1. Nolen, Lindsey

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A cancer diagnosis is often accompanied by a myriad of side effects caused by either the disease itself or the necessary treatment. While side effects commonly range from nausea to fatigue and pain, one often overlooked side effect is depression. Depression is a devastating condition that impacts both quality of life and disease outcome in as many as 30 percent of cancer patients.

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There are many possible causes of depression in cancer patients. From the initial diagnosis, cancer patients are faced with a new reality filled with potentially life-altering decisions and lifestyle changes. Yet, a new study published in the journal Cancer found that inflammation may represent an important biological cause of depression, and certain measurable indicators of inflammation may provide a useful, screenable indication of which cancer patients are at risk (2022;


To date, there have not been any studies that systematically and comprehensively evaluate the link between inflammation and depression in cancer patients. According to Andrew H. Miller, MD, senior author and Research Director of Psychiatric Oncology at Winship Cancer Institute of Emory University and the William P. Timmie Professor of Psychiatry and Behavioral Sciences at Emory University School of Medicine, previous studies suggesting that inflammation may contribute to depression in oncology patients have had inconsistent findings because of small sample sizes and patients with different types of cancers in different stages of treatment.


In this first-ever systematic review and meta-analysis of these earlier, related studies, the team from Winship Cancer Institute of Emory University, in collaboration with colleagues from Memorial Sloan Kettering Cancer Center and Northwell Health/Lenox Hill Hospital/Manhattan Eye, Ear, & Throat Hospital, examined 47 individual studies, including more than 4,200 patients with cancer. Additionally, 54 studies (n=5,017) were included in meta-analyses.


Miller explained that an advantage of these large meta-analyses is that researchers are able to look at different cancers in different treatment settings, rather than see if one single type of cancer in one setting is associated with increased inflammation and depression. By being able to reason that inflammation exists across different types of cancers and treatment settings, researchers and medical professionals can better understand its potential contribution to depression during the cancer experience.


Given the high prevalence of cancer-related inflammation, the authors sought to ultimately establish a relationship between inflammation and depression in cancer patients using Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and registered under Prospero ID CRD42021226743 when beginning the study. Three databases were searched, including PubMed, the Cochrane Library, and PsycINFO, using the following criteria for inclusion:


* measurement of a peripheral inflammatory marker;


* use of a validated tool/scale to measure depression and;


* a cancer diagnosis.



The risk of publication bias was assessed by the funnel plot and Egger test.


Upon completion of this analysis, the researchers were able to determine that the associations with depressive symptoms were significant for peripheral blood interleukin (IL)-6 (standardized mean difference [SMD]=0.59; 95% CI, 0.35-0.82), I2=57.9 percent; tumor necrosis factor (TNF) (SMD=0.73; 95% CI, 0.35-1.11), I2=74.1 percent; and C-reactive protein (CRP) (SMD=0.57; 95% CI, 0.27-0.87), I2=0 percent. IL-5, IL-13, albumin, and neutrophil-to-lymphocyte ratio were associated with depressive symptoms, but based on fewer studies. Further, most cancer settings were represented, with the number of studies per inflammatory marker varying from 1 to 52.


From their analysis, the researchers determined that patients with cancer and depression exhibited reliable increases in several inflammatory molecules, including IL-6, TNF, and CRP.


While it is well-known that cancer treatments can cause such inflammation, there are other causational factors patients and practitioners must consider. According to 2019 research, tumor-extrinsic inflammation is one type of inflammation considered to be caused by many factors, such as bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption. According to the research, all of these factors are also known to increase cancer risk and stimulate malignant progression.


Published in Annals of African Medicine (2019; doi: 10.4103/aam.aam_56_18), the research further stated that cancer-intrinsic or cancer-elicited inflammation can be triggered by "cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells."


"There's also a tremendous amount of stress associated with finding out that you have cancer. Then there's all the uncertainty about what the nature of cancer is, how aggressive it is, and if it has spread. Stressors in the later stages of cancer, like the fear of the disease's return, are also a challenge. This psychological stress is another source of increased inflammation."


While assessing inflammation and depression in cancer patients can present challenges, Miller noted that inflammation can itself be readily measured using a blood test that is available in most clinics and hospitals. The test targets CRP, a molecule that's produced by the liver in response to inflammatory cytokines (which are the mediators of inflammation). Cytokines are the molecules that are released by immune cells that do the "business end" of the inflammatory response, Miller explained. Cytokines contribute directly to depression by their effects on neurotransmitters and neurocircuits in the brain.


If inflammatory molecules can identify patients with cancer at risk for depression, screening for depression across populations of cancer patients may become a reality, the researchers hope. This new reality may then help guide antidepressant therapy and ascertain which antidepressant medications are likely to be more effective than others.


"Several studies indicate that depressed patients with increased inflammation may not do as well on drugs that primarily affect serotonin, such as fluoxetine, paroxetine, and escitalopram," said Miller. "These are often the frontline drugs used to treat depression."


He suggested that antidepressant drugs that affect dopamine, such as bupropion, may work better. Miller also cautioned, however, that studies are underway to test this hypothesis, noting that "while there is promise, we need proof."


Yet, there is great promise that Miller's team's findings will help identify and manage depressive symptoms in patients with cancer. Although the results offer insight, the researchers note that additional studies are warranted.


Miller shared that the next step for this particular research is to find if there are specific treatments that are better for patients with cancer who are much more vulnerable to having this increased inflammation as a major driver of the way they're feeling. If there are, this would begin to personalize therapy for depression in the context of cancer and specialize the approach to the cancer patient versus anyone else suffering from depression.


Also moving forward, his team is trying to develop a large clinical trial comparing standard antidepressants that primarily target serotonin versus drugs that affect dopamine. They intend to test these medications head to head in cancer patients with high inflammation. In the meantime, diet and exercise are some of the best ways to limit inflammation.


Lindsey Nolen is a contributing writer.


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