Immune cells as biomarkers of depression 

Éimear Foley discusses a new systematic review examining links between inflammation and depression.

Depression is an illness that is estimated to affect around 10-20% of the world’s population in a lifetime. However, for many people, current treatment strategies do not work sufficiently well. Depression is a multifactorial condition and there is mounting evidence that several biological and non-biological mechanisms may be at play.

One aetiological factor of increasing interest is inflammation. Prof Golam Khandaker, Head of the Immunopsychiatry Programme at the University of Bristol’s MRC Integrative Epidemiology Unit, tries to illustrate this point by asking people to think of the symptoms they experience when they have a cold or flu. Along with a runny nose and a cough, people often experience fatigue, a change to usual appetite or sleeping patterns, and/or a reduced ability to experience pleasure. He points out that these are also typical symptoms of major depressive disorder. Moreover, were you to have a blood sample taken, you would also find evidence of high levels of inflammation due to the activation of an immune response. Recent research suggests that up to a quarter of all depressed patients consistently show evidence of inflammation in their blood, as defined by C-reactive protein levels. Other studies have supported these findings, showing that depression may be causally linked to elevated concentrations of proinflammatory cytokines (i.e., proteins often used as markers of inflammation), like interleukin 6.

Our bodies are equipped with two immune systems. The innate response acts quickly and non-specifically to all foreign substances, while the adaptive response works more slowly and specifically targets germs the body has previously encountered. White blood cells both produce and are influenced by cytokines and play key roles in orchestrating innate and adaptive immune responses. However, their role in depression is unclear. While some individual studies have linked depression with increased counts of certain peripheral immune cells, a systematic summary of existing research is needed. Only then can we begin to understand how, or even whether, immune cells can inform novel therapeutic techniques for the treatment of depression.

How did we address this issue?

We searched two research databases, namely PubMed and PsychINFO, from inception to 5th April 2022 for all studies comparing blood immune cell concentrations in adults with a depression diagnosis and healthy controls. Inclusion criteria for all studies included:

  • Original articles
  • Available in the English language
  • Based on human participants
  • Used flow or mass cytometry
  • Reported immune cell counts and/or percentages
  • Compared patients to healthy controls
  • Defined depression using an established method (e.g., International Classification of Diseases)
  • Defined controls as those with no psychiatric history

Separate inverse-variance weighted, random-effect meta-analyses were conducted for studies reporting mean absolute counts of immune cells in depressed cases, compared to controls. Heterogeneity between studies, overall study quality, and potential for bias were also assessed.

What did we find?

Our literature search yielded 1,153 potentially relevant studies (see Image 2). A total of 33 studies met inclusion criteria and were included in the review. Due to the availability of data, meta-analysis was conducted on 27 of these studies.

We found that depression was associated with an increase in mean absolute cell counts of several immune cell types, including white blood cells, granulocytes, neutrophils, monocytes, helper T cells, natural killer cells, B cells, and activated T cells, as compared to healthy controls.

What does this mean?

It appears that depression is associated with alterations in both lymphoid (e.g., T cells and B cells) and myeloid (e.g., monocytes and neutrophils) cells. This suggests that both the innate and adaptive immune response may be dysfunctional in the illness.

While the role of cytokines in depression is well understood, this research may help elucidate a cellular source of these known cytokine alterations. This may be particularly useful for illness subtyping for the purpose of patient stratification in future immunotherapy trials. Moreover, if the association between the immune cell alterations and depression are deemed to be causal, immune cells may represent suitable treatment targets for major depressive disorder.

What next?

This paper is the first systematic review and meta-analysis of the peripheral blood cellular immunophenotype in depression using flow cytometry studies. However, much more evidence is needed before we can begin to see the therapeutic implications of this research put into practice.

Most included studies controlled for confounding (particularly age and sex), but this was not the case for all studies. Therefore, more robust confounding adjustment, for example, ethnicity, socio-economic status, medications, physical illness, and/or body mass index, is required in future studies.

Lastly, by design it is difficult to infer causality from case-control studies, and so future research is needed to examine whether observed associations are likely to be causal. Genetic approaches, such as Mendelian Randomization analysis, could be particularly useful for this purpose.

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