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    Mechanisms Underpinning the Polypharmacy Effects of Medications in Psychiatry

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    Author
    Bortolasci, CC; Spolding, B; Callaly, E; Martin, S; Panizzutti, B; Kidnapillai, S; Connor, T; Hasebe, K; Mohebbi, M; Dean, OM; ...
    Date
    2018-06-01
    Source Title
    International Journal of Neuropsychopharmacology
    Publisher
    OXFORD UNIV PRESS
    University of Melbourne Author/s
    Dean, Olivia; Dodd, Seetal; Berk, Michael
    Affiliation
    Psychiatry
    Metadata
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    Document Type
    Journal Article
    Citations
    Bortolasci, C. C., Spolding, B., Callaly, E., Martin, S., Panizzutti, B., Kidnapillai, S., Connor, T., Hasebe, K., Mohebbi, M., Dean, O. M., McGee, S. L., Dodd, S., Gray, L., Berk, M. & Walder, K. (2018). Mechanisms Underpinning the Polypharmacy Effects of Medications in Psychiatry. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 21 (6), pp.582-591. https://doi.org/10.1093/ijnp/pyy014.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256039
    DOI
    10.1093/ijnp/pyy014
    Abstract
    Background: Bipolar disorder is a mental health condition with progressive social and cognitive function disturbances. Most patients' treatments are based on polypharmacy, but with no biological basis and little is known of the drugs' interactions. The aim of this study was to analyze the effects of lithium, valproate, quetiapine, and lamotrigine, and the interactions between them, on markers of inflammation, bioenergetics, mitochondrial function, and oxidative stress in neuron-like cells and microglial cells. Methods: Neuron-like cells and lipopolysaccharide-stimulated C8-B4 cells were treated with lithium (2.5 mM), valproate (0.5 mM), quetiapine (0.05 mM), and lamotrigine (0.05 mM) individually and in all possible combinations for 24 h. Twenty cytokines were measured in the media from lipopolysaccharide-stimulated C8-B4 cells. Metabolic flux analysis was used to measure bioenergetics, and real-time PCR was used to measure the expression of mitochondrial function genes in neuron-like cells. The production of superoxide in treated cells was also assessed. Results: The results suggest major inhibitory effects on proinflammatory cytokine release as a therapeutic mechanism of these medications when used in combination. The various combinations of medications also caused overexpression of PGC1α and ATP5A1 in neuron-like cells. Quetiapine appears to have a proinflammatory effect in microglial cells, but this was reversed by the addition of lamotrigine independent of the drug combination. Conclusion: Polypharmacy in bipolar disorder may have antiinflammatory effects on microglial cells as well as effects on mitochondrial biogenesis in neuronal cells.

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