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There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets. [ABSTRACT FROM AUTHOR]

Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing. [ABSTRACT FROM AUTHOR]

Although neurogenesis is affected in several psychiatric diseases, the effects and mechanisms of action of psychoactive drugs on neurogenesis remain unknown and/or controversial. This study aims to evaluate the effects of psychoactive drugs on the expression of genes involved in neurogenesis. Neuronal-like cells (NT2-N) were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), or valproate (0.5 mM) for 24 h. Genome wide mRNA expression was quantified and analysed using gene set enrichment analysis, with the neurogenesis gene set retrieved from the Gene Ontology database and the Mammalian Adult Neurogenesis Gene Ontology (MANGO) database. Transcription factors that are more likely to regulate these genes were investigated to better understand the biological processes driving neurogenesis. Targeted metabolomics were performed using gas chromatography-mass spectrometry. Six of the eight drugs decreased the expression of genes involved in neurogenesis in both databases. This suggests that acute treatment with these psychoactive drugs negatively regulates the expression of genes involved in neurogenesis in vitro. SOX2 and three of its target genes (CCND1, BMP4, and DKK1) were also decreased after treatment with quetiapine. This can, at least in part, explain the mechanisms by which these drugs decrease neurogenesis at a transcriptional level in vitro. These results were supported by the finding of increased metabolite markers of mature neurons following treatment with most of the drugs tested, suggesting increased proportions of mature relative to immature neurons consistent with reduced neurogenesis. [ABSTRACT FROM AUTHOR]