Gender Differences in Depression: The Role of Inflammation

This article is authored by Eva Li, Samantha Eisert, and Danny Rahal and is part of the 2020 pre-graduate spotlight week. 

According to the National Institute of Mental Health, depression is one of the most common mental disorders in the US affecting 7.1% of the adult population (NIMH, 2017), and it can greatly reduce individuals’ quality of life if left untreated. Depression is usually marked by symptoms such as constant sadness, hopelessness, loss of interest, and abnormal fatigue. Much research has been conducted to try to identify the causes of depression, but this work is difficult since there are multiple pathways to depressive symptoms and onset of depression. Someone’s genetics, family background, culture, or encounters of traumatic events might all be factors that contribute to the breakout of a depression (Durand et al., 2019). Inflammation has emerged as yet another factor that can drive differences in depressive symptoms.

Multiple studies have shown that inflammation contributes to depression for sick patients and that people with inflammatory diseases are more susceptible to depression. Some scientists have proposed that depression is an adaptive response to biological stressors, such as injury and illness, because it promotes energy conservation in the time of sickness. When we become ill with an infection, our body’s evolutionary response is to enact what are called sickness behaviors. These behaviors include isolating from others to prevent spread of illness and resting in order to preserve energy and fight infection, (Stieglitz et al., 2015). Social disconnection and lack of energy are also common depressive symptoms, which suggests that inflammation may induces depressive states to promote these sickness behaviors and thereby protect the body from infection.  Even relatively healthy individuals with inflammatory symptoms experience more depressed mood (Covic et al., 2012; Duivis et al., 2011; Margaretten et al., 2011).

Recent research has investigated the means by which inflammation can directly cause depression. This research can be challenging because we cannot ethically cause people to have depression. However, in this article we highlight two designs to assess causes of depression: an experimental way to induce depressive symptoms and a longitudinal study of how depression emerges and progresses.

As described last time (click here if you missed it), researchers can inject endotoxin into participants to elicit an inflammatory response, and they found that endotoxin injection led to elevated levels of inflammation in the participants about two hours after injection. Participants reported their depressive mood and feelings of social disconnection every hour, and depressive mood and social disconnection also peaked about two hours after injection, suggesting that inflammation may elicit depressive symptoms. Interestingly, this association was only present in females. This finding is especially important because females show higher rates of depression than males (Kessler et al., 1993; Weissman et al., 1996; Weissman & Klerman, 1977).

These findings have been further supported with another non-experimental study design. An alternative to experimental design is to assess temporal precedence, or to identify what events precede others. Researchers conducted a longitudinal study to identify whether inflammation preceded or was a consequence of depression. More than 20,000 Americans, mostly over the age of 50, participated in this study. Their depression symptoms and inflammatory markers were measured at two time points separated by four years (Niles et al., 2018). Again, inflammation was found to lead to worsening depressive symptoms over time, but only among women. In contrast, men displayed the opposite pathway, as depression actually led to greater inflammation in men. Taken together with the experimental findings, it appears that inflammation may be a risk factor for depression in females, and further work will need to investigate whether pathways that physiology leads to depression—and potentially by which depression leads to poorer physical health—may vary by sex.

Taken together, the findings illustrate that inflammation can have psychological effects that may increase risk for depression. Over time, this can manifest into greater depressive symptoms and even major depression, especially in females. This research also brings attention to the factors that contribute to higher inflammation. For instance, diseases such as chronic bowel disease lead to chronical high inflammation. Furthermore, chronically ill patients and people who experience greater psychological stress often experience higher inflammation (e.g., Chiang et al., 2019; Dantzer, 2016). Knowing that these people are more susceptible to depression, these findings shed light on research for depression treatments and prevention. Importantly, inflammation can actually be modified by health behaviors—eating well (e.g., plant-based diet, Mediterranean diet) and getting proper, longer sleep can actually reduce inflammation (e.g., Bailey & Holscher, 2018; Eichelmann et al., 2016; Irwin, Olmstead, & Carroll, 2016). Perhaps working to keep our society more physically healthy may lead to improved mental health outcomes in a society so burdened with depression.


Bailey, M. A., & Holscher, H. D. (2018). Microbiome-mediated effects of the Mediterranean diet on inflammation. Advances in Nutrition9(3), 193-206.

Chiang, J. J., Park, H., Almeida, D. M., Bower, J. E., Cole, S. W., Irwin, M. R., … & Fuligni, A. J. (2019). Psychosocial stress and C-reactive protein from mid-adolescence to young adulthood. Health Psychology38(3), 259.

Covic, T., Cumming, S. R., Pallant, J. F., Manolios, N., Emery, P., Conaghan, P. G., & Tennant, A. (2012). Depression and anxiety in patients with rheumatoid arthritis: prevalence rates based on a comparison of the Depression, Anxiety and Stress Scale (DASS) and the hospital, Anxiety and Depression Scale (HADS). BMC Psychiatry, 12(6).

Dantzer, R. (2016). Role of the kynurenine metabolism pathway in inflammation-induced depression: preclinical approaches. In Inflammation-Associated Depression: Evidence, Mechanisms and Implications (pp. 117-138). Springer, Cham.

Duivis, H. E., de Jonge, P., Penninx, B. W., Na, B. Y., Cohen, B. E., Whooley, M. A. (2011). Depressive symptoms, health behaviors, and subsequent inflammation in patients with coronary heart disease: prospective findings from the heart and soul study. The American Journal of Psychiatry 168(9), 913–920.

Durand, V. M., Barlow, D. H., & Hofmann, S. G. (2019). Essentials of abnormal psychology. Boston: Cengage Learning.

Eichelmann, F., Schwingshackl, L., Fedirko, V., & Aleksandrova, K. (2016). Effect of plant‐based diets on obesity‐related inflammatory profiles: a systematic review and meta‐analysis of intervention trials. Obesity Reviews17(11), 1067-1079.

Irwin, M. R., Olmstead, R., & Carroll, J. E. (2016). Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biological Psychiatry80(1), 40-52.

Kessler, R. C., McGonagle, K. A., Swartz, M., Blazer, D. G., & Nelson, C. B. (1993). Sex and depression in the National Comorbidity Survey I: Lifetime prevalence, chronicity and recurrence. Journal of Affective Disorders, 29, 85–96.

Margaretten, M., Julian, L., Katz, P., & Yelin, E. (2011). Depression in patients with rheumatoid arthritis: description, causes and mechanisms. International Journal of Clinical Rheumatology, 6, 617–623.

Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews Immunology, 16(1), 22–34.

National Institute of Mental Health. (Data from 2017 National Survey on Drug Use and Health.)

Niles, A. N., Smirnova, M., Lin, J., & O’Donovan, A. (2018). Gender differences in longitudinal relationships between depression and anxiety symptoms and inflammation in the health and retirement study. Psychoneuroendocrinology95, 149-157.

Stieglitz, J., Trumble, B. C., Thompson, M. E., Blackwell, A. D., Kaplan, H., & Gurven, M. (2015). Depression as sickness behavior? A test of the host defense hypothesis in a high pathogen population. Brain, Behavior, and Immunity49, 130-139.

Weissman, M. M., & Klerman, G. L. (1977). Sex differences and the epidemiology of depression. Archives of General Psychiatry, 34(1), 98–111.

Weissman, M. M., Bland, R. C., Canino, G. J., Faravelli, C., Greenwald, S., Hwu, H. G., … & Lépine, J. P. (1996). Cross-national epidemiology of major depression and bipolar disorder. JAMA. 276(4), 293–299.