Polygenic Risk Score Predicts Drug Efficacy with Schizophrenia

A polygenic risk score (PRS) may be able to predict response to antipsychotic drug treatment in patients with their first episode of psychosis from schizophrenia, according to a study published Nov. 5 in the American Journal of Psychiatry. Specifically, higher PRSs were associated with poorer treatment response.

“Polygenic risk scores represent the combined effects of many thousands of genetic variants across the entire genome, and better represent the very complex genetic nature of schizophrenia,” said Jian-Ping Zhang, M.D., Ph.D., the study’s lead author, in a statement. “These results suggest that polygenic burden may affect severity of illness, in addition to reflecting risk for developing psychosis.”

Despite adoption of targeted treatment in other clinical areas, prescribing in psychiatry remains largely a trial-and-error endeavor, with an estimated 40 percent of patients with schizophrenia failing to respond to common antipsychotic drugs.

In the present study, researchers chose patients with first-episode psychosis in order to minimize previous drug exposure and presumably increase the effect size of the genotype-phenotype association. Researchers used a discovery cohort of 77 patients from the Zucker Hillside Hospital First-Episode schizophrenia trial, as well as three validation cohorts —the European First Episode Schizophrenia Trial (EUFEST; n = 141), the Programa Asistencial Fases Iniciales de Psicosisde Cantabria, Spain (PAFIP; n = 192), and the Center for Intervention Development and Applied Research (CIDAR; n = 100).

The PRS was based on the Psychiatric Genomics Consortium schizophrenia genome-wide association study, which identified 102,636 single nucleotide polymorphisms. The PRS was calculated for each participant as the weighted sum of all risk alleles carried. Symptoms were measured using total symptom rating scales at baseline through week 12. Response rate defined as at least a 50 percent reduction in total symptoms scores.

The researchers found that higher PRS significantly predicted greater post-treatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Patients with low PRS were more likely to be treatment responders compared to patients with high PRS (90 percent more likely to respond in the two Caucasian samples). In the low PRS group the response rate was 60.9 percent versus52.1 percent in the high PRS group. PRS was not significantly correlated with baseline total symptoms in any of the cohorts.

“PRS represents the total genetic burden of liability to schizophrenia. Conceivably, higher genetic burden may implicate a broader range of etiopathophysiologic mechanisms, thereby rendering patients less responsive to drug treatment based primarily on a single mechanism of action (dopaminergic blockade),” writes Zhang, from the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York. “As such, the PRS approach may be useful in both a practical and a theoretical sense in predicting clinical treatment response.”

Future studies with larger samples may also result in the ability to identify a PRS cutoff with sufficient explanatory power to attain clinical utility.

Takeaway: PRS burden may have potential utility as a prognostic marker of treatment response in patients with schizophrenia.