Lipid-lowering and glucose-lowering drug targets differentially modulate antipsychotic treatment efficacy in schizophrenia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41850236.
- Also identified by DOI 10.1016/j.xcrm.2026.102653 and PMC identifier 13006399.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Schizophrenia is frequently comorbid with dyslipidemia and hyperglycemia. However, whether metabolic-modifying agents aggravate schizophrenia progression remains unclear. We perform a drug-target genetic association study in two independent Han Chinese schizophrenia cohorts (N = 2,111/292 for discovery/validation). Leveraging metabolic genome-wide association studies, we generate genetic risk scores (GRSs) for lipid-modifying and hypoglycemic targets. Those with higher APOC3 (inhibited by volanesorsen/olezarsen) GRS exhibit attenuated triglycerides and improvement in negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) (β = 1.23, 95% confidence interval [CI]: 0.30-2.16). Higher GCK (activated by dorzagliatin) GRS is associated with decreased glucose and less improvement across PANSS total (β = -1.70, 95% CI: -2.91-0.50), positive, negative, general subscales. Causal associations of GCK are replicated in independent validation. The effects of APOC3 and GCK on negative symptom recovery are robust in hyperlipidemic/diabetic subgroups. Genetically proxied proteomics analysis provides further functional validation for the identified target-outcome associations. Our findings suggest volanesorsen/olezarsen as potential adjunctive candidates; dorzagliatin warrants prudence in schizophrenia with metabolic disturbance.
Medical subject headings
- Schizophrenia
- Antipsychotic Agents
- Hypoglycemic Agents
- Hypolipidemic Agents