Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment
Articolo
Data di Pubblicazione:
2018
Citazione:
Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment / D. Scheggia, R. Mastrogiacomo, M. Mereu, S. Sannino, R.E. Straub, M. Armando, F. Manago, S. Guadagna, F. Piras, F. Zhang, J.E. Kleinman, T.M. Hyde, S.S. Kaalund, M. Pontillo, G. Orso, C. Caltagirone, E. Borrelli, M.A. De Luca, S. Vicari, D.R. Weinberger, G. Spalletta, F. Papaleo. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 9:1(2018 Jun), pp. 2265.1-2265.11. [10.1038/s41467-018-04711-w]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Adolescent; Adult; Aged; Animals; Antipsychotic Agents; Brain; Cognition; Dysbindin; Executive Function; Genetic Variation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Prefrontal Cortex; Receptors, Dopamine D2; Risperidone; Schizophrenia; Schizophrenic Psychology; Young Adult
Elenco autori:
D. Scheggia, R. Mastrogiacomo, M. Mereu, S. Sannino, R.E. Straub, M. Armando, F. Manago, S. Guadagna, F. Piras, F. Zhang, J.E. Kleinman, T.M. Hyde, S.S. Kaalund, M. Pontillo, G. Orso, C. Caltagirone, E. Borrelli, M.A. De Luca, S. Vicari, D.R. Weinberger, G. Spalletta, F. Papaleo
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