This article is more than 5 years old. Information may no longer be current.

Genotype, metabolizer status influence response to risperidone for schizophrenia

Recent data show Kv11.1 channels influence the efficacy of antipsychotics, particularly risperidone, for schizophrenia, further suggesting the utility of genotype-guided therapy for individuals with schizophrenia.

“Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications,” Juliane Heide, PhD, of Victor Chang Cardiac Research Institute, Darlinghurst, Australia, and colleagues wrote.

To determine if these effects are influenced by differential drug binding to Kv11.1 channel isoforms, researchers tested drug block of Kv11.1 isoforms in cellular assays. Effects of drug metabolism and KCNH2 genotypes on clinical responses to risperidone were assessed among 362 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which analyzed differences in therapeutic benefits and risk for side effects of antipsychotics among patients with schizophrenia.

Researchers found that risperidone led to greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, while its metabolite paliperidone and other atypical antipsychotics had similar potencies for these isoforms.

CATIE study participants with genotypes associated with increased Kv11.1-3.1 expression (n = 52) had better treatment response to risperidone compared with other drugs, though this was dependent on metabolism status.

Participants with KCNH2 risk genotypes and slow metabolizer status exhibited significant symptom improvement when receiving risperidone compared with participants with fast metabolizer status or without KCNH2 risk genotypes.

“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,” Heide and colleagues wrote. “Based on the numbers in this study, we estimate that ~7% 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.” – by Amanda Oldt

Disclosure: Heide reports receiving support from a postgraduate scholarship from the Schizophrenia Research Institute. Please see the full study for a list of all authors’ relevant financial disclosures.