Interleukin-6 in Bipolar Disorder: A Systematic Review and Meta-analysis

Background: Bipolar disorder is a prevalent mental health condition which remains challenging to diagnose accurately. The cytokine interleukin-6 (IL-6) has been reported to be elevated in individuals with bipolar disorder. Additional primary studies have emerged since the most comprehensive previous meta-analysis on this topic by Solmi et al. (2021), warranting an updated synthesis of evidence. Aims: This study aimed to compare IL-6 levels in blood or plasma in patients with bipolar disorder versus healthy comparison groups by meta-analysis. Methods: A systematic search was conducted, incorporating recent studies, and addressing methodological limitations, such as skewed data distributions, and differences between mood states. Random-effects models, with and without inverse variance weighting, were used. The systematic search included observational studies published between 1993 and 2023. Subgroup analyses were conducted to explore variations in IL-6 levels across mood states (manic, depressive, euthymic or mixed). Results: This study included 62 scientific articles. A meta-analysis with default weighting showed that IL-6 was higher in patients (standardized mean difference 0.77 [0.46, 1.08]), but in presence of high heterogeneity (I2=96.92%). A meta-analysis with inverse variance weighting showed a smaller difference between patients and controls (0.37 [-0.03, 0.80]. Subgroup analyses suggested elevated levels of IL-6 in manic states. Conclusions: IL-6 levels were elevated in bipolar patients versus healthy comparison groups, though effect sizes were smaller than previously reported and not statistically significant when using inverse variance weighting. Uncertainty remains concerning any role for IL-6 in the pathophysiology of bipolar disorder.