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

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.

Retinal biomarkers and pharmacological targets for Hermansky-Pudlak syndrome 7

“…In conclusion, our findings on retinal miRNAs dysregulation in Dys −/− mice, along with retinal dysfunction data, suggest that the Dys −/− mouse represents a good paradigm for HSP-7, beyond a schizophrenia model as previously demonstrated 11,17,19 . Our data suggest that retinal function in ocular albinism could be modulated by miRNAs and also by dopaminergic tone.…”

“…Procedures were carried out in accordance to the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research. Dys −/− , Dys +/− and WT mice used in this study, were produced using a heterozygous (Dys +/− ) breeding strategy as previously described 11,19 . Wild-type C57BL/6 J mice were purchased from Envigo (San Pietro al Natisone, Udine, Italy).…”

Hermansky–Pudlak syndrome: Mutation update

“…Several association studies have identified DTNBP1 as a risk allele for schizophrenia, including in European‐Americans (Donohoe et al, 2008; Straub et al, 2002; Wang, Xu, Lazarovici, & Zheng, 2017; Zuo et al, 2009). Schizophrenic subjects have reduced hippocampus DTNBP1 mRNA expression (Weickert, Straub, Kleinman, Hyde, & Rothmond, 2006) and DTNBP1 variants are associated with a cognitive response to antipsychotic drug treatment (Scheggia et al, 2018), however, the association of DTNBP1 with schizophrenia has also been challenged (Ghiani & Dell'Angelica, 2011). Notably, no psychiatric illness in HPS‐7 subjects has been reported but it is reasonable to consider such features in HPS‐7 and BLOC‐1 cases.…”

Polygenic Risk Scores Shed Light on the Relationship between Schizophrenia and Cognitive Functioning: Review and Meta-Analysis

“…Moreover, cognition is a particularly important endophenotype because discovering its underlying genetic mechanisms may help identify promising targets for improving cognitive functioning in patients. Indeed, there are already evidence that genetics might help predict cognitive responses to drugs in schizophrenia [28,29]. GWASs that examine millions of genetic variants are a powerful tool to identify common variants responsible for susceptibility to common and complex diseases.…”

“…Other data indicate a strong and specific genetic link between cognitive impairment and loss of functioning [36], yet with few data to date. Recent findings suggest that the genetic risk of schizophrenia may differentially impact cognition in patients versus not, shedding an insight on the underpinning of cognitive impairment related to schizophrenia [28,29]. However, no study has provided a meta-analytic approach of this differential effect.…”