Inflammation and depression in young people: a systematic review and proposed inflammatory pathways

Abstract

Depression onset peaks during adolescence and young adulthood. Current treatments are only moderately effective, driving the search for novel pathophysiological mechanisms underlying youth depression. Inflammatory dysregulation has been shown in adults with depression, however, less is known about inflammation in youth depression. This systematic review identified 109 studies examining the association between inflammation and youth depression and showed subtle evidence for inflammatory dysregulation in youth depression. Longitudinal studies support the bidirectional association between inflammation and depression in youth. We hypothesise multiple inflammatory pathways contributing to depression. More research is needed on antiinflammatory treatments, potentially tailored to individual symptom profiles.

Neurological Symptoms and Their Associations With Inflammatory Biomarkers in the Chronic Phase Following Traumatic Brain Injuries

“…Some studies have documented an association between inflammation and depression and reported that higher concentrations of pro-inflammatory cytokines possibly directly contribute to the development of depressive symptoms (11,82,83). The current study found that the serum IL-6 level was positively associated with depression; however, this association was not significant after controlling for the age effect.…”

Cytokine alterations in pediatric internalizing disorders: Systematic review and exploratory multi-variate meta-analysis

“…In this analysis, peripheral cytokine levels were observed to be elevated in pediatric internalizing disorders compared to controls. A recent meta-analysis by Toenders et al (2022) reported a significant elevation of peripheral IL-1β levels in youth depression ( k = 7, Cohen's d = 0.37) that was not observed in our moderator analysis. However, we acknowledge the differences in our statistical approach (univariate versus multi-variate), larger sample sizes in our IL-1β moderator analysis, and our mixed sample of anxiety and depression as potential reasons for the deviation when comparing our findings.…”

“…Data from this study was converted to an estimated mean and standard deviation using a precise, low bias statistical method under the assumption of a skewed raw dataset ( Wan et al, 2014 ; Weir et al, 2018 ). A quality assessment of the studies included in the systematic review was performed and based on the criteria developed by Toenders et al (2022) utilizing the Cochrane Consumers and Communication Review Group Study Quality Guide (2013) and the Critical Appraisal Skills Programme (CASP) ( Ryan et al, 2013 ).…”

“…Cytokines are produced primarily by macrophages that can be recruited to the central nervous system (CNS) or produced within by microglia, resident macrophages, and dendritic cells ( Slavich et al, 2014 ). In the CNS, cytokines influence degradation, release, and re-uptake of neurotransmitters (e.g., serotonin, norepinephrine, and dopamine) ( Gabbay et al, 2010 ; Michels et al, 2018 ; Oztürk et al, 2020 ), autoimmunity and production of antibodies ( Himmerich et al, 2019 ), regulation and stimulation of the HPA axis ( Mills et al, 2013 ), stimulation and inhibition of vagal nerve tone ( Toenders et al, 2022 ), and promotion or suppression of neuroplasticity (e.g., neurogenesis, synaptic re-modeling) ( Miller et al, 2009 ).…”

“…This meta-analysis observed a marginal association between TNF-α and depressive disorders in children and adolescents; however, the statistical power was considerably low compared to analyses conducted in adults. Moderator analyses were also not performed on the data and therefore, it is unclear whether confounders related to immune system alterations (e.g., changes in hormonal inputs and immune system organ size) or changes in communication between the brain-gut-immune axis (e.g., synaptic pruning/plasticity, adiposity, immune cell responsivity) that occur during youth development contributed to false negative findings ( Himmerich et al, 2019 ; Toenders et al, 2022 ). A second meta-analysis focused on pediatric depression including both cross-sectional and longitudinal studies found a positive association with concurrent and future inflammation, but not peripheral cytokine levels specifically ( Colasanto et al, 2020 ).…”