# Lipid-lowering and glucose-lowering drug targets differentially modulate antipsychotic treatment efficacy in schizophrenia

## TL;DR

This study finds that lipid-lowering drugs may improve schizophrenia symptoms, while glucose-lowering drugs may worsen them.

## Contribution

It identifies APOC3 and GCK as drug targets that differentially affect antipsychotic treatment outcomes in schizophrenia.

## Key findings

- Higher APOC3 genetic risk scores are linked to improved negative symptoms in schizophrenia.
- Higher GCK genetic risk scores are associated with reduced symptom improvement across multiple domains.
- The effects of APOC3 and GCK on symptoms are consistent in patients with metabolic disorders.

## 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.

•APOC3-proxied lipid lowering elevates antipsychotic efficacy of negative symptoms•GCK-proxied glucose lowering reduces positive, negative, general-symptom recovery•APOC3/GCK negative-symptom effects persist in hyperlipidemic/diabetic subgroups•Genetic proteomics validate blood-APOC3, brain-GCK effects on negative symptoms

APOC3-proxied lipid lowering elevates antipsychotic efficacy of negative symptoms

GCK-proxied glucose lowering reduces positive, negative, general-symptom recovery

APOC3/GCK negative-symptom effects persist in hyperlipidemic/diabetic subgroups

Genetic proteomics validate blood-APOC3, brain-GCK effects on negative symptoms

Whether metabolic-modifying agents aggravate schizophrenia progression remains unclear. Zhu et al. identify that APOC3-proxied lipid lowering improves schizophrenia negative-symptom recovery, and GCK-related glucose lowering worsens antipsychotic efficacy. Causal effects of APOC3/GCK on negative symptoms are robust in hyperlipidemic/diabetic subgroups. This study suggests volanesorsen/olezarsen as potential adjunctive candidates, and dorzagliatin warrants prudence in schizophrenia-metabolic comorbidity.