Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study

Huang, Minxuan; Su, Shaoyong; Goldberg, Jack; Miller, Andrew H.; Levantsevych, Oleksiy; Shallenberger, Lucy; Pimple, Pratik; Pearce, Bradley D.; Bremner, J. Douglas; Vaccarino, Viola

doi:10.1016/j.bbi.2018.10.007

Cited by 52 publications

(44 citation statements)

References 66 publications

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“…In contrast to a number of observational studies suggesting bidirectional associations between inflammation markers and depression 15,16 , the present MR analysis found limited evidence to support a causal effect of genetic liability to MDD on inflammatory markers. These findings suggest that subclinical manifestations and/or pathophysiological mechanisms underpinning development of depression are unlikely to a large effect on levels of inflammatory markers examined.…”

Section: Discussioncontrasting

confidence: 99%

“…Additionally, IL-6 genetic polymorphisms have been found to be associated with the outcomes of antidepressant treatment, and specifically relapse, remission time and treatment resistant depression 42 . Further, an emerging body of longitudinal studies have reported links between measured IL-6 levels and risk of depression across different populations 14,16,43,44 . Finally, a causal role of IL6 in depression is in agreement with a recent MR study investigating the associations between genetically proxied serum inflammatory markers and risk of depression in UK Biobank, suggesting a strong causal role of IL-6 in increasing the risk of probable lifetime major depression (moderate/severe) (OR per unit increase in log-transformed IL-6: 0.74, 95% CI: 0.62–0.89) 21 .…”

Section: Discussionmentioning

confidence: 99%

“…However, there are important challenges when appraising the potential causal role of inflammatory markers in depression from observational studies. This is because conventional epidemiological study designs, including case-control studies and prospective studies with insufficient follow-up time, may fail to distinguish whether the inflammatory response is a cause or consequence of depression (“reverse causation”) 15,16 . Further, such analyses are prone to residual confounding due to unmeasured or imprecisely measured confounders (i.e., common causes of inflammation and depression that are not on the causal pathway between these traits).…”

Section: Introductionmentioning

confidence: 99%

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Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

Dardani

Yarmolinsky

Robinson

et al. 2019

Preprint

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BackgroundThe inflammatory markers C-reactive protein (CRP), interleukin-1 receptor antagonist (IL1-Ra), and interleukin-6 (IL-6) have been associated with depression risk in observational studies. The causal nature of these associations is unclear as conventional observational designs are susceptible to reverse causation and residual confounding. Bidirectional Mendelian randomization (MR) analysis uses genetic variants to proxy for risk factors to help elucidate the presence, magnitude, and direction of causal relationships between traits.MethodsWe performed bidirectional two-sample MR to examine causal associations between circulating CRP, IL1-Ra, and IL-6 and major depressive disorder (MDD) in 135,458 cases and 344,901 controls in the Psychiatric Genetics Consortium. Genetic instruments to proxy inflammatory markers and liability to MDD were constructed by obtaining single-nucleotide polymorphisms (SNPs) associated with these phenotypes in genome-wide association study meta-analyses. Wald ratios and inverse-variance weighted random-effects models were employed to generate causal effect estimates and various sensitivity analyses were performed to examine violations of MR assumptions.ResultsThere was evidence supporting a causal effect of circulating IL-6 on risk of MDD (per natural-log increase: OR 0.85, 95% CI: 0.75-0.96, P=0.007). Higher circulating levels of IL-6 as influenced by variants in the IL6R gene region represent lower cellular binding of IL-6 to its receptor and therefore the present results suggest that IL-6 increases the risk of MDD. We found limited evidence supporting a causal effect of CRP (1.06, 95% CI 0.93-1.22; P=0.36) or IL1-Ra (OR 0.95, 95% CI: 0.87-1.03, P=0.20) on risk of MDD. Reverse direction MR analyses suggested limited evidence for a causal effect of genetic liability to MDD on any of the inflammatory markers examined.ConclusionsThese findings support a causal role of IL-6-related pathways in development of major depressive disorder and suggest the possible efficacy of interleukin-6 inhibition as a therapeutic target for depression.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

