Gene Variants Tied to Antipsychotic Response in Schizophrenia

Megan Brooks

November 14, 2018

Genetic variation in glutamatergic or N-methyl-D-aspartate (NMDA) neurotransmission may determine antipsychotic medication response in patients with schizophrenia, a new study shows.

Researchers with the Chinese Antipsychotics Pharmacogenetics Consortium found that patients who do not respond to antipsychotic drugs have a greater burden of rare, damaging variants in two synpase-relaetd gene sets (reduced NMDA–mediated synaptic currents and reduced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA]–mediated synaptic currents).

"The present study provides evidence of the importance of gene sets involved in the glutamatergic system to the response to antipsychotic drugs," write Tao Li, MD, PhD, from West China Hospital of Sichuan University, and colleagues.

"Because the involved genes potentially have an effect on glutamate transmission, drugs that target glutamate transmission may be of benefit to patients who do not respond to traditional antipsychotic drugs," they add.

The study was published online November 7 in JAMA Psychiatry.

Biomarker of Antipsychotic Response?

The multicenter, open-label, randomized clinical trial included patients with schizophrenia whose total score on the Positive and Negative Syndrome Scale was 60 or greater. They were treated with one of seven antipsychotic medications. The study outcome was symptom reduction after 6 weeks.

From a total sample of 2336 patients, whole-exome sequencing was performed in 156 patients who had the best treatment response and in 160 who had no treatment response. The researchers assessed 79 gene sets associated with alterations in neurotransmission, signal transduction, and synaptic activity.

Two of these gene sets &mdash reduced NMDA–mediated and AMPA-mediated synaptic currents &mdash were found to be enriched with rare genetic variants in those patients who did not respond to antipsychotic medication. No statistically significant differences in antipsychotic drug response were found among patients who received different antipsychotic drugs.

The enrichment for the gene set associated with reduced NMDA–mediated synaptic current phenotypes was replicated using targeted sequencing in an independent sample of 1920 patients with schizophrenia. This suggests that glutamatergic signaling through NMDA receptors mediates antipsychotic efficacy, the researchers note.

"This seems consistent with studies showing improvement in symptoms when NMDA receptor coagonists, such as glycine and D-serine, are used as adjuncts to antipsychotic therapy," write Edwin van den Oord, PhD, of the Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University in Richmond, and colleagues in a linked commentary.

However, the fact that this biomarker involves rare variants "may limit the ability to prognosticate drug response in individual patients because most of them may not have any rare variant," they note.

The field of precision medicine has "struggled to develop accurate approaches for predicting psychotropic drug response," van den Oord and colleagues point out. And although these new findings "reinforce the promise of genomic approaches, challenges associated with heterogeneity and sample availability that have historically plagued pharmacogenomics remain," they add.

Although, for patients with schizophrenia, "generic factors associated with specific outcomes may exist, reliable algorithms will likely need to include factors unique to certain antipsychotic medications, specific symptoms or adverse effects, or subgroups of patients with schizophrenia," the editorial writers say.

"In practice, finding these factors is challenging, because clinical trials often lack the sample sizes needed to detect their associated outcomes. An encouraging development in this respect involves combining population-based genetic studies with electronic medical records.

"These studies will lack the rigor of clinical trials and be subject to biases associated with their nonexperimental nature. However, they may generate and replicate novel hypotheses about variants relevant for specific drug-outcome combinations," van den Oord and colleagues predict.

The study was funded in part by grants from the National Nature Science Foundation of China, the Ministry of Science and Technology of China, and the West China Hospital, Sichuan University. The authors and editorialists have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online November 5, 2018. Full text, Commentary

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