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. 2018 Jun 1;21(6):582-591.
doi: 10.1093/ijnp/pyy014.

Mechanisms Underpinning the Polypharmacy Effects of Medications in Psychiatry

Chiara C Bortolasci  1   2 , Briana Spolding  1 , Edward Callaly  1 , Sheree Martin  1 , Bruna Panizzutti  3 , Srisaiyini Kidnapillai  1 , Timothy Connor  1 , Kyoko Hasebe  1 , Mohammadreza Mohebbi  4 , Olivia M Dean  5   6 , Sean L McGee  1 , Seetal Dodd  5   6   7 , Laura Gray  1   5 , Michael Berk  5   6   8   7 , Ken Walder  1
Affiliations

Mechanisms Underpinning the Polypharmacy Effects of Medications in Psychiatry

Chiara C Bortolasci et al. Int J Neuropsychopharmacol. .

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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Figures

Figure 1.
Figure 1.
Effects of lipopolysaccharide (LPS) on C8-B4 cells (fold change relative to vehicle treated cells). LPS treatment increased the release of a number of proinflammatory cytokines, including interleukin (IL)-1a, IL-3, IL-4, IL-5, IL-6, IL-12, GCSF, KC, RANTES, and tumor necrosis factor (TNF)α. These data confirm that LPS had a proinflammatory effect on C8-B4 cells. n=3 samples in duplicate. *P<.05 compared with vehicle treated cells (descriptive statistical test).
Figure 2.
Figure 2.
Mitochondrial function and basal bioenergetics in NT2-N treated cells. Basal oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of NT2-N cells exposed for 24 h to either vehicle or bipolar disorder (BD) drugs alone and in combinations. All values are reported as perecent of vehicle±SEM (n=6/group).
Figure 3.
Figure 3.
Aerobic respiration and glycolysis in differentiated NT2-N cells as determined by oxygen consumption rate flux in response to mitochondrial probes (for oxygen consumption rate [OCR]) and by flux bioanalysis (for extracellular acidification rate [ECAR]). Data represented as mean OCR (pmol/min) or ECAR (pM/min)±SEM; n=4 to 6 per group. *P<.05 compared with vehicle treated cells (descriptive statistical test).
Figure 4.
Figure 4.
Effects of bipolar disorder (BP) drugs alone and in combination on the intracellular reactive oxygen species (ROS) production in NT2-N cells (relative to vehicle treated cells). n=5 samples. *P<.05 compared with vehicle treated cells (descriptive statistical test).
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