Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia: A Randomized Clinical Trial.

摘要: Importance The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. Objective To discover genes and gene sets harboring rare variants associated with short-term efficacy. Design, Setting, Participants In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, December 31, 2011, 3023 patients recruited China of Chinese Han descent schizophrenia total Positive Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment medications randomly chosen from 5 atypical 2 typical medications. Whole-exome sequencing (WES) was performed 316 participants (grouped into those the best [n=156] who had no [n=160] prescribed), according PANSS reduction rate after 6 weeks treatment. Validation using targeted an independent sample 1920 patients. Data analyses March 15, 2016, 1, 2017. Main Outcomes Measures Drug efficacy at week assessed change scores baseline. Extremely good extremely poor responders were selected initial WES association study, which subset showing putative replication approach. Results Of (1549 [51.24%] female 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) eligible genetic analysis. After quality-control exclusions, (10.5%) included (63.5%) replication. discovery stage, (reduced NMDA [N-methyl-D-aspartate]–mediated synaptic currents reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]–mediated currents) found be enriched damaging nonresponder group, suggesting involvement these Reduced NMDA–mediated set further replicated targeting sequencing. No statistically significant drug among different drugs. Conclusions Relevance Genetic variation glutamatergic or neurotransmission is implicated efficacy; may have utility study pharmacogenetics. Trial Registration Clinical Trials Registry Identifier:ChiCTR-TRC-10000934