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Drugs used in the treatment of bipolar disorder and their effects on cholesterol biosynthesis – a possible therapeutic mechanism

Version 2 2024-05-30, 14:35
Version 1 2019-09-26, 08:10
journal contribution
posted on 2024-05-30, 14:35 authored by S Kidnapillai, CC Bortolasci, B Panizzutti, Briana RandallBriana Randall, Timothy ConnorTimothy Connor, K Bonifacio, A Sanigorski, Olivia DeanOlivia Dean, Tamsyn CrowleyTamsyn Crowley, S Jamain, Laura GrayLaura Gray, M Leboyer, Michael BerkMichael Berk, Ken WalderKen Walder
Objectives: To understand the therapeutic mechanisms of bipolar disorder (BD) drugs at molecular and cellular levels. Methods: Next generation sequencing was used to determine the transcriptional effects of a combination of four commonly prescribed BD drugs (lithium, valproate, lamotrigine and quetiapine) or vehicle (0.2% DMSO) in NT2-N (human neuronal) cells and rats. Differential expression of genes and pathway analysis were performed using edgeR in R and Gene Set Enrichment Analysis software respectively. Free cholesterol levels and neurite outgrowth were quantified in NT2-N cells following combination and individual BD drug treatments. Results: Pathway analysis showed up-regulation of many elements of the cholesterol biosynthesis pathway in NT2-N cells and oxidative phosphorylation in rat brains. Intracellular cholesterol transport genes were upregulated (NPC1, NPC2 and APOE), while the cholesterol efflux gene (ABCA1) was downregulated. BD drug combination tended to increase intracellular cholesterol levels and neurite outgrowth, but these effects were not seen for the drugs when used individually. Conclusions: These data suggest that BD drug combination is increasing cholesterol biosynthesis and the newly synthesised cholesterol is being utilised within the cells, possibly for synthesis of new membranes to facilitate neurite outgrowth. This mechanism possibly underpins clinical efficacy in individuals with BD treated with polypharmacy.

History

Journal

World Journal of Biological Psychiatry

Volume

20

Pagination

766-777

Location

London, Eng.

ISSN

1562-2975

eISSN

1814-1412

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Issue

10

Publisher

Taylor & Francis