Researchers Identify Genes Associated With Clinical Response in Schizophrenia

A little over a year ago, the Psychiatric Genomics Consortium (PGC) uncovered over 100 gene variants that appear to be associated with an increased risk of developing schizophrenia. It was a landmark achievement that expanded scientists’ knowledge of psychosis and opened the door to new research paths.

While knowing an individual’s risk of developing psychosis can assist clinicians in efforts to design preventative or disease-monitoring strategies, some worry that informing patients of their risk of psychosis could have negative outcomes.

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James Kennedy, M.D., the head of the Tanenbaum Centre for Pharmacogenetics at the Centre for Addiction and Mental Health in Toronto, recently conducted a survey among medical students that illustrated this conundrum. The students were asked various questions on their attitudes toward different kinds of genetic tests.

“For disease testing, participants were pretty evenly split on whether there was value to knowing their genetic risk,” Kennedy told Psychiatric News. “But 94 percent said they would want tests that would tell them about potential drug response and side effects.”

In addition to offering clues about a patient’s potential risk of schizophrenia, dozens of the genes uncovered by the PCG may hold clues about the severity of the disorder as well as a patient’s response to medications.

Kennedy, the recipient of the 2015 David Mrazek Award for pharmacogenomics research, recently teamed up with other researchers, including former APA President Jeffrey Lieberman, M.D., on a study that revealed a variant of the DRD2 gene known as rs2514218—one of the newly uncovered PGC risk variants—might help predict clozapine response.

DRD2 encodes the dopamine D2 receptor, and as Kennedy explained, while there are some mechanistic differences among antipsychotics, every one blocks D2 receptor activity; thus, this gene likely contributes in some part to the therapeutic effects of all antipsychotics.

For the study, 208 patients with schizophrenia from three separate clinics took clozapine daily for six months. When the researchers assessed their response to the medication in relation to rs2514218 status, they found that the presence of this variant was associated with a greater improvement in symptoms, as measured by the Brief Psychiatric Rating Scale. This study appeared in the January issue of Pharmacogenomics.

“We still need the all-important replication of these findings, but it’s definitely a step toward greater clinical use of clozapine. Even though it works well, you don’t want to put patients on clozapine unless you’re fairly confident they’re going to respond, because of the risk of adverse events such as agranulocytosis,” Kennedy said.

Unlike DRD2, the association between the rs1344706 variant of the ZNF804A gene and an increased risk of psychosis is better established. (Some studies suggest the gene may also be associated with an increased risk of bipolar disorder.) However, very little work has been done to assess whether the variant is associated with differences in clinical outcomes.

Recently, a team led by Robert Stewart, M.D., a professor of psychiatric epidemiology and clinical informatics at King’s College London, published a study in Translational Psychiatry showing that the ZNF804A risk gene variant is associated with the length of hospital stays for patients with schizophrenia.

The group followed 291 patients after their first psychotic episode for two years and found that each copy of the ZNF804A gene risk variant increased the average length of inpatient stay by about 38 days (for example, a person with two copies of the risk variant was in the hospital about 76 days longer than a person without the variant).

In contrast, the researchers found that the prevalence of patients who require admission to the hospital or the total number of admissions by patients over the two-year period did not differ based on genetic type.

According to Stewart, patients with the rs1344706 risk variant may have a higher degree of negative symptoms of schizophrenia compared with those without the variant, which could explain the differences in the hospital length of stay. Because the study did not analyze medication response, the longer hospital stays could also be due to the rs1344706 variant lowering the effectiveness of antipsychotics.

Stewart and his team hope to tease out the mechanisms in more detail, though there is one biological stumbling block. The risk profile of ZNF804A might be well known, but what this protein actually does in the body is not.

Stewart’s work was funded by the National Institute for Health Research, King’s College London, and others. Kennedy’s study was funded by the Canadian Institute for Health Research and others. ■