment outcome and response to aid precision psychiatry.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Pardiñas AF, Smart SE, Willcocks IR, et al. Interaction testing and polygenic risk scoring to estimate the association of common genetic variants with treatment resistance in schizophrenia. JAMA Psychiatry. 2022;e213799. doi:10.1001/jamapsychiatry.2021.3799