Dardani

Yarmolinsky

Robinson

et al. 2019

Preprint

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“…We are not aware of previous studies that examined the symptomspecific associations with LPS-induced inflammatory agents. Moreover, examining individual symptoms longitudinally is important as inflammation may be related differently to depression symptoms longitudinally [36][37][38][39][40] . A recent longitudinal study for example found that inflammation was especially related to atypical symptoms 40 .…”

Section: Introductionmentioning

confidence: 99%

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression

et al. 2020

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Multiple studies show an association between inflammatory markers and major depressive disorder (MDD). People with chronic low-grade inflammation may be at an increased risk of MDD, often in the form of sickness behaviors. We hypothesized that inflammation is predictive of the severity and the course of a subset of MDD symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise. We tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual MDD symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) over a period of up to 9 years using multivariate-adjusted mixed models in 1147-2872 Netherlands Study of Depression and Anxiety (NESDA) participants. At baseline, participants were on average 42.2 years old, 66.5% were women and 53.9% had a current mood or anxiety disorder. We found that basal and LPSstimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow-up compared with non-sickness behavior symptoms of depression. However, we also found significant associations with some symptoms that are not typical of sickness behavior (e.g., sympathetic arousal among others). Inflammation was not related to depression as a unified syndrome but rather to the presence and the course of specific MDD symptoms, of which the majority were related to sickness behavior. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.

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“…A recent twin study by Huang, et al, suggests that the causal connection between depression and neuroinflammation may be bidirectional. (21)…”

Section: Introductionmentioning

confidence: 99%

Microglial Phagocytosis of Neurons: Diminishing Neuronal Loss in Traumatic, Infectious, Inflammatory, and Autoimmune CNS Disorders

Yanuck

2019

Front. Psychiatry

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Errors in neuron-microglial interaction are known to lead to microglial phagocytosis of live neurons and excessive neuronal loss, potentially yielding poorer clinical outcomes. Factors that affect neuron-microglial interaction have the potential to influence the error rate. Clinical comorbidities that unfavorably impact neuron-microglial interaction may promote a higher rate of neuronal loss, to the detriment of patient outcome. This paper proposes that many common, clinically modifiable comorbidities have a common thread, in that they all influence neuron-microglial interactions. Comorbidities like traumatic brain injury, infection, stress, neuroinflammation, loss of neuronal metabolic integrity, poor growth factor status, and other factors, all have the potential to alter communication between neurons and microglia. When this occurs, microglial phagocytosis of live neurons can increase. In addition, microglia can shift into a morphological form in which they express major histocompatibility complex II (MHC-II), allowing them to function as antigen presenting cells that present neuronal debris as antigen to invading T cells. This can increase risk for the development of CNS autoimmunity, or can exacerbate existing CNS autoimmunity. The detrimental influence of these comorbidities has the potential to contribute to the mosaic of factors that determine patient outcome in some CNS pathologies that have neuropsychiatric involvement, including TBI and CNS disorders with autoimmune components, where excessive neuronal loss can yield poorer clinical outcomes. Recognition of the impact of these comorbidities may contribute to an understanding of the common clinical observation that many seemingly disparate factors contribute to the overall picture of case management and clinical outcome in these complex disorders. In a clinical setting, knowing how these comorbidities can influence neuron-microglial interaction can help focus surveillance and care on a broader group of potential therapeutic targets. Accordingly, an interest in the mechanisms underlying the influence of these factors on neuron-microglial interactions is appropriate. Neuron-microglial interaction is reviewed, and the various mechanisms by which these potential comorbidities influence neuro-microglial interaction are described.

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Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study

Cited by 52 publications

References 66 publications

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression

Microglial Phagocytosis of Neurons: Diminishing Neuronal Loss in Traumatic, Infectious, Inflammatory, and Autoimmune CNS Disorders

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