Mixed features in bipolar disorder (BD) is defined as an episode of the disorder where depressive and manic symptoms coexist (Solé et al., 2016). The occurrence of mixed presentations is highly prevalent in BD, occurring in approximately 40% of individuals (Fagiolini et al., 2015), and it represents the most severe form of the disorder, being associated with earlier age of onset, worse clinical outcomes, greater treatment resistance, higher rates of comorbidities, and a more severe course and prognosis of the illness (Rosenblat et al., 2016; Solé et al., 2016).

Robust evidence has shown that patients with psychiatric disorders present alterations in immune-inflammatory mechanisms, generally indicating low-grade systemic inflammation (Teixeira et al., 2018; Misiak et al., 2020; Ivanovska et al., 2020). Alterations in the bloodstream of bipolar patients have already been reported, and research has focused its attention on the role of pro- and anti-inflammatory cytokines in the pathophysiology of BD (Misiak et al., 2020). Furthermore, increased levels of pro-inflammatory cytokines have been observed in different phases of this disorder (Sayana et al., 2017). Specifically, one pro-inflammatory cytokine that has been highlighted is the chemokine eotaxin-1 (CCL11).

CCL11 is a cytokine capable of inducing chemotaxis due to its strong chemotactic effect on eosinophils, leading to their accumulation at sites of inflammation (Magalhães et al., 2014). However, recent studies have also demonstrated its role associated with aging, neurogenesis, neurodegeneration, and cognitive deficit, when found in higher circulating levels (Villeda et al., 2011; Teixeira et al., 2018; Ivanovska et al., 2020). This association can be confirmed by the fact that this chemokine can cross the blood-brain barrier (BBB), and neurons and glial cells have receptors for it (Magalhães et al., 2014; Teixeira et al., 2018).

A study that evaluated chemokine levels in patients with BD, compared to healthy controls, found higher serum levels of CCL11 in BD patients (Barbosa et al., 2013). Another study with the same objective, but in patients with early and advanced stages of BD compared to a control group, found elevated levels of CCL11 only in patients with advanced stages. This result is in line with the literature that points to progressive cognitive impairment that occurs throughout the course of the disease (neuroprogression), and that CCL11 seems to be related (Panizzutti et al., 2015; Miller, 2016).

While individuals with BD tend to have alterations in their immune-inflammatory mechanisms, they also have a high prevalence of metabolic disorders, and chronic immune dysfunction seems to contribute significantly to this (Silarova et al., 2015; Fries et al., 2019). The metabolic syndrome (MetS), characterized by a cluster of metabolic alterations (NCEP/ATPIII), appears to be associated with higher serum levels of CCL11, as shown by a study that evaluated this association. The study compared a group with MetS to a group without MetS and found that CCL11 levels were increased in the MetS group (Loughrey et al., 2013). MetS is a disease that has been associated with a more severe presentation of BD and has a prevalence of around 37% in these individuals (Grundy et al., 2005; Moreina et al., 2017). Moreover, the prevalence of MetS seems to be higher among those who experience mood episodes with mixed features (Chen et al., 2018).

To the best of our knowledge, no studies have explored the relationship between CCL11, MetS, and BD, especially among individuals presenting a mood episode with mixed features in BD. Most of the studies found only relate two of these components in different contexts. Therefore, the present study aimed to investigate the mediating effect of metabolic syndrome on the relationship between CCL11 levels and the presence of a mood episode with mixed features in BD, in a population-based study.