Mental health problems are common, affecting one in four people (Mcmanus et al., 2009). Despite the increase in availability of treatment, many people do not seek or respond to currently available treatments (Fava, 2003). The heterogeneity of these disorders has highlighted the need for new targeted treatments.

One promising therapeutic target is inflammation (Khandaker et al., 2018). There is growing evidence that inflammation may play a causal role in the development of mental health problems, at least for some individuals. Patients with depression and schizophrenia have higher levels of circulating inflammatory markers (interleukin 6, IL-6; C-reactive protein, CRP) compared to healthy controls (Howren et al., 2009; Miller et al., 2011; Wang & Miller, 2018). Longitudinal studies also report that higher IL-6 at age 9 is associated with an increased risk of depression and psychosis at age 18, in a dose dependent fashion (Khandaker et al., 2014). Moreover, Mendelian Randomization (MR) studies provide stronger evidence of causality: genetic variants which regulate the level/activity of IL-6 and CRP are associated with risk of depression and psychosis (Hartwig et al., 2017; Khandaker et al., 2020). Nevertheless, there are divergent findings in MR studies regarding different inflammatory markers, with evidence of a risk-increasing effect of IL-6, but a risk-decreasing effect of CRP, on depression (Ye et al., 2021).

Cognitive function is also a core feature associated with psychiatric risk. For example, people with depression display impairments across a range of cognitive tasks including executive functioning, memory, attention and emotion recognition (Dalili et al., 2015; Nikolin et al., 2021; Rock et al., 2014). Cognitive dysfunction in prodromal psychosis is also associated with an increased risk of transitioning to schizophrenia and poorer prognosis (Bolt et al., 2019; Fusar-Poli et al., 2012; Seidman et al., 2016). However, an outstanding question is whether inflammation contributes to cognitive functioning in the general population.

We will address this question using cross-sectional associations, MR, and trajectory-based modelling. Triangulating across multiple methods to assess the role of inflammation on cognitive functioning will enable more robust conclusions to be drawn about the relationship.