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JAMA Psychiatry. 2018 Dec 1;75(12):1261-1269. doi: 10.1001/jamapsychiatry.2018.3039.

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.

Author information

1
Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
2
West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
3
State Key Laboratory of Brain and Cognitive Sciences, Centre for Genomic Sciences, and Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
4
Peking University Sixth Hospital (Institute of Mental Health), Beijing, China.
5
National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
6
Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
7
Beijing Anding Hospital, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
8
Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China.
9
Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China.
10
Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.
11
Hebei Mental Health Center, Baoding, Hebei, China.
12
Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
13
Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China.
14
Beijing HuiLongGuan Hospital, Beijing, China.
15
Department of Psychiatry, Jining Medical University, Jining, China.
16
Biobank, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Erratum in

Abstract

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 antipsychotic medication efficacy.

Design, Setting, and Participants:

In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017.

Main Outcomes and Measures:

Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach.

Results:

Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs.

Conclusions and Relevance:

Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics.

Trial Registration:

Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934.

PMID:
30422257
PMCID:
PMC6583032
DOI:
10.1001/jamapsychiatry.2018.3039
[Indexed for MEDLINE]
Free PMC Article

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