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Genetic variation may affect efficacy of short-term antipsychotics

Using whole-exome and targeted sequencing, researchers found that damaging variants on two gene sets may affect the efficacy of short-term antipsychotic medications.

“Systematic search for common variants influencing antipsychotic drug response by genome-wide association study so far has been unsuccessful,” Qiang Wang, MD, PhD, from the Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, and colleagues wrote in JAMA Psychiatry. “The heritability of antipsychotic drug response is not easy to quantify because the phenotype can be assessed only in individuals who have schizophrenia and who received antipsychotic medications.”

Researchers conducted a randomized clinical trial of antipsychotic drug response in schizophrenia to determine the genes and gene sets harboring rare variants tied to short-term antipsychotic medication efficacy.

After participants received an antipsychotic randomly chosen from five atypical and two typical antipsychotic drugs, the investigators performed whole-exome sequencing in 156 participants with the best response and 160 of those who had no response to the prescribed medication, measured via total Positive and Negative Syndrome Scale (PANSS) scores after 6 weeks of treatment. Wang and colleagues also performed validation analysis using targeted sequencing in an independent sample of 1,920 patients. They measured medication efficacy via change in PANSS scores from baseline to week 6.

In the whole-exome sequencing discovery stage, researchers found that there was a greater burden of rare damaging variants in two gene sets among patients with schizophrenia who did not respond to antipsychotic medication: reduced N-methyl-D-aspartate (NMDA)-mediated synaptic currents and reduced -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated synaptic currents. This may indicate the involvement of these gene sets in antipsychotic medication efficacy, according to the researchers.

Wang and colleagues replicated the reduced NMDA-mediated synaptic currents gene set in the independent sample using targeting sequencing. They also found no statistically significant differences in antipsychotic medication response in the patients who received different antipsychotics.

“To our knowledge, this is the first study to demonstrate that rare genetic variants in the glutamate transmission are potentially implicated in the response to antipsychotic drugs among patients with schizophrenia,” the researchers wrote. “These findings warrant further replication and investigation.”

Though genetic factors may be linked to specific outcomes, the reliable algorithms needed to detect these factors need to include factors unique to certain antipsychotic medications, specific symptoms or adverse effects, or subgroups of patients with schizophrenia — which can be a challenge to find in clinical practice because of small sample sizes, Edwin J. C. G. van den Oord, PhD, Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, and colleagues wrote in an invited commentary.

“A variety of pharmacogenetics tests are currently on the market to support clinical decision making, but these generally lack robust prognostic power,” they wrote. “The field of precision medicine, however, has undergone a proof of concept, and new research tools may generate a next generation of tests that meet the widespread clinical demand for precision medicine.” – by Savannah Demko

Disclosure: The authors and commentary authors report no relevant financial disclosures.