For as long as lithium has been used in medicine, we still don’t have a complete understanding of its underlying effects on our physiology. It is well known that lithium has benefits for mental health conditions. One hypothesis as to why involves lithium’s anti-inflammatory effects. Mental health conditions are known to have an inflammatory component. Depression, bipolar disorder, anxiety and schizophrenia all have significant correlations with inflammation (Miller 2016, Pereira 2021, Muller 2018, Salim 2012). In addition, inflammation has been shown to contribute to treatment resistant depression as well (Strawbridge 2019). The anti-inflammatory effects of lithium, are likely at least part of the treatment benefits seen with its use.
The effects of lithium on inflammation are profound and complex. Research has documented both pro and anti-inflammatory activity from lithium, although long-term, anti-inflammatory mechanisms are thought to dominate and may provide at least part of the benefits seen in bipolar disorder with lithium treatment (Nassar 2014).
Inflammation, Cytokines, Bipolar and Lithium
A number of studies have evaluated blood levels of inflammatory cytokines in bipolar disorder. A recent meta-analysis found significant changes in cytokine levels, including increased high sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α) and numerous changes in levels of interleukins and soluble interleukin receptors (Modabbernia 2013, Rowland 2018). Brain derived neurotrophic factor (BDNF), which also appears to have anti-inflammatory effects (Xu 2017), is lower in bipolar disorder as well. For many cytokines in bipolar, the phase of the illness matters, with manic and depressive episodes typically showing more inflammatory signalling molecules than euthymia.
Studies looking at the effects of lithium on inflammatory markers in bipolar have also shown beneficial effects. One recent study found that higher hsCRP correlated with worse prognosis in bipolar disorder. With lithium treatment, hsCRP was shown to decrease. In addition, longer treatment duration correlated with larger improvements (Queissner 2021).
Effects of Lithium on Inflammatory Pathways
Cyclooxygenase
The data around lithium’s effects on specific inflammatory pathways appears somewhat tissue specific, but still has some consistency. Early reports from the 1970s initially started to suggest that lithium is able to block prostaglandin activity (Murphy 1973). Prostaglandins are inflammatory mediators often produced from arachidonic acid by cyclooxygenase enzymes (COX). Of the family of COX enzymes, increases in COX-2 activity have been hypothesized to contribute to bipolar disorder (Rapoport 2002).
Studies in rats have shown that long-term lithium treatment decreases arachidonic acid turnover in brain tissue. This change is likely mediated through decreases in the production of phospholipase A2, the enzyme responsible for release of arachidonic acid from cell membranes. In addition, COX-2 activity is decreased with lithium, reducing levels of the inflammatory prostaglandin E2 (PGE2) typically produced from arachidonic acid (Rao 2008).
TNF-α
TNF-α in a cytokine involved with immune system regulation. In excess, TNF-α can contribute to tissue damage in numerous diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis and ankylosing spondylitis (Tracey 2008). The use of antibodies that neutralize TNF-α have become a mainstay for treatment of these conditions.
Evidence for the importance of TNF-α in mental health is also growing. As previously mentioned, elevated levels are found in bipolar. In addition, TNF-α appears intimately tied to the clinical course of major depressive disorder. Due to this relationship, it has been suggested that TNF-α may be a state marker for the condition (Tuglu 2003).
While some studies have shown increases, overall, the majority of the research suggests that long-term lithium treatment helps reduce TNF-α (Nassar 2014). Preliminary evidence has also found reductions of TNF-α in patients with bipolar was associated with successful lithium treatment response (Guloksuz 2012).
Interleukins
Interleukin molecules are a family of cytokines produced by immune cells. They are intimately involved with regulating immune responses. Evidence that lithium has anti-inflammatory effects on interleukins is strong, although at times contradictory.
In general, the majority of studies have shown that lithium decreases the inflammatory interleukins IL-1β and IL-6. As for anti-inflammatory interleukins, lithium has generally been shown to increase IL-2 and IL-10 (Nassar 2014). On the whole, these changes induced from lithium would work to decrease inflammation present throughout the body.
BDNF
While generally thought of as a nerve growth factor, in some situations, BDNF appears to have significant anti-inflammatory activity. In osteoarthritis, low levels of BDNF in the blood and joints has been associated with higher pain levels (Simão 2014). In a rat model of stroke, BDNF was shown to increase IL-10 and decrease TNF-α, thus modulating local inflammation (Jiang 2010). Research in women has also shown that BDNF appears to decrease inflammatory damage from elevated hsCRP (Noren Hooten 2015).
Lithium typically increases BDNF production during bipolar treatment (Wu 2014). Preclinical and animal models also confirm the effects of lithium on BDNF (Chiu 2010). At least part of the anti-inflammatory activity of lithium is likely mediated through BDNF production.
Conclusion
Lithium has complex interactions affecting immune function that, long-term, appear to primarily decrease inflammation. These anti-inflammatory effects are likely a part of the therapeutic potential of lithium, contributing to benefits in mental health conditions. While in its infancy, the research on the anti-inflammatory effects of lithium may have utility in helping treat other inflammatory conditions. More research on lithium is needed to help us unravel its full potential for use against inflammation.
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