Many pharmacological treatments for psychiatric disorders are thought to target serotonin, either its neurotransmission or bioavailability. Lithium has been used since the mid-19th century to treat psychiatric disorders however, its underlying mechanisms have yet to be fully elucidated. Lithium treatment has been shown to increase serotonin neurotransmission in animal studies. Since tryptophan underpins both serotonin and the kynurenine pathway it is critical to understand how therapeutics impact the balance of these biological pathways.
A recent study published by Dr. Ria Göttert et al. in Glia investigated the impact lithium treatment has on the inflammation-induced kynurenine pathway. Microglia cells stimulated with the inflammatory mediator interferon-γ expressed higher levels of mRNA encoding IDO1 compared to unstimulated cells. Interestingly, when treated with lithium IDO1 mRNA was significantly reduced in stimulated cells resulting in less activation of the kynurenine pathway (kynurenine/tryptophan ratio). Furthermore, inflammatory induction of STAT1 (Signal transducer and activator of transcription 1) and STAT3 was significantly reduced following lithium treatment. An enzyme, glycogen synthase kinase (GSK)3β, has been demonstrated to play a key role during inflammatory responses and lithium has been shown to inhibit this enzyme. Here the researchers show that lithium treatment of microglia induces the phosphorylation of GSK3β blocking STAT1 and STAT3 activation which results in increases in the anti-inflammatory cytokine, interleukin 10. Psychiatric disorders have been associated with inflammation; therefore, part of lithium’s underlying mechanism may target and reduce inflammatory pathways as well as increase the overall bioavailability of tryptophan as is suggested by these data.