Genetic Variant May Foretell Cognitive Response to Antipsychotics

Antipsychotics are known to be effective at managing positive symptoms of schizophrenia (hallucinations and delusions), but these medications can be unpredictable when it comes to alleviating symptoms of social withdrawal and cognitive deficits.

A study published in June in Nature Communications suggests that the dysbindin-1 protein may be a biomarker to identify which patients are most likely to show cognitive improvements on antipsychotics.

Dysbindin-1 regulates the recycling of dopamine D2 receptors—the targets of antipsychotics. A variant in the dybindin-1 gene known as T-A-A results in the production of less dysbindin-1 protein. Less dysbindin-1 means less recycling of dopamine receptors, which leads to excess dopamine signaling. This overactivity can affect thinking, and studies in both humans and mice have shown that reduced dysbindin-1 impairs cognitive flexibility, or the ability to easily modify one’s thinking as circumstances change.

A team of researchers from Europe and the United States analyzed genetic data from 259 patients with chronic schizophrenia, all of whom were taking antipsychotics. As part of the study, the patients completed the Wisconsin Card Sorting Task, which measures cognitive flexibility. The researchers found that individuals who had the T-A-A variant performed better on average in the card task than patients without the variant.

The researchers conducted a second test with 45 patients with first-episode psychosis who had been exposed to antipsychotics for only four weeks. As with the other study group, patients who had the T-A-A variant did better on the card-sorting task.

The researchers acknowledged that a placebo group for comparison would be valuable to confirm the improved performance in patients with T-A-A was due to antipsychotic therapy. However, they noted that it would be ethically challenging to withhold medication from some patients. Instead, the authors used mice engineered to produce less dysbindin-1. These mice performed worse on a flexible-thinking task than normal mice, but after two weeks of antipsychotic treatment, their performance improved. Mice given placebo injections did not improve after two weeks.

Lead study author Francesco Papaleo, Ph.D., a researcher at the Department of Neuroscience and Brain Technologies and the Italian Institute of Technology in Genoa, said that this finding brings researchers one step closer to precision medicine for schizophrenia.

The “findings highlight one of the mechanisms that could be used to identify a subset of patients with schizophrenia whose executive functions are likely to respond better to antipsychotics,” Papaleo and colleagues wrote. “Ultimately, these results might be potentially applied to increase the effectiveness of antipsychotics and reduce the duration of the empirical testing often required to select appropriate medication or doses of antipsychotic drugs.”

Papaleo cautioned that while the Wisconsin Card Sorting Task measured only one component of cognition (flexibility), people with schizophrenia typically have broad cognitive deficits. He told Psychiatric News that his team is currently collecting other cognitive data from people with the dybindin-1 T-A-A variant to see if they also show signs of other cognitive improvements while taking antipsychotics.

Papaleo noted that the T-A-A variant was not one of the 108 genetic variants implicated as being associated with schizophrenia risk in a landmark genome-wide analysis (Psychiatric News, September 5, 2014). “Oftentimes genes important in drug response have no connection to the underlying disorder,” he said.

He added that more research is needed to explore the connection between dysbindin-1, dopamine receptors, schizophrenia, and cognition.

This study was supported by the Italian Institute for Technology, the Marie Curie FP7-Reintegration-Grant, the Italian Ministry of Health, the Brain and Behavior Research Foundation, and the Compagnia di San Paolo. ■