Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment

Diego Scheggia, Rosa Mastrogiacomo, Maddalena Mereu, Sara Sannino, Richard E Straub, Marco Armando, Francesca Managò, Simone Guadagna, Fabrizio Piras, Fengyu Zhang, Joel E Kleinman, Thomas M Hyde, Sanne S Kaalund, Maria Pontillo, Genny Orso, Carlo Caltagirone, Emiliana Borrelli, Maria A De Luca, Stefano Vicari, Daniel R WeinbergerGianfranco Spalletta, Francesco Papaleo

Research output: Contribution to journalArticlepeer-review

Abstract

Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.

Original languageEnglish
Pages (from-to)2265
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Jun 11 2018

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