TY - JOUR
T1 - Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment
AU - Scheggia, Diego
AU - Mastrogiacomo, Rosa
AU - Mereu, Maddalena
AU - Sannino, Sara
AU - Straub, Richard E.
AU - Armando, Marco
AU - Managò, Francesca
AU - Guadagna, Simone
AU - Piras, Fabrizio
AU - Zhang, Fengyu
AU - Kleinman, Joel E.
AU - Hyde, Thomas M.
AU - Kaalund, Sanne S.
AU - Pontillo, Maria
AU - Orso, Genny
AU - Caltagirone, Carlo
AU - Borrelli, Emiliana
AU - De Luca, Maria A.
AU - Vicari, Stefano
AU - Weinberger, Daniel R.
AU - Spalletta, Gianfranco
AU - Papaleo, Francesco
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-04711-w
DO - 10.1038/s41467-018-04711-w
M3 - Article
C2 - 29891954
AN - SCOPUS:85048455683
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2265
ER -