Antidepressants as a potential candidate to reduce microglia activation in neurodegenerative diseases. A systematic review and meta-analysis of preclinical studies

Lisa Nicolai, Pauline Nettesheim, Lot D. de Witte, Gijsje Snijders

There is special interest in antidepressants as potential repurposing drugs for neurodegenerative disorders (ND). Microglia activation is implicated to play a causal role in the pathogenesis of ND. Furthermore, preclinical studies showed profound impact of antidepressants on microglial cells. However, the underlying mechanisms remain unclear. We carried out a systematic review and meta-analysis that investigated the effects of antidepressants on microglial cells. In total 89 studies were quantitatively reviewed and 24 in vitro and 28 in vivo studies were suitable for meta-analysis. Random-effects meta-analysis showed an overall significant decrease in microglial activation markers after antidepressant administration in cell studies, animal stress models, and animal LPS models. Also, 30 out of 31 animal disease models showed a decrease in microglial activation after antidepressant treatment. We did not observe significant differences when microglial cells were not activated prior to treatment. There is a robust anti-inflammatory effect of antidepressants in activated microglial cells in cell or animal studies. However, the summary of the effect could be an overestimation of the true effect since we observed high heterogeneity between studies, potential publication bias and control subjects were shared between different experimental groups. Microglia can respond differently depending on the underlying process. A next step will be to understand the effects of antidepressants on microglia activation in the human brain, and more specifically on activated microglia in different brain pathologies.

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