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. Weinberger, Gianfranco Spalletta and Francesco Papaleo ()
Additional contact information
Diego Scheggia: Istituto Italiano di Tecnologia
Rosa Mastrogiacomo: Istituto Italiano di Tecnologia
Maddalena Mereu: Istituto Italiano di Tecnologia
Sara Sannino: Istituto Italiano di Tecnologia
Richard E. Straub: Johns Hopkins University Medical Campus
Marco Armando: Bambino Gesù Children’s Hospital
Francesca Managò: Istituto Italiano di Tecnologia
Simone Guadagna: Istituto Italiano di Tecnologia
Fabrizio Piras: Neuropsychiatry Laboratory
Fengyu Zhang: Johns Hopkins University Medical Campus
Joel E. Kleinman: Johns Hopkins University Medical Campus
Thomas M. Hyde: Johns Hopkins University Medical Campus
Sanne S. Kaalund: Bispebjerg University Hospital
Maria Pontillo: Bambino Gesù Children’s Hospital
Genny Orso: IRCCS E. Medea Scientific Institute
Carlo Caltagirone: Neuropsychiatry Laboratory
Emiliana Borrelli: University of California
Maria A. De Luca: Università di Cagliari
Stefano Vicari: Bambino Gesù Children’s Hospital
Daniel R. Weinberger: Johns Hopkins University Medical Campus
Gianfranco Spalletta: Neuropsychiatry Laboratory
Francesco Papaleo: Istituto Italiano di Tecnologia

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04711-w

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