Study Identifies Factors Predictive of Response to Risperidone

The presence of a genetic polymorphism and the speed with which a patient metabolizes risperidone may help to predict those with schizophrenia who are the most likely to respond to the medication, according to a report in AJP in Advance.

Moreover, the report indicates a possible mechanism for this association involving the binding of risperidone to a specific potassium channel that has been associated with schizophrenia.

“One of the major challenges in psychiatric therapeutics, indeed in medical therapeutics in general, is to individualize medicine to optimize response,” wrote senior author Daniel Weinberger, M.D., of the Lieber Institute for Brain Development in Baltimore and colleagues.

Previous studies show that patients with slow metabolizer status and variants in the potassium channel gene KCNH2 associated with increased expression of Kv11.1-3.1 tend to have better responses to antipsychotic medications. (The expression of Kv11.1-3.1 has been shown to be increased in the brains of people with schizophrenia and is believed to be associated with disorganized neuronal firing.)

In the study, the authors analyzed drug clearance data in patients receiving risperidone in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study in order to test the hypothesis that a better response to the medication is associated with binding to the Kv11.1-3.1 potassium channel.

They found that 52 patients with genotypes associated with increased Kv11.1-3.1 expression showed a better treatment response to risperidone compared with other drugs. But they also found that this association was dependent on metabolism status; that is, patients with KCNH2 risk genotypes and slow metabolizer status showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes.

Moreover, risperidone caused greater in vitro block of the Kv11.1-3.1 potassium channel than other atypical antipsychotics.

While more research is needed to inform clinical decision making, “The data in this study strongly suggest that schizophrenia patients who are slow metabolizers and have KCNH2 risk-associated genotypes do better when treated with risperidone than with other antipsychotics, and they have by far the best response of anyone in the CATIE trial,” the authors wrote.

“Based on the numbers in this study, we estimate that approximately 7 percent of schizophrenia patients would have the risk genotypes and slow risperidone metabolism and so would obtain the selective enhanced benefit from risperidone treatment. Conversely, the data suggest that individuals who are not slow metabolizers and do not have KCNH2 genotypes associated with Kv11.1-3.1 expression do not have a beneficial response to risperidone.”

The results of the in vitro analysis of risperidone binding to the Kv11.1-3.1 channel also provides a “plausible mechanistic explanation for the clinical observations that response to risperidone treatment is influenced both by KCNH2 genotype and metabolizer status,” the group noted. “Not only do these data have implications for pharmacogenomics and individualized therapy in schizophrenia, they also suggest that development of drugs with an even greater selectivity for inhibition of Kv11.1-3.1 channels relative to Kv11.1-1A channels could be of significant clinical benefit. …”

Paul Shepard, Ph.D., of the Maryland Psychiatric Research Center and an associate professor of psychiatry and pharmacology at the University of Maryland School of Medicine, told Psychiatric News that several potassium channels have been known to exist in the heart, effecting electrical activity, and only more recently were discovered to reside in the brain, including in dopamine neurons. In a paper in Schizophrenia Bulletin (September 28, 2007), he wrote “the discovery of [a particular type of potassium] channel in the brain suggests that central actions of antipsychotic drugs could include alterations in the intrinsic electrical properties of neurons. … Indeed, it seems quite possible that partial block of [potassium] channels in dopamine neurons by antipsychotic drugs could increase neuronal excitability, … a phenomenon that has been implicated in the therapeutic effects of these agents.”

He explained that what the study by Weinberger and colleagues suggests is that there is a synergy between the action of risperidone and slow metabolism of the drug: the slower the breakdown of the drug, the higher the levels circulating in the bloodstream, and the more effectively the drug blocks the specific potassium channel presumed to be disrupting norm al neuronal activity.

As the cost associated with genotyping continues to decrease and the technique becomes easier to perform, Shepard predicts it likely won’t be long until it becomes “a normal part of clinical practice.”

“It’s pretty clear that tailoring the therapeutic approach based on genetic predisposition is the way forward. Weinberger and colleagues have given us two variables that appear to synergize in a way that may provide for a small group of patients to have a better therapeutic option,” he said. ■