Metabolic pathway modulation by olanzapine: Multitarget approach for treating violent aggression in patients with schizophrenia

Abstract

Background: The use of network pharmacology and blood metabolomics to study the pathogenesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for reducing the risk of violent aggression and optimizing treatment plans.

Aim: To explore the metabolic regulatory mechanism of olanzapine in treating patients with schizophrenia with a moderate to high risk of violent aggression.

Methods: Metabolomic technology was used to screen differentially abundant metabolites in patients with schizophrenia with a moderate to high risk of violent aggression before and after olanzapine treatment, and the related metabolic pathways were identified. Network pharmacology was used to establish protein-protein interaction networks of the core targets of olanzapine. Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were subsequently performed.

Results: Compared with the healthy group, the patients with schizophrenia group presented significant changes in the levels of 24 metabolites related to the disruption of 9 metabolic pathways, among which the key pathways were the alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. After treatment with olanzapine, the levels of 10 differentially abundant metabolites were significantly reversed in patients with schizophrenia. Olanzapine effectively regulated six metabolic pathways, among which the key pathways were alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. Ten core targets of olanzapine were involved in several key pathways.

Conclusion: The metabolic pathways of alanine, aspartate, and glutamate metabolism and arginine biosynthesis are the key pathways involved in olanzapine treatment for aggressive schizophrenia.

Keywords: Metabolomics; Network pharmacology; Olanzapine; Schizophrenia; Violent aggression.

Figure 1

Metabolomic profiling analysis of the two groups. A: Positive ion modes; B: Negative ion modes. Principal component analysis and orthogonal partial least squares discriminant analysis score plots and permutation tests of the two groups in positive (A) and negative (B) ion modes.

Figure 2

Relative peak areas of differentially abundant metabolites in the experimental group regulated by olanzapine. A: Positive ion mode; B: Negative ion mode. All data are presented as the median ± min to max (n = 11).

Figure 3

Metabolic pathway analysis. A: The disordered metabolic pathways in Schizophrenia patients with a moderate to high risk of violent attacks; B: The metabolic pathways regulated by olanzapine. The size and color of each circle indicate the significance of the pathway ranked by the P value and the pathway impact score, respectively. Red represents higher P values, and yellow represents lower P values. The larger the circle is, the higher the impact score.

Figure 4

Venn diagram of common targets.

Figure 5

Protein-protein interaction network and hub genes. A: Protein-protein interaction network; B: Hub genes.

Figure 6

Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. A: Gene Ontology function; B: Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis.

Figure 7

Metabolite-target-disease network diagram